Associations between types and sources of dietary carbohydrates and liver fat: a UK Biobank study.

BACKGROUND AND AIMS: Excess energy intake can lead to metabolic dysfunction-associated steatotic liver disease (MASLD), but the relationship between dietary carbohydrate intake and liver fat content remains unclear. This study aimed to examine the associations between types and sources of dietary carbohydrates and liver fat content. METHODS: UK Biobank participants with no pre-existing diabetes, liver disease or cardiovascular disease reported dietary intake of types and sources of carbohydrates (total carbohydrates, free sugars, non-free sugars, starch from whole grains, starch from refined grains, and fibre) on at least two 24-h dietary assessments. In cross-sectional analyses, (n = 22,973), odds ratios (OR) of high liver fat content (defined as a score of ≥ 36 in the hepatic steatosis index) by quintiles of carbohydrate intakes were estimated using multivariable logistic regression models. In prospective analyses, a second sample (n = 9268) had liver proton density fat fraction (PDFF) measured by magnetic resonance imaging (2014-2020). Multivariable linear regression models estimated geometric means of PDFF (%) by quintiles of carbohydrate intakes. Models were adjusted for demographic and lifestyle confounders, including total energy intake. RESULTS: In the cross-sectional analyses, 6894 cases of high liver fat content were identified. Inverse associations between intakes of fibre (OR of highest vs. lowest quintile 0.46 [95% CI: 0.41-0.52]), non-free sugars (0.63 [0.57-0.70]) and starch from whole grains (0.52 [0.47-0.57]) with liver fat were observed. There were positive associations between starch from refined grains and liver fat (1.33 [1.21-1.46]), but no association with free sugars (p=0.61). In prospective analyses, inverse associations with PDFF (%) were observed for intakes of fibre (- 0.48 geometric mean difference between highest and lowest quintile of intake [- 0.60 to - 0.35]), non-free sugars (- 0.37 [- 0.49 to - 0.25]) and starch from whole grains (- 0.31 [- 0.42 to - 0.19]). Free sugars, but not starch from refined grains, were positively associated with PDFF (0.17 [0.05 to 0.28]). CONCLUSION: This study suggests that different carbohydrate types and sources have varying associations with liver fat, which may be important for MASLD prevention. Non-free sugars, fibre, and starch from whole grains could be protective, while associations with free sugars and starch from refined grains are less clear.

Using gold nanoparticles for enhanced intradermal delivery of poorly soluble auto-antigenic peptides.

Ultra-small 1-2 nm gold nanoparticles (NP) were conjugated with a poorly-soluble peptide auto-antigen, associated with type 1 diabetes, to modify the peptide pharmacokinetics, following its intradermal delivery. Peptide distribution was characterized, in vivo, after delivery using either conventional intradermal injection or a hollow microneedle device. The poorly-soluble peptide was effectively presented in distant lymph nodes (LN), spleen and draining LN when conjugated to the nanoparticles, whereas peptide alone was only presented in the draining LN. By contrast, nanoparticle conjugation to a highly-soluble peptide did not enhance in vivo distribution. Transfer of both free peptide and peptide-NPs from the skin to LN was reduced in mice lacking lymphoid homing receptor CCR7, suggesting that both are actively transported by migrating dendritic cells to LN. Collectively, these data demonstrate that intradermally administered ultra-small gold nanoparticles can widen the distribution of poorly-soluble auto-antigenic peptides to multiple lymphoid organs, thus enhancing their use as potential therapeutics.

Lifestyle interventions affecting hepatic fatty acid metabolism.

PURPOSE OF REVIEW: Prevalence of metabolic-associated fatty liver disease (MAFLD) is increasing, and as pharmacological treatment does not exist, lifestyle interventions (i.e. diet and exercise) represent the cornerstone management and treatment strategy. Although the available data clearly demonstrate that changes in lifestyle influence intrahepatic triglyceride (IHTG) content, the mechanisms through which this is achieved are seldom investigated. Here, we review recent evidence demonstrating the influence of lifestyle interventions on hepatic fatty acid metabolism and IHTG content. RECENT FINDINGS: Diet and exercise influence IHTG content through various, and often interrelated factors. These include alterations in whole-body and tissue-specific insulin sensitivity, which may influence the flux of fatty acid and lipogenic substrates to the liver, and changes in intrahepatic fatty acid synthesis and partitioning. Notably, there are only a few studies that have investigated intrahepatic fatty acid metabolism in vivo in humans before and after an intervention. SUMMARY: Lifestyle interventions represent an effective means of influencing hepatic fatty acid metabolism. IHTG content is decreased without weight-loss either through exercise or by changing the macronutrient composition of the diet, although what the optimal macronutrient composition is to achieve this has yet to be defined.

Acute Hyperenergetic, High-Fat Feeding Increases Circulating FGF21, LECT2, and Fetuin-A in Healthy Men.

BACKGROUND: Hepatokines such as fibroblast growth factor 21 (FGF21), leukocyte cell-derived chemotaxin 2 (LECT2), fetuin-A, fetuin-B, and selenoprotein P (SeP) are liver-derived proteins that are modulated by chronic energy status and metabolic disease. Emerging data from rodent and cell models indicate that hepatokines may be sensitive to acute nutritional manipulation; however, data in humans are lacking. OBJECTIVE: The aim was to investigate the influence of hyperenergetic, high-fat feeding on circulating hepatokine concentrations, including the time course of responses. METHODS: In a randomized, crossover design, 12 healthy men [mean ± SD: age, 24 ± 4 y; BMI (kg/m2), 24.1 ± 1.5] consumed a 7-d hyperenergetic, high-fat diet [HE-HFD; +50% energy, 65% total energy as fat (32% saturated, 26% monounsaturated, 8% polyunsaturated)] and control diet (36% total energy as fat), separated by 3 wk. Whole-body insulin sensitivity was assessed before and after each diet using oral-glucose-tolerance tests. Fasting plasma concentrations of FGF21 (primary outcome), LECT2, fetuin-A, fetuin-B, SeP, and related metabolites were measured after 1, 3, and 7 d of each diet. Hepatokine responses were analyzed using 2-factor repeated-measures ANOVA and subsequent pairwise comparisons. RESULTS: Compared with the control, the HE-HFD increased circulating FGF21 at 1 d (105%) and 3 d (121%; P ≤ 0.040), LECT2 at 3 d (17%) and 7 d (32%; P ≤ 0.004), and fetuin-A at 7 d (7%; P = 0.028). Plasma fetuin-B and SeP did not respond to the HE-HFD. Whole-body insulin sensitivity was reduced after the HE-HFD by 31% (P = 0.021). CONCLUSIONS: Acute high-fat overfeeding augments circulating concentrations of FGF21, LECT2, and fetuin-A in healthy men. Notably, the time course of response varies between proteins and is transient for FGF21. These findings provide further insight into the nutritional regulation of hepatokines in humans and their interaction with metabolic homeostasis. This study was registered at clinicaltrials.gov as NCT03369145.

Psychophysiological Correlates of Emotional- and Alcohol-Related Cues Processing in Offspring of Alcohol-Dependent Patients.

AIMS: To determinate if offspring of alcohol-dependent patients (OA) process affective stimuli and alcohol-related cues in a different manner than control subjects do. METHODS: Event-related potentials (early posterior negativity [EPN]/ late positive potential [LPP]) and event-related oscillations (Theta) were obtained by electroencephalographic (EEG) recording during the viewing of International Affective Picture System (IAPS) images with positive, negative and neutral valence, as well as alcohol-related cues. The total sample was comprised of 60 participants, divided into two groups: one group consisted of OA (30) and the control group of participants with negative family history of alcohol use disorders (30). RESULTS: Theta power analysis implies a significant interaction between condition, region and group factors. Post-hoc analysis indicates an increased theta power for the OA at different regions, during pleasant (frontal, central, parietal, occipital, right temporal); unpleasant (frontal, central, occipital); alcohol (frontal, central, parietal, occipital, right and left temporal) and neutral (occipital) cues. There are no group differences regarding any of the event-related potential measurements (EPN/LPP). CONCLUSIONS: There is evidence of alterations in the processing of affective stimuli and alcohol-related information, evidenced by changes in theta brain oscillations. These alterations are characterized by an increased emotional reactivity, evidenced by increased theta at posterior sites. There is also an increased recruitment of emotion control, which could be a compensation mechanism, evidenced by increased theta power at anterior sites during affective stimuli and alcohol cues.

Multicentre, prospective, double-blind, randomised controlled clinical trial comparing different non-opioid analgesic combinations with morphine for postoperative analgesia: the OCTOPUS study.

BACKGROUND: Head-to-head comparisons of combinations of more than one non-opioid analgesic (NOA) with morphine alone, for postoperative analgesia, are lacking. The objective of this multicentre, randomised, double-blind controlled trial was to compare the morphine-sparing effects of different combinations of three NOAs-paracetamol (P), nefopam (N), and ketoprofen (K)-for postoperative analgesia. METHODS: Patients from 10 hospitals were randomised to one of eight groups: control (C) received saline as placebo, P, N, K, PN, PK, NK, and PNK. Treatments were given intravenously four times a day during the first 48 h after surgery, and morphine patient-controlled analgesia was used as rescue analgesia. The outcome measures were morphine consumption, pain scores, and morphine-related side-effects evaluated 24 and 48 h after surgery. RESULTS: Two hundred and thirty-seven patients undergoing a major surgical procedure were included between July 2013 and November 2016. Despite a failure to reach a calculated sample size, 24 h morphine consumption [median (inter-quartile range)] was significantly reduced in the PNK group [5 (1-11) mg] compared with either the C group [27 (11-42) mg; P<0.05] or the N group [21 (12-29) mg; P<0.05]. Results were similar 48 h after surgery. Patients experienced less pain in the PNK group compared with the C, N, and P groups. No difference was observed in the incidence of morphine-related side-effects. CONCLUSIONS: Combining three NOAs with morphine allows a significant morphine sparing for 48 h after surgery associated with superior analgesia the first 24 h when compared with morphine alone. CLINICAL TRIAL REGISTRATION: EudraCT: 2012-004219-30; NCT01882530.

P3 Component as a Potential Endophenotype for Control Inhibition in Offspring of Alcoholics.

AIMS: To assess inhibitory processes and the ongoing event-related potential (ERP) activity of offspring of alcoholics (OA) during a Go/No-Go task, with the purpose of characterizing possible psychophysiological endophenotypes for alcohol-dependent vulnerability. SHORT SUMMARY: EEG recordings and ERP measurements of young adults with positive and negative family history of alcoholism where obtained while they performed a Go/No-Go task to assess inhibitory processes. Offspring of alcoholics showed a different ERP pattern compared to the control group and exerted greater effort than the control group. METHODS: ERP measurements were obtained by electroencephalogram (EEG) recordings of 65 participants divided into two groups: one group of 30 subjects with positive family history of alcoholism and a control group of 35 subjects with negative family history of alcoholism. They performed a Go/No-Go task, where each individual was required to classify visual stimuli by colour (Go) and inhibit their response to a No-Go signal. RESULTS: OA have higher P3 amplitudes during the Go condition in all of the regions analysed and higher No-Go P3 amplitudes than control subjects in the frontal region. Unlike controls, OA have no differences between the P3 amplitudes across conditions. CONCLUSIONS: The absence of differences between the P3 Go and No-Go observed in the OA group can be interpreted as a possible alteration related with inhibition, in a way that they may need to recruit similar resources for inhibitory and classificational processes for both conditions. Therefore, the P3 component may be considered as a useful endophenotype and a vulnerability marker to develop addictive behaviour.

Short-term, high-fat overfeeding impairs glycaemic control but does not alter gut hormone responses to a mixed meal tolerance test in healthy, normal-weight individuals.

Obesity is undoubtedly caused by a chronic positive energy balance. However, the early metabolic and hormonal responses to overeating are poorly described. This study determined glycaemic control and selected gut hormone responses to nutrient intake before and after 7 d of high-fat overfeeding. Nine healthy individuals (five males, four females) performed a mixed meal tolerance test (MTT) before and after consuming a high-fat (65 %), high-energy (+50 %) diet for 7 d. Measurements of plasma glucose, NEFA, acylated ghrelin, glucagon-like peptide-1 (GLP-1), gastric inhibitory polypeptide (GIP) and serum insulin were taken before (fasting) and at 30-min intervals throughout the 180-min MTT (postprandial). Body mass increased by 0·79 (sem 0·14) kg after high-fat overfeeding (P<0·0001), and BMI increased by 0·27 (sem 0·05) kg/m2 (P=0·002). High-fat overfeeding also resulted in an 11·6 % increase in postprandial glucose AUC (P=0·007) and a 25·9 % increase in postprandial insulin AUC (P=0·005). Acylated ghrelin, GLP-1 and GIP responses to the MTT were all unaffected by the high-fat, high-energy diet. These findings demonstrate that even brief periods of overeating are sufficient to disrupt glycaemic control. However, as the postprandial orexigenic (ghrelin) and anorexigenic/insulintropic (GLP-1 and GIP) hormone responses were unaffected by the diet intervention, it appears that these hormones are resistant to short-term changes in energy balance, and that they do not play a role in the rapid reduction in glycaemic control.

Accelerating Topical Anaesthesia Using Microneedles.

BACKGROUND/AIMS: Topical anaesthetics reduce pain during venous access procedures in children. However, clinical use is hindered by a significant anaesthetic onset time. Restricted diffusion of the topical anaesthetic through the stratum corneum barrier is the principal reason for the delayed onset. Microneedles can painlessly pierce the skin. This study evaluated microneedle pre-treatment of ex vivo human skin as a means to increase the rate of tetracaine permeation, in order to accelerate the onset of anaesthesia. METHODS: Franz-type diffusion cells were used to determine permeation of a commercial tetracaine formulation, Ametop gel, through human skin epidermis. Microneedle-assisted permeation was compared to untreated epidermis. Upon completion of the permeation studies, the epidermal membranes were visually characterised. RESULTS: At 30 min, 5.43 µg/cm2 of tetracaine had permeated through the untreated membrane compared to 12.13 µg/cm2 through the microneedle-treated membrane. Insertion of a hypodermic needle created a large single channel in the epidermis (approx. 4,250 µm2) whilst the punctured surface area following microneedle treatments was estimated to be 75,000 µm2. CONCLUSION: Pre-treatment of skin with microneedles significantly enhances the permeation of tetracaine. Microneedles have the potential to more than halve the onset time for anaesthesia when applying Ametop gel.

Topical steroid therapy induces pro-tolerogenic changes in Langerhans cells in human skin.

We have investigated the efficacy of conditioning skin Langerhans cells (LCs) with agents to promote tolerance and reduce inflammation, with the goal of improving the outcomes of antigen-specific immunotherapy. Topical treatments were assessed ex vivo, using excised human breast skin maintained in organ bath cultures, and in vivo in healthy volunteers by analysing skin biopsies and epidermal blister roof samples. Following topical treatment with a corticosteroid, tumour necrosis factor-α levels were reduced in skin biopsy studies and blister fluid samples. Blister fluid concentrations of monocyte chemoattractant protein-1, macrophage inflammatory proteins -1α and 1ß and interferon-γ inducible protein-10 were also reduced, while preserving levels of interleukin-1α (IL-1α), IL-6, IL-8 and IL-10. Steroid pre-treatment of the skin reduced the ability of LCs to induce proliferation, while supernatants showed an increase in the IL-10/interferon-γ ratio. Phenotypic changes following topical steroid treatment were also observed, including reduced expression of CD83 and CD86 in blister-derived LCs, but preservation of the tolerogenic signalling molecules immunoglobulin-like transcript 3 and programmed death-1. Reduced expression of HLA-DR, CD80 and CD86 were also apparent in LCs derived from excised human skin. Topical therapy with a vitamin D analogue (calcipotriol) and steroid, calcipotriol alone or vitamin A elicited no significant changes in the parameters studied. These experiments suggest that pre-conditioning the skin with topical corticosteroid can modulate LCs by blunting their pro-inflammatory signals and potentially enhancing tolerance. We suggest that such modulation before antigen-specific immunotherapy might provide an inexpensive and safe adjunct to current approaches to treat autoimmune diseases.

An analysis of the relationship between microneedle spacing, needle force and skin strain during the indentation phase prior to skin penetration.

Microneedle (MN) array patches present a promising new approach for the minimally invasive delivery of therapeutics and vaccines. However, ensuring reproducible insertion of MNs into the skin is challenging. The spacing and arrangement of MNs in an array are critical determinants of skin penetration and the mechanical integrity of the MNs. In this work, the finite element method was used to model the effect of MN spacing on needle reaction force and skin strain during the indentation phase prior to skin penetration. Spacings smaller than 2-3 mm (depending on variables, e.g., skin stretch) were found to significantly increase these parameters.

Assessing the risk of a clinically significant infection from a Microneedle Array Patch (MAP) product.

Microneedle Array Patches (MAPs) are an emerging dosage form that creates transient micron-sized disruptions in the outermost physical skin barrier, the stratum corneum, to facilitate delivery of active pharmaceutical ingredients to the underlying tissue. Numerous MAP products are proposed and there is significant clinical potential in priority areas such as vaccination. However, since their inception scientists have hypothesized about the risk of a clinically significant MAP-induced infection. Safety data from two major Phase 3 clinical trials involving hundreds of participants, who in total received tens of thousands of MAP applications, does not identify any clinically significant infections. However, the incumbent data set is not extensive enough to make definitive generalizable conclusions. A comprehensive assessment of the infection risk is therefore advised for MAP products, and this should be informed by clinical and pre-clinical data, theoretical analysis and informed opinions. In this article, a group of key stakeholders identify some of the key product- and patient-specific factors that may contribute to the risk of infection from a MAP product and provide expert opinions in the context of guidance from regulatory authorities. Considerations that are particularly pertinent to the MAP dosage form include the specifications of the finished product (e.g. microbial specification), it's design features, the setting for administration, the skill of the administrator, the anatomical application site, the target population and the clinical context. These factors, and others discussed in this article, provide a platform for the development of MAP risk assessments and a stimulus for early and open dialogue between developers, regulatory authorities and other key stakeholders, to expedite and promote development of safe and effective MAP products.

Models and methods to characterise levonorgestrel release from intradermally administered contraceptives.

Microneedle (MN)-based technologies have been proposed as a means to facilitate minimally invasive sustained delivery of long-acting hormonal contraceptives into the skin. Intradermal administration is a new route of delivery for these contraceptives and therefore no established laboratory methods or experimental models are available to predict dermal drug release and pharmacokinetics from candidate MN formulations. This study evaluates an in vitro release (IVR) medium and a medium supplemented with ex vivo human skin homogenate (SH) as potential laboratory models to investigate the dermal release characteristics of one such hormonal contraceptive that is being tested for MN delivery, levonorgestrel (LNG), and provides details of an accompanying novel two-step liquid-liquid drug extraction procedure and sensitive reversed-phase HPLC-UV assay. The extraction efficiency of LNG was 91.7 ± 3.06% from IVR medium and 84.6 ± 1.6% from the medium supplemented with SH. The HPLC-UV methodology had a limit of quantification of 0.005 µg/mL and linearity between 0.005 and 25 µg/mL. Extraction and detection methods for LNG were exemplified in both models using the well-characterised, commercially available sustained-release implant (Jadelle®). Sustained LNG release from the implant was detected in both media over 28 days. This study reports for the first time the use of biologically relevant release models and a rapid, reliable and sensitive methodology to determine release characteristics of LNG from intradermally administered long-acting drug delivery systems.

In vivo, in situ imaging of microneedle insertion into the skin of human volunteers using optical coherence tomography.

PURPOSE: To gather sub-surface in situ images of microneedle-treated human skin, in vivo, using optical coherence tomography (OCT). This is the first study to utilise OCT to investigate the architectural changes that are induced in skin following microneedle application. METHODS: Steel, silicon and polymer microneedle devices, with different microneedle arrangements and morphologies, were applied to two anatomical sites in human volunteers following appropriate ethical approval. A state-of-the-art ultrahigh resolution OCT imaging system operating at 800 nm wavelength and <3 µm effective axial resolution was used to visualise the microneedle-treated area during insertion and/or following removal of the device, without any tissue processing. RESULTS: Transverse images of a microneedle device, in situ, were captured by the OCT system and suggest that the stratified skin tissue is compressed during microneedle application. Following removal of the device, the created microchannels collapse within the in vivo environment and, therefore, for all studied devices, microconduit dimensions are markedly smaller than the microneedle dimensions. CONCLUSIONS: Microchannels created in the upper skin layers by microneedles are less invasive than previous histology predicts. OCT has the potential to play a highly influential role in the future development of microneedle devices and other transdermal delivery systems.

Oxidation of dietary linoleate occurs to a greater extent than dietary palmitate in vivo in humans.

BACKGROUND: It has been suggested that dietary polyunsaturated fatty acids (PUFA) are partitioned into oxidation pathways to a greater extent than dietary saturated fatty acids (SFA). Whilst this has been demonstrated in animal models, evidence in humans is lacking. The potential divergence in the metabolic fate of these dietary fatty acids (FA) may explain some of the reported differences in ectopic fat deposition with SFA and PUFA enriched diets. AIMS: To compare whole-body oxidation of dietary palmitate and linoleate after consumption of a single test meal. METHODS: In a randomized, crossover design 24 healthy volunteers (12 males and 12 females, matched for age and BMI) underwent two study days separated by 2-week washout period. During each study day participants consumed a standardized test meal which contained [U13C]palmitate or [U13C]linoleate. Blood and breath samples were collected over the 6 h postprandial period and the 13C enrichment in breath CO2 samples and plasma lipid fractions was determined. RESULTS: Appearance of 13C in expired CO2 was significantly (p < 0.05) increased after consumption of the meal containing [U13C]linoleate compared to the meal containing [U13C]palmitate. The recovery of tracer was 8.9 ± 1.2% [U13C]linoleate vs. 5.6 ± 0.4% [U13C]palmitate (p < 0.05). The incorporation of 13C from [U13C]palmitate was greater in plasma triacylglycerol and non-esterified fatty acids than [U13C]linoleate, whereas the incorporation of 13C from [U13C]linoleate was greater than [U13C]palmitate in plasma phospholipids. Although 13CO2 was significantly (p < 0.05) higher in females compared to males after consumption of [U13C]palmitate, there was no difference in 13CO2 between sexes after consumption of [U13C]linoleate. CONCLUSIONS: We demonstrate that whole-body oxidation of dietary linoleate is comparatively higher than that of dietary palmitate in humans following consumption of a single mixed-test meal. We found indications of sexual dimorphism for dietary palmitate but not dietary linoleate. STUDY REGISTRATION: http://www.clinicaltrials.org/ ID number NCT03587753.

The influence of nutritional state on the fatty acid composition of circulating lipid fractions: implications for their use as biomarkers of dietary fat intake.

BACKGROUND: The fatty acid (FA) composition of blood can be used as an objective biomarker of dietary FA intake. It remains unclear how the nutritional state influences the FA composition of plasma lipid fractions, and thus their usefulness as biomarkers in a non-fasted state. OBJECTIVES: To investigate the associations between palmitate, oleate and linoleate in plasma lipid fractions and self-reported dietary FA intake, and assess the influence of meal consumption on the relative abundance of these FA in plasma lipid fractions (i.e. triglyceride [TG], phospholipids [PLs] and cholesterol esters [CEs]). DESIGN: Analysis was performed in plasma samples collected from 49 (34 males and 15 females) participants aged 26-57 years with a body mass index (BMI) between 21.6 and 34.2 kg/m2, all of whom had participated in multiple study visits, thus a pooled cohort of 98 data sets was available for analysis. A subset (n = 25) had undergone nutritional interventions and was therefore used to investigate the relationship between the FA composition of plasma lipid fractions and dietary fat intake. RESULTS: Significant (P < 0.05) positive associations were observed between dietary polyunsaturated fat and linoleate abundance in plasma CE. When investigating the influence of meal consumption on postprandial FA composition, we found plasma TG palmitate significantly (P < 0.05) decreased across the postprandial period, whereas oleate and linoleate increased. A similar pattern was observed in plasma PL, whereas linoleate abundance decreased in the plasma CE. CONCLUSION: Our data demonstrate that the FA composition of plasma CE may be the lipid fraction to utilise as an objective biomarker when investigating recent (i.e. previous weeks-months) dietary FA intakes. In addition, we show that the consumption of a high-fat meal influences the FA composition of plasma TG, PL and CE over the course of the postprandial period, and therefore, suggest that fasting blood samples should be utilised when using FA composition as a biomarker of dietary FA intake.

Human-centred design of a new microneedle-based hormonal contraceptive delivery system.

Background: It is estimated that 225 million women worldwide have an unmet need for family planning, and more than half live in low- and middle-income countries. Increasing the choice of contraceptive methods available can reduce this unmet need. Microneedle drug delivery systems represent a new technology for minimally invasive self-administration of contraceptives. We explored stakeholders' views on different aspects of a proposed microneedle-based hormonal contraceptive delivery system. The feedback was used to iteratively develop this delivery system. Methods: Focus group discussions and semi-structured interviews were conducted with potential stakeholders (women and trans males of childbearing age, their partners, and health professionals and organisations that provide family planning advice and contraception services) in Uganda, The Gambia, Malawi, and the UK, exploring concept acceptability and gathering feedback on different aspects of design and usability of the proposed delivery system. Results: Participants viewed the concept of a new, microneedle-based contraceptive favourably. In Uganda, participants were presented with 7 different prototype applicators and identified desirable features of a preferred delivery device; their input reducing the number of prototypes that were subsequently evaluated by stakeholders in The Gambia and the UK. Participants in these countries helped to identify and/or confirm the most desirable characteristics of the applicator, resulting in design consolidation into a refined concept applicator. The final, optimised applicator prototype was validated during user research in Malawi. This human-centred design approach was also used to iteratively develop an information leaflet for the device. During these user studies, other preferred aspects of a contraceptive delivery system were also evaluated, such as anatomical site of application, duration of action, and return to fertility. Conclusions: A new microneedle-based contraceptive delivery system was iteratively developed using a human-centred design approach and was favourably received by potential stakeholders. The product is now being refined for testing in pre-clinical studies.

Managing NAFLD in Type 2 Diabetes: The Effect of Lifestyle Interventions, a Narrative Review.

The prevalence of non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D) is increasing. As a strong association between these two diseases exist, it is unsurprising that the number of patients with coexisting NAFLD and T2D is also increasing. These patients display a deleterious metabolic profile (e.g. hypertriglyceridemia), and increased mortality rates relative to those with only NAFLD or T2D in isolation; therefore, effective treatment strategies are required. Here we review the available intervention studies that have investigated the effects of changes in lifestyle (diet and exercise/physical activity) on NAFLD in patients with both NAFLD and T2D. On the basis of the available evidence, it appears that the addition of any kind of exercise (i.e. resistance, aerobic, or high-intensity intermittent exercise) is beneficial for patients with both NAFLD and T2D. These effects appear to occur independently of changes in body weight. Hypocaloric diets leading to weight loss are also effective in improving metabolic parameters in patients with both NAFLD and T2D, with data indicating that ~ 7-10% weight loss is required in order to observe beneficial effects. It is unclear if multidisciplinary interventions incorporating changes in both diet and physical activity levels are a more effective treatment strategy in this population than diet or exercise interventions in isolation. In conclusion, it is clear that lifestyle interventions are an effective treatment strategy in patients with both NAFLD and T2D, although further research is required to optimise these interventions and determine their scalability.

The influence of dietary fatty acids on liver fat content and metabolism.

Non-alcoholic fatty liver disease encompasses a spectrum of conditions from hepatic steatosis through to cirrhosis; obesity is a known risk factor. The liver plays a major role in regulating fatty acid metabolism and perturbations in intrahepatic processes have potential to impact on metabolic health. It remains unclear why intra-hepatocellular fat starts to accumulate, but it likely involves an imbalance between fatty acid delivery to the liver, fatty acid synthesis and oxidation within the liver and TAG export from the liver. As man spends the majority of the day in a postprandial rather than postabsorptive state, dietary fatty acid intake should be taken into consideration when investigating why intra-hepatic fat starts to accumulate. This review will discuss the impact of the quantity and quality of dietary fatty acids on liver fat accumulation and metabolism, along with some of the potential mechanisms involved. Studies investigating the role of dietary fat in liver fat accumulation, although surprisingly limited, have clearly demonstrated that it is total energy intake, rather than fat intake per se, that is a key mediator of liver fat content; hyperenergetic diets increase liver fat whilst hypoenergetic diets decrease liver fat content irrespective of total fat content. Moreover, there is now, albeit limited evidence emerging to suggest the composition of dietary fat may also play a role in liver fat accumulation, with diets enriched in saturated fat appearing to increase liver fat content to a greater extent when compared with diets enriched in unsaturated fats.