Sex differences in risk of incident microvascular and macrovascular complications: a population-based data-linkage study among 25 713 people with diabetes.

BACKGROUND: The global prevalence of diabetes is similar in men and women; however, there is conflicting evidence regarding sex differences in diabetes-related complications. The aim of this study was to investigate sex differences in incident microvascular and macrovascular complications among adults with diabetes. METHODS: This prospective cohort study linked data from the 45 and Up Study, Australia, to administrative health records. The study sample included 25 713 individuals (57% men), aged ≥45 years, with diabetes at baseline. Incident cardiovascular disease (CVD), eye, lower limb, and kidney complications were determined using hospitalisation data and claims for medical services. Multivariable Cox proportional hazards models were used to assess the association between sex and incident complications. RESULTS: Age-adjusted incidence rates per 1000 person years for CVD, eye, lower limb, and kidney complications were 37, 52, 21, and 32, respectively. Men had a greater risk of CVD (adjusted hazard ratio (aHR) 1.51, 95% CI 1.43 to 1.59), lower limb (aHR 1.47, 95% CI 1.38 to 1.57), and kidney complications (aHR 1.55, 95% CI 1.47 to 1.64) than women, and a greater risk of diabetic retinopathy (aHR 1.14, 95% CI 1.03 to 1.26). Over 10 years, 44%, 57%, 25%, and 35% of men experienced a CVD, eye, lower limb, or kidney complication, respectively, compared with 31%, 61%, 18%, and 25% of women. Diabetes duration (<10 years vs ≥10 years) had no substantial effect on sex differences in complications. CONCLUSIONS: Men with diabetes are at greater risk of complications, irrespective of diabetes duration. High rates of complications in both sexes highlight the importance of targeted complication screening and prevention strategies from diagnosis.

Benchmarking online food delivery applications against menu labelling laws: a cross-sectional observational analysis.

OBJECTIVE: It is unknown how well menu labelling schemes that enforce the display of kilojoule (kJ) labelling at point-of-sale have been implemented on online food delivery (OFD) services in Australia. This study aimed to examine the prevalence of kJ labelling on the online menus of large food outlets with more than twenty locations in the state or fifty locations nationally. A secondary aim was to evaluate the nutritional quality of menu items on OFD from mid-sized outlets that have fewer locations than what is specified in the current scheme. DESIGN: Cross-sectional analysis. Prevalence of kJ labelling by large food outlets on OFD from August to September 2022 was examined. Proportion of discretionary ('junk food') items on menus from mid-sized outlets was assessed. SETTING: Forty-three unique large food outlets on company (e.g. MyMacca's) and third party OFD (Uber Eats, Menulog, Deliveroo) within Sydney, Australia. Ninety-two mid-sized food outlets were analysed. PARTICIPANTS: N/A. RESULTS: On company OFD apps, 35 % (7/23) had complete kJ labelling for each menu item. In comparison, only 4·8 % (2/42), 5·3 % (2/38) and 3·6 % (1/28) of large outlets on Uber Eats, Menulog and Deliveroo had complete kJ labelling at all locations, respectively. Over three-quarters, 76·3 % (345/452) of menu items from mid-sized outlets were classified as discretionary. CONCLUSIONS: Kilojoule labelling was absent or incomplete on a high proportion of online menus. Mid-sized outlets have abundant discretionary choices and yet escape criteria for mandatory menu labelling laws. Our findings show the need to further monitor the implementation of nutrition policies on OFD.

Darolutamide does not interfere with OATP-mediated uptake of docetaxel.

The addition of darolutamide, an androgen receptor signalling inhibitor, to therapy with docetaxel has recently been approved as a strategy to treat metastatic prostate cancer. OATP1B3 is an SLC transporter that is highly expressed in prostate cancer and is responsible for the accumulation of substrates, including docetaxel, into tumours. Given that darolutamide inhibits OATP1B3 in vitro, we sought to characterise the impact of darolutamide on docetaxel pharmacokinetics. We investigated the influence of darolutamide on OATP1B3 transport using in vitro and in vivo models. We assessed the impact of darolutamide on the tumour accumulation of docetaxel in a patient-derived xenograft (PDX) model and on an OATP1B biomarker in patients. Darolutamide inhibited OATP1B3 in vitro at concentrations higher than the reported Cmax. Consistent with these findings, in vivo studies revealed that darolutamide does not influence the pharmacokinetics of Oatp1b substrates, including docetaxel. Docetaxel accumulation in PDX tumours was not decreased in the presence of darolutamide. Metastatic prostate cancer patients had similar levels of OATP1B biomarkers, regardless of treatment with darolutamide. Consistent with a low potential to inhibit OATP1B3-mediated transport in vitro, darolutamide does not significantly impede the transport of Oatp1b substrates in vivo or in patients. Our findings support combined treatment with docetaxel and darolutamide, as no OATP1B3 transporter based drug-drug interaction was identified.

Use of online food retail platforms throughout the COVID-19 pandemic and associated diet-related chronic disease risk factors: A systematic review of emerging evidence.

Food accessibility was considerably impacted by restrictions during the coronavirus disease 2019 (COVID-19) pandemic, leading to growth in the online food retail sector, which offered contact-free delivery. This systematic review aimed to assess the change in use of online food retail platforms during COVID-19. The secondary aim was to identify diet-related chronic disease risk factors including dietary intake, eating behaviors, and/or weight status associated with the use of online food retail platforms during the pandemic. The review was registered in the International Prospective Register of Systematic Reviews (PROSPERO) (CRD42022320498) and adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Nine electronic databases were searched between January 2020 and October 2023. Studies that reported the frequency or change in use of online groceries, meal delivery applications, and/or meal-kit delivery services before and during the pandemic were included. A total of 53 studies were identified, including 46 cross-sectional studies, 4 qualitative studies, 2 longitudinal cohort studies, and 1 mixed-methods study. Overall, 96% (43/45) of outcomes showed an increase in the use of online groceries during COVID-19, while 55% (22/40) of outcomes showed a decrease in meal delivery applications. Eight of nine outcomes associated the use of online food retail with weight gain and emotional eating. Further research is needed to investigate the links between online food retail and obesity.

Sex and age differences in the use of medications for diabetes and cardiovascular risk factors among 25,733 people with diabetes.

AIM: To determine sex and age differences in the use of medications for diabetes and cardiovascular risk factors in people with diabetes in Australia. METHODS: Pharmaceutical claims data of participants in the 45 and Up Study who self-reported having diabetes before 2013, were alive on 1st January 2013 and had at least one medication dispensing record between 1st January 2013 and 31st December 2019 were analysed. Annual sex and age-specific percentages of participants supplied specific medications were estimated for years 2013 to 2019. Percentages were reported for any glucose lowering medications and by drug class, any lipid modifying agents, and any blood pressure lowering medications. RESULTS: Altogether 25,733 participants (45.2% women) with diabetes were included. The percentage of participants who were supplied with glucose lowering medications was consistently lower in women compared to men. In both sexes, the percentage of participants who were supplied with glucose lowering medications was lowest among those aged ≥75 years and this decreased over time. Similar findings were observed for lipid modifying agents and blood pressure lowering medications. The use of sodium glucose co-transporter 2 inhibitors increased substantially in participants aged <75 years since it became available in 2013. However, no sex differences were observed in its use among people with hospital-recorded history of cardiovascular disease. CONCLUSIONS: Practitioners should be aware of possible sex disparities in the pharmacological treatment of diabetes and cardiovascular risk factors in people with diabetes in Australia. There is a possible time lag between reporting of research findings and uptake of sodium glucose co-transporter 2 inhibitors prescribing in individuals with diabetes and high cardiovascular risk in clinical practice, nevertheless, the result observed was consistent with the management guidelines at the time of the study.

Impact of lifestyle risk factors on admission to nursing home care: a cohort study of 127 108 people aged 60 years and over.

BACKGROUND: Little is known on how lifestyle factors, individually or in combination, may relate to nursing home admission, an outcome of great societal and economic importance with increased population ageing. The aim of this study was to determine the association of lifestyle risk factors with nursing home admission. METHODS: This prospective cohort study linked data from the 45 and Up Study, Australia, to health records. 127 108 men and women, aged ≥60 years, were recruited between 2006 and 2009. A healthy lifestyle score categorised participants into three risk groups based on five equally contributing risk factors: smoking status, physical activity, sedentary behaviour, sleep duration and diet quality. HRs for incident nursing home admission were estimated using multivariable Cox proportional hazards model. RESULTS: One-quarter of participants were in the low-risk lifestyle group, 62% were in the medium-risk group and 14% in the high-risk (least healthy) group. During a median (IQR) follow-up of 11.3 years, 23 094 (18%) participants were admitted to a nursing home. Compared with those in the low-risk group, risk of nursing home admission was 43% higher among participants in the high-risk group (multivariable adjusted HR (aHR) 1.43; 95% CI 1.36 to 1.50); and participants in the medium-risk group had an intermediate 12% greater risk (aHR 1.12; 95% CI 1.08 to 1.16). Participants aged 60-64 years in the high-risk (aHR 2.15; 95% CI 1.82 to 2.54) lifestyle group had the greatest risk of nursing home admission. CONCLUSION: An unhealthy lifestyle was associated with a marked increased risk of admission to a nursing home in adults aged 60+ years. Interventions focused on lifestyle modifications may prevent or delay nursing home admission.

Association of oral health with risk of incident micro and macrovascular complications: A prospective cohort study of 24,862 people with diabetes.

AIMS: To investigate the association between self-reported oral health and incident micro and macrovascular diabetes complications. METHODS: This prospective cohort study linked data from the 45 and Up Study, Australia, to administrative health records. The participants were 24,862 men and women, aged ≥45 years, with diabetes at baseline (2006-2009). The oral health of participants was assessed by questionnaire. Incident diabetes complications were determined using hospitalisation data and claims for medical services up until 2019. Hazard ratios for the association between oral health and incident complications were calculated using multivariable cox proportional hazards models. RESULTS: Almost 60 % of participants had <20 teeth, and 38 % rated their teeth and gums as fair or poor. Compared with those with ≥20 teeth, those with 0 teeth had an increased risk of cardiovascular disease (aHR 1.24, 95 % CI: 1.15, 1.35), lower limb (aHR 1.22, 95 % CI: 1.11, 1.33) and kidney (aHR 1.19, 95 % CI: 1.11, 1.29) complications. Individuals with 1-9 teeth had an increased risk of eye complications (aHR 1.14, 95 % CI: 1.07, 1.22). The associations were generally consistent for poor self-rated teeth and gums. CONCLUSIONS: Self-reported oral health measures may be a marker of elevated risk of complications in people with diabetes.

Oral health status and risk of incident diabetes: A prospective cohort study of 213,389 individuals aged 45 and over.

AIMS: To examine whether simple measures of oral health are associated with incident diabetes. METHODS: This prospective cohort study linked data from the 45 and Up Study, Australia, to administrative health records. The study participants were 213,389 men and women, aged ≥45 years, with no diabetes at baseline. The oral health of participants was assessed by questionnaire. Incident diabetes cases were ascertained based on self-report in follow-up questionnaires, linked data on medical and pharmaceutical claims, and hospitalisation data up until 2019. The association between oral health and incident diabetes were calculated using multivariable cox proportional hazards models. RESULTS: During 2,232,215 person-years of follow-up, 20,487 (9.6%) participants developed diabetes. Compared with those with ≥20 teeth, the adjusted hazard ratio (aHR) for incident diabetes was 1.12 (95% Confidence Interval (CI): 1.08, 1.17) for 10-19 teeth, 1.20 (1.14, 1.26) for 1-9 teeth and 1.15 (1.09, 1.21) for no teeth. Compared with those with excellent/very good teeth and gums, the aHR for incident diabetes was 1.07 (1.03, 1.12) for fair and 1.13 (1.07, 1.20) for poor teeth and gums. CONCLUSIONS: Simple measures of oral health were associated with risk of developing diabetes, demonstrating the potential importance of oral health screening for diabetes prevention.

Targeting a xenobiotic transporter to ameliorate vincristine-induced sensory neuropathy.

Vincristine is a widely used chemotherapeutic drug for the treatment of multiple malignant diseases that causes a dose-limiting peripheral neurotoxicity. There is no clinically effective preventative treatment for vincristine-induced sensory peripheral neurotoxicity (VIPN), and mechanistic details of this side effect remain poorly understood. We hypothesized that VIPN is dependent on transporter-mediated vincristine accumulation in dorsal root ganglion neurons. Using a xenobiotic transporter screen, we identified OATP1B3 as a neuronal transporter regulating the uptake of vincristine. In addition, genetic or pharmacological inhibition of the murine orthologue transporter OATP1B2 protected mice from various hallmarks of VIPN - including mechanical allodynia, thermal hyperalgesia, and changes in digital maximal action potential amplitudes and neuronal morphology - without negatively affecting plasma levels or antitumor effects of vincristine. Finally, we identified α-tocopherol from an untargeted metabolomics analysis as a circulating endogenous biomarker of neuronal OATP1B2 function, and it could serve as a companion diagnostic to guide dose selection of OATP1B-type transport modulators given in combination with vincristine to prevent VIPN. Collectively, our findings shed light on the fundamental basis of VIPN and provide a rationale for the clinical development of transporter inhibitors to prevent this debilitating side effect.

Economic evaluation of a mobile phone text-message intervention for Australian adults with type 2 diabetes.

Background: The rising prevalence of type 2 diabetes in Australia is a public health concern, contributing to significant disease burden and economic costs. Text-message programs have been shown to improve health outcomes for people with type 2 diabetes, however they remain underutilized, and no evidence exists on their cost-effectiveness or costs of scale up to a population level in Australia. This study aimed to determine the cost-effectiveness and cost-utility of a 6-month text-message intervention (DTEXT) to improve glycated hemoglobin (HbA1c) and self-management behaviors for Australian adults with type 2 diabetes. Methods: A within-trial economic evaluation was conducted on the DTEXT randomized controlled trial. Incremental cost-effectiveness ratios (ICERs) were determined per 11 mmol/mol (1%) reduced HbA1c and per quality adjusted life year (QALY) gained, compared to usual care. Cost-effectiveness acceptability curves (CEAC) determined the probability of the intervention being cost-effective over a range of willingness to pay thresholds. A scenario analysis was conducted to determine how cost-effectiveness was impacted by using current implementation costs. Results: The DTEXT intervention cost AU$36 (INT$24) per participant, with an ICER of AU$311 (INT$211) per 11 mmol/mol (1%) reduced HbA1c. Based on HbA1c outcomes, DTEXT had a 33% probability of being effective and cost-saving. Based on the QALY outcomes, the intervention had only a 24% probability of being cost-effective. Scenario analysis indicated costs per participant of AU$13 (INT$9) to deliver the intervention, with a reduced incremental cost effectiveness ratio of AU$151 (INT$103) per 11 mmol/mol (1%) reduced HbA1c and a 38% probability of being effective and cost-saving. Conclusions: DTEXT was low cost and potentially scalable, but only had a low to moderate probability of being effective and cost saving. Further research should determine more targeted approaches that may improve cost-effectiveness. Trial Registration: ACTRN12617000416392.

Targeting OCT2 with Duloxetine to Prevent Oxaliplatin-Induced Peripheral Neurotoxicity.

Oxaliplatin-induced peripheral neurotoxicity (OIPN) is a debilitating side effect that afflicts ~90% of patients that is initiated by OCT2-dependent uptake of oxaliplatin in DRG neurons. The antidepressant drug duloxetine has been used to treat OIPN, although its usefulness in preventing this side effect remains unclear. We hypothesized that duloxetine has OCT2-inhibitory properties and can be used as an adjunct to oxaliplatin-based regimens to prevent OIPN. Transport studies were performed in cells stably transfected with mouse or human OCT2 and in isolated mouse DRG neurons ex vivo. Wild-type and OCT2-deficient mice were used to assess effects of duloxetine on hallmarks of OIPN, endogenous OCT2 biomarkers, and the pharmacokinetics of oxaliplatin, and the translational feasibility of a duloxetine-oxaliplatin combination was evaluated in various models of colorectal cancer. We found that duloxetine potently inhibited the OCT2-mediated transport of several xenobiotic substrates, including oxaliplatin, in a reversible, concentration-dependent manner, and independent of species and cell context. Furthermore, duloxetine restricted access of these substrates to DRG neurons ex vivo and prevented OIPN in wild-type mice to a degree similar to the complete protection observed in OCT2-deficient mice, without affecting the plasma levels of oxaliplatin. Importantly, the uptake and cytotoxicity of oxaliplatin in tumor cell lines in vitro and in vivo were not negatively influenced by duloxetine. The observed OCT2-targeting properties of duloxetine, combined with the potential for clinical translation, provide support for its further exploration as a therapeutic candidate for studies aimed at preventing OIPN in cancer patients requiring treatment with oxaliplatin. Significance: We found that duloxetine has potent OCT2-inhibitory properties and can diminish excessive accumulation of oxaliplatin into DRG neurons. In addition, pre-treatment of mice with duloxetine prevented OIPN without significantly altering the plasma pharmacokinetics and antitumor properties of oxaliplatin. These results suggest that intentional inhibition of OCT2-mediated transport by duloxetine can be employed as a prevention strategy to ameliorate OIPN without compromising the effectiveness of oxaliplatin-based treatment.

Unhealthy Food at Your Fingertips: Cross-Sectional Analysis of the Nutritional Quality of Restaurants and Takeaway Outlets on an Online Food Delivery Platform in New Zealand.

Online food delivery (OFD) platforms have become increasingly popular due to advanced technology, which is changing the way consumers purchase food prepared outside of the home. There is limited research investigating the healthiness of the digital food environment and its influence on consumer choice and dietary behaviours. This study is the first to examine the nutritional quality and marketing attributes of menu items from popular independent and franchise restaurants and takeaway outlets on New Zealand's market leading OFD platform (UberEATS®). A total of 374 popular independent and franchise restaurants and takeaway outlets were identified to form a database of complete menus and marketing attributes. All 25,877 menu items were classified into 38 food and beverage categories based on the Australian Dietary Guidelines. Of complete menus, 73.3% (18,955/25,877) were discretionary. Thirty-six percent (9419/25,877) were discretionary cereal-based mixed meals, the largest of the 38 categories. Discretionary menu items were more likely to be categorized as most popular (OR: 2.0, 95% CI 1.7−2.2), accompanied by a photo (OR: 1.7, 95% CI 1.6−1.8), and offered as a value bundle (OR: 4.6, 95% CI 3.2−6.8). Two of the three discretionary mixed meal categories were significantly less expensive than their healthier counterparts (p < 0.001). The overwhelming availability and promotion of discretionary choices offered by restaurants and takeaway outlets on OFD platforms have implications for public health policy. Further research to explore direct associations between nutritional quality and consumers' dietary choices is required.

A Metabolomics Approach for Predicting OATP1B-Type Transporter-Mediated Drug-Drug Interaction Liabilities.

In recent years, various endogenous compounds have been proposed as putative biomarkers for the hepatic uptake transporters OATP1B1 and OATP1B3 that have the potential to predict transporter-mediated drug-drug interactions (DDIs). However, these compounds have often been identified from top-down strategies and have not been fully utilized as a substitute for traditional DDI studies. In an attempt to eliminate observer bias in biomarker selection, we applied a bottom-up, untargeted metabolomics screening approach in mice and found that plasma levels of the conjugated bile acid chenodeoxycholate-24-glucuronide (CDCA-24G) are particularly sensitive to deletion of the orthologous murine transporter Oatp1b2 (31-fold increase vs. wild type) or the entire Oatp1a/1b(-/-)cluster (83-fold increased), whereas the humanized transgenic overexpression of hepatic OATP1B1 or OATP1B3 resulted in the partial restoration of transport function. Validation studies with the OATP1B1/OATP1B3 inhibitors rifampin and paclitaxel in vitro as well as in mice and human subjects confirmed that CDCA-24G is a sensitive and rapid response biomarker to dose-dependent transporter inhibition. Collectively, our study confirmed the ability of CDCA-24G to serve as a sensitive and selective endogenous biomarker of OATP1B-type transport function and suggests a template for the future development of biomarkers for other clinically important xenobiotic transporters.

Effects of total diet replacement programs on mental well-being: A systematic review with meta-analyses.

This systematic review with meta-analyses assessed the effects of total diet replacement (TDR) programs on mental well-being in clinical trial participants with a body mass index greater than or equal to 25 kg/m2 . TDR programs involve replacing all dietary requirements with nutritionally replete formula foods and are generally administered to induce rapid weight loss. To date, it is largely unclear what effects TDR programs may have on mental well-being, particularly in the long-term. To address this, we screened 25,976 references across six databases and extracted 35 publications. These 35 publications provided sufficient data to evaluate the effects of TDR programs on depression, anxiety, stress, positive affect, negative affect, vitality, role-emotional, social functioning, mental health, mental composite summary score, self-esteem, and general psychological health in 24 meta-analyses. Due to the lack of research comparing TDR programs to comparator groups, 22 of our 24 meta-analyses explored change in these mental well-being sub-domains over time in TDR programs without comparators. Specifically, we assessed the change from pre-diet (before the TDR program) to either post-diet (up to and including two months after the TDR program); and/or follow-up (more than two months after the TDR program). For depression and anxiety, we were also able to assess the change from pre-diet to mid-diet (which fell within two weeks of the diet half-way point). The remaining two meta-analyses assessed the difference in depression scores between a TDR group and a food-based comparator group from pre-diet to post-diet and from pre-diet to follow-up. Across all meta-analyses, our results found no marked adverse effects of TDR programs on any mental well-being sub-domain. In fact, clear improvements were observed for depression, anxiety, stress, vitality, role-emotional, and social functioning at post-diet. Interestingly, the improvements for depression, vitality and role-emotional were maintained at follow-up. All improvements were observed in meta-analyses without comparators. While the two comparator-based meta-analyses showed no difference between TDR programs and food-based diets in depression symptoms, there was low statistical power. For all meta-analyses containing three or more independent samples, we constructed prediction intervals to determine the range within which the mean of the true effects may fall for future populations. While these prediction intervals varied between sub-domains, we found that mean depression scores are only likely to increase (i.e., depression will worsen) in less than 3% of future TDR interventions which meet our inclusion/exclusion criteria. Taken together, we concluded that for adults with a body mass index greater than or equal to 25 kg/m2 , TDR programs are unlikely to lead to marked adverse effects on mental well-being. These findings do not support the exclusion of participants from trials or interventions involving TDR programs based on concerns that these programs may adversely affect mental well-being. In fact, by excluding these participants, they may be prevented from improving their metabolic health and mental well-being.

MATE1 Deficiency Exacerbates Dofetilide-Induced Proarrhythmia.

Dofetilide is a rapid delayed rectifier potassium current inhibitor widely used to prevent the recurrence of atrial fibrillation and flutter. The clinical use of this drug is associated with increases in QTc interval, which predispose patients to ventricular cardiac arrhythmias. The mechanisms involved in the disposition of dofetilide, including its movement in and out of cardiomyocytes, remain unknown. Using a xenobiotic transporter screen, we identified MATE1 (SLC47A1) as a transporter of dofetilide and found that genetic knockout or pharmacological inhibition of MATE1 in mice was associated with enhanced retention of dofetilide in cardiomyocytes and increased QTc prolongation. The urinary excretion of dofetilide was also dependent on the MATE1 genotype, and we found that this transport mechanism provides a mechanistic basis for previously recorded drug-drug interactions of dofetilide with various contraindicated drugs, including bictegravir, cimetidine, ketoconazole, and verapamil. The translational significance of these observations was examined with a physiologically-based pharmacokinetic model that adequately predicted the drug-drug interaction liabilities in humans. These findings support the thesis that MATE1 serves a conserved cardioprotective role by restricting excessive cellular accumulation and warrant caution against the concurrent administration of potent MATE1 inhibitors and cardiotoxic substrates with a narrow therapeutic window.

Influence of Tyrosine Kinase Inhibition on Organic Anion Transporting Polypeptide 1B3-Mediated Uptake.

The organic anion transporting polypeptide family member (OATP) 1B3 is a hepatic uptake transporter that has a broad substrate recognition and plays a significant role in regulating elimination of endogenous biomolecules or xenobiotics. OATP1B3 works in tandem with OATP1B1, with which it shares approximately 80% sequence homology and a high degree of substrate overlap. Despite some substrates being recognized solely by OATP1B3, its ability to compensate for loss of OATP1B1-mediated elimination and recognition by regulatory agencies, little is known about OATP1B3 regulatory factors and how they are involved with drug-drug interaction. It was recently discovered that OATP1B1 function is mediated by the activity of a particular tyrosine kinase that is sensitive to a variety of tyrosine kinase inhibitors (TKIs). This study reports that OATP1B3 is similarly regulated, as at least 50% of its activity is reduced by 20 US Food and Drug Administration -approved TKIs. Nilotinib was assessed as the most potent OATP1B3 inhibitor among the investigated TKIs, which can occur at clinically relevant concentrations and acted predominantly through noncompetitive inhibition without impacting membrane expression. Finally, OATP1B3 function was determined to be sensitive to the knockdown of the Lck/Yes novel tyrosine kinase that is sensitive to nilotinib and has been previously implicated in mediating OATP1B1 activity. Collectively, our findings identify tyrosine kinase activity as a major regulator of OATP1B3 function which is sensitive to kinase inhibition. Given that OATP1B1 is similarly regulated, simultaneous disruption of these transporters can have drastic effects on systemic drug concentrations, which would promote adverse events. SIGNIFICANCE STATEMENT: The organic anion transporting polypeptide family member (OATP) 1B3 is a facilitator of hepatic drug elimination, although much is unknown of how OATP1B3 activity is mediated, or how such regulators contribute to drug-drug interactions. This study reports that OATP1B3 activity is dependent on the Lck/Yes novel tyrosine kinase, which is sensitive to numerous tyrosine kinase inhibitors. These findings provide insight into the occurrence of many clinical drug-drug interactions, and a rationale for future study of tyrosine kinases regulating drug disposition.

Perspective: Are Online Food Delivery Services Emerging as Another Obstacle to Achieving the 2030 United Nations Sustainable Development Goals?

Online food delivery usage has soared during the 2019 novel coronavirus (COVID-19) pandemic which has seen increased demand for home-delivery during government mandated stay-at-home periods. Resulting implications from COVID-19 may threaten decades of development gains. It is becoming increasingly more important for the global community to progress toward sustainable development and improve the wellbeing of people, economies, societies, and the planet. In this perspective article, we discuss how the rising use of these platform-to-consumer delivery operations may impede advances toward the United Nations 2030 Sustainable Development Goals (SDGs). Specifically, online food delivery services may disrupt SDGs that address good health and wellbeing, responsible consumption and production, climate action and decent work and economic growth. To mitigate potential negative impacts of these meal delivery apps, we have proposed a research and policy agenda that is aligned with entry points within a systems approach identified by the World Health Organization. Food industry reforms, synergised public health messaging and continuous monitoring of the growing impact of online food delivery should be considered for further investigation by researchers, food industry, governments, and policy makers.

Effect of severe compared with moderate energy restriction on physical activity among postmenopausal female adults with obesity: a prespecified secondary analysis of the Type of Energy Manipulation for Promoting optimum metabolic health and body composition in Obesity (TEMPO) Diet randomized controlled Trial.

BACKGROUND: An under-explored strategy for increasing physical activity is the dietary treatment of obesity, but empirical evidence is lacking. OBJECTIVES: We aimed to compare the effects of weight loss via severe as opposed to moderate energy restriction on physical activity over 36 mo. METHODS: A total of 101 postmenopausal female adults (45-65 y, BMI 30-40 kg/m2, <180 min/wk of structured exercise) were randomly assigned to either 12 mo of moderate energy restriction (25%-35% of energy requirement) with a food-based diet, or a severe intervention involving 4 mo of severe energy restriction (65%-75% of energy requirement) with a total meal replacement diet, followed by 8 mo of moderate energy restriction. Physical activity was encouraged, but no tailored or supervised exercise prescription was provided. Physical activity was assessed with an accelerometer worn for 7 d before baseline (0 mo) and 0.25, 1, 4, 6, 12, 24, and 36 mo after intervention commencement. RESULTS: Compared with the moderate group, the severe group exhibited greater mean: total volume of physical activity; duration of moderate-to-vigorous-intensity physical activity (MVPA); duration of light-intensity physical activity; step counts, as well as lower mean duration of sedentary time. All these differences (except step counts) were apparent at 6 mo [e.g., 1006 metabolic equivalent of task (MET)-min/wk; 95% CI: 564, 1449 MET-min/wk for total volume of physical activity], and some were also apparent at 4 and/or 12 mo. There were no differences between groups in the 2 other outcomes investigated (self-efficacy to regulate exercise; and proportion of participants meeting the WHO's 2020 Physical Activity Guidelines for MVPA). When the analyses were adjusted for weight at each time point, the differences between groups were either attenuated or abolished. CONCLUSIONS: Among female adults with obesity, including a dietary component to reduce excess body weight-notably one involving severe energy restriction-could potentially enhance the effectiveness of physical activity interventions.This trial was registered at www.anzctr.org.au as ACTRN12612000651886.

In Vitro and In Vivo Inhibition of MATE1 by Tyrosine Kinase Inhibitors.

The membrane transport of many cationic prescription drugs depends on facilitated transport by organic cation transporters of which several members, including OCT2 (SLC22A2), are sensitive to inhibition by select tyrosine kinase inhibitors (TKIs). We hypothesized that TKIs may differentially interact with the renal transporter MATE1 (SLC47A1) and influence the elimination and toxicity of the MATE1 substrate oxaliplatin. Interactions with FDA-approved TKIs were evaluated in transfected HEK293 cells, and in vivo pharmacokinetic studies were performed in wild-type, MATE1-deficient, and OCT2/MATE1-deficient mice. Of 57 TKIs evaluated, 37 potently inhibited MATE1 function by >80% through a non-competitive, reversible, substrate-independent mechanism. The urinary excretion of oxaliplatin was reduced by about 2-fold in mice with a deficiency of MATE1 or both OCT2 and MATE1 (p < 0.05), without impacting markers of acute renal injury. In addition, genetic or pharmacological inhibition of MATE1 did not significantly alter plasma levels of oxaliplatin, suggesting that MATE1 inhibitors are unlikely to influence the safety or drug-drug interaction liability of oxaliplatin-based chemotherapy.

Diet Quality following Total Meal Replacement Compared with Food-Based Weight-Loss Diets in Postmenopausal Women with Obesity: A Secondary Analysis of the TEMPO Diet Trial.

BACKGROUND: Severely energy-restricted diets that utilize meal-replacement products are the most effective dietary treatment for obesity. However, there are concerns they may fail to educate individuals on how to adopt a healthy food-based diet after weight loss. OBJECTIVES: The aim of this research was to compare changes in diet quality following total meal replacement compared with food-based weight-loss diets. METHODS: In this secondary analysis of a randomized controlled trial, 79 postmenopausal women aged 45-65 y, with a BMI (in kg/m2) of 30-40, were randomly assigned to either a total meal-replacement diet (energy intake restricted by 65-75% relative to requirements) for 16 wks, followed by a food-based diet (energy intake restricted by 25-35% relative to requirements) until 52 wks, or the food-based diet for the entire 52-wk period. Diet quality was scored at baseline and 52 wks using the Healthy Eating Index for Australian Adults, with score changes compared between groups using an independent t test. RESULTS: Diet quality improved from baseline in both groups, but less so in the total meal-replacement group, with a mean (SD) increase of 3.6 (10.8) points compared with 11.8 (13.9) points in the food-based group, resulting in a mean between-group difference of -8.2 (P = 0.004; 95% CI: -13.8, -2.7) points. This improvement in diet quality within both groups was mostly driven by a reduction in the intake of discretionary foods. Intake remained below the recommendations at 52 wks for 4 of the 5 food groups in both dietary interventions. CONCLUSIONS: In postmenopausal women with obesity, weight-loss interventions that involve either a total meal-replacement diet or a food-based diet both improve diet quality, however, not sufficiently to meet recommendations. This highlights the importance of addressing diet quality as a part of all dietary weight-loss interventions. This trial is registered with the Australia and New Zealand Clinical Trials Registry as 12612000651886.