A comparison of the World Health Organisation's HEAT model results using a non-linear physical activity dose response function with results from the existing tool

IntroductionThe WHO-Europe’s Health Economic Assessment Tool is a tool used to estimatethe costs and benefits of changes in walking and cycling. Due to data limitationsthe tool’s physical activity module assumes a linear dose response relationship be-tween physical activity and mortality.MethodsThis study estimates baseline population physical activity distributions for 44 coun-tries included in the HEAT. It then compares, for three different scenarios, the re-sults generated by the current method, using a linear dose-response relationship,with results generated using a non-linear dose-response relationship.ResultsThe study finds that estimated deaths averted are relatively higher (lower) using thenon-linear effect in countries with less (more) active populations. This difference islargest for interventions which affect the activity levels of the least active the most.Since more active populations, e.g. in Eastern Europe, also tend to have lowerValue of a Statistical Life estimates the net monetary benefit estimated by the sce-narios are much higher in western-Europe than eastern-Europe.ConclusionsUsing a non-linear dose response function results in materially different estimateswhere populations are particularly inactive or particularly active. Estimating base-line distributions is possible with limited additional data requirements, although themethod has yet to be validated. Given the significant role of the physical activitymodule within the HEAT tool it is likely that in the evaluation of many interventionsthe monetary benefit estimates will be sensitive to the choice of the physical activitydose response function.

The risk of perchlorate and iodine on the incidence of thyroid tumors and nodular goiter: a case-control study in southeastern China

Background The incidence rates of thyroid tumors and nodular goiter show an upward trend worldwide. There are limited reports on the risk of perchlorate and iodine on thyroid tumors, but evidence from population studies is scarce, and their impact on thyroid function is still uncertain. Therefore, the objective of this study was to investigate the association of perchlorate and iodine with the risk of nodular goiter (NG), papillary thyroid microcarcinoma (PTMC), and papillary thyroid carcinoma (PTC) and to assess the correlation between perchlorate and iodine with thyroid function indicators. Methods A case–control population consisting of 184 pairs of thyroid tumors and nodular goiter matched by gender and age (±2 years) was recruited in this study. Serum and urine samples were collected from each participant. Thyroid function indicators in serum were tested by automatic chemical immunofluorescence, and perchlorate and iodine levels in urine were determined by ultra-high performance liquid chromatography tandem-mass spectrometry and inductively coupled plasma-mass spectrometry, respectively. Conditional logistic regressions and multiple linear regressions were used to analyze the associations. Results Urinary perchlorate concentration was significantly higher in total cases, NG and PTC than in the corresponding controls (P < 0.05). Perchlorate was positively associated with PTC (OR = 1.058, 95% CI: 1.009, 1.110) in a non-linear dose–response relationship, but there was no association between perchlorate and NG or PTMC. Iodine was not associated with the risk of thyroid tumors and NG and did not correlate with the thyroid function indicators. Furthermore, perchlorate showed a positive correlation with thyroid stimulating hormone (TSH) at iodine adequate levels (P < 0.05), and a negative correlation with free triiodothyronine (FT3) and a positive correlation with thyroglobulin antibody (TgAb) at iodine more than adequate or excess levels (P < 0.05). Conclusions Perchlorate can increase the risk of PTC in a non-linear dose–response relationship and disturb the thyroid hormone homeostasis and thyroid autoantibody levels.

Ultra-Processed Food Consumption and Adult Diabetes Risk: A Systematic Review and Dose-Response Meta-Analysis

(1) Background: Recent individual studies have demonstrated that consumption of ultra-processed food (UPF) may be related to type two diabetes mellitus (T2DM). We aimed to synthesize the results from these individual studies by conducting an updated systematic review and meta-analysis of observational studies evaluating the association between UPF consumption and the risk of T2DM. (2) Methods: A systematic search was conducted using ISI Web of Science, PubMed/MEDLINE and Scopus electronic databases from inception up to August 2021. Data were extracted from five studies (one cross-sectional study and four cohort studies, totaling 230,526 adults from four different countries). Risk ratios (RR) of pooled results were estimated using a random-effects model. (3) Results: Our results revealed that higher UPF consumption was significantly associated with an increased risk of T2DM (RR = 1.74; 95% CI: 1.36, 2.22; I2 = 68.9%; p < 0.001; n = 5). Linear dose-response analysis indicated that each 10% increase in UPF consumption (kcal/d) was associated with a 15% higher risk of T2DM (RR = 1.15; 95% CI: 1.06, 1.26; I2 = 86.0%; p < 0.001; n = 5) among adults. Non-linear dose-response analysis demonstrated a positive linear association between UPF consumption and T2DM (pnonlinearity = 0.13, pdose-response < 0.001; n = 5) among adults. (4) Conclusions: A higher intake of UPF was significantly associated with an increased risk of T2DM. However, underlying mechanisms remain unknown and future experimental studies are warranted.

Chemotherapy-Induced Cachexia and Model-Informed Dosing to Preserve Lean Mass in Cancer Treatment

Although chemotherapy is a standard treatment for cancer, it comes with significant side effects. In particular, certain agents can induce severe muscle loss, known as cachexia, worsening patient quality of life and treatment outcomes. 5-fluorouracil, an anti-cancer agent used to treat several cancers, has been shown to cause muscle loss. Experimental data indicates a non-linear dose-dependence for muscle loss in mice treated with daily or week-day schedules. We present a mathematical model of chemotherapy-induced muscle wasting that captures this non-linear dose-dependence. Area-under-the-curve metrics are proposed to quantify the treatment’s effects on lean mass and tumour control. Model simulations are used to explore alternate dosing schedules, aging effects, and morphine use in chemotherapy treatment with the aim of better protecting lean mass while actively targeting the tumour, ultimately leading to improved personalization of treatment planning and improved patient quality of life.Author SummaryIn this paper we present a novel mathematical model for muscle loss due to cancer chemotherapy treatment. Loss of muscle mass relates to increased drug toxicity and side-effects, and to decreased patient quality of life and survival rates. With our model, we examine the therapeutic efficacy of various dosing schedules with the aim of controlling a growing tumour while also preserving lean mass. Preservation of body composition, in addition to consideration of inflammation and immune interactions, the gut microbiome, and other systemic health measures, may lead to improved patient-specific treatment plans that improve patient quality of life.

Safety, tolerability, pharmacokinetics and immunogenicity of a monoclonal antibody (SCTA01) targeting SARS-CoV-2 in healthy adults: A randomized, double-blind, placebo-controlled, phase I study

SCTA01 is a novel monoclonal antibody with promising prophylactic and therapeutic potential for COVID-19. This study aimed to evaluate the safety, tolerability, pharmacokinetics (PK) and immunogenicity of SCTA01 in healthy adults. This was a randomized, double-blind, placebo-controlled, dose-escalation phase I clinical trial. Healthy adults were randomly assigned into the following four cohorts, Cohort 1 (n=5, 3:2), Cohort 2 (n=8, 6:2), Cohort 3 and Cohort 4 (both n=10, 8:2), to receive SCTA01 (5, 15, 30 and 50 mg/kg, respectively) versus placebo. All participants were followed up for clinical, laboratory, PK and immunogenicity assessments for 84 days. The primary outcomes were the dose-limiting toxicity (DLT) and maximal tolerable dose (MTD), and the secondary outcomes included PK parameters, immunogenicity and adverse events (AE). Of the 33 participants, 18 experienced treatment-related AEs; the frequency was 52.0% (13/25) in participants receiving SCTA01 and 62.5% (5/8) in those receiving placebo. All AEs were mild. There was no serious AE or death. No DLT was reported, and MTD of SCTA01 was not reached. SCTA01 with a dose range 5-50mg/kg had nearly linear dose-proportional increases in C max and AUC parameters. An anti-drug antibody response was detected in four (16.0%) participants receiving SCTA01, with low titers, between the baseline and day 28, but all became negative later. In conclusion, SCTA01 up to 50mg/kg was safe and well-tolerated in healthy participants. Its PK parameters were nearly linear dose-proportional.

Mitochondrial DNA 4977 bp Deletion in Peripheral Blood Is Associated With Polycystic Ovary Syndrome

BackgroundPolycystic ovary syndrome (PCOS) is a common endocrine disorder worldwide. We aimed to examine the associations of two mitochondrial DNA (mtDNA) biomarkers in the peripheral blood, mtDNA copy number (CN), and mtDNA4977 deletion rate (DR), with PCOS in a clinical setting.MethodsWe performed a study involving 263 women with PCOS and 326 age-matched controls between June 2015 and June 2019. The mtDNA CN and mtDNA4977 DR were measured using multiplex probe-based qPCR. The associations of the mtDNA CN and mtDNA4977 DR with the risk of PCOS were estimated using logistic regression.ResultsAnalysis of the associations between mtDNA biomarkers and PCOS indicate that the mtDNA CN (P = 0.003) and mtDNA4977 DR (P &lt; 0.001) in PCOS patients were significantly higher than those in the controls. After adjusting for the body mass index, luteinizing hormone/follicle-stimulating hormone ratio, and testosterone level, only higher mtDNA4977 DR was associated with PCOS (odds ratio 1.053, 95% confidence interval 1.024 to 1.083; P &lt; 0.001). The linear dose-response trends of the mtDNA4977 DR were also supported by the quartile analysis.ConclusionMultivariable models suggest that mtDNA4977 DR levels are strongly associated with PCOS and represent an independent risk factor for PCOS. Further investigation of the utility of mtDNA as a biomarker for PCOS is warranted.

Ethnic Differences in the Association Between Body Mass Index and Type 2 Diabetes Risk: A Meta-Analysis of Prospective Cohort Studies

Objectives The association between body mass index (BMI) and total body adiposity differs across ethnic groups. For instance, South Asians (SA) and East Asians (EA) have lower body fat for a given BMI level than Europeans, while the opposite is true for African-Caribbeans (AC). This suggests that the relationship between BMI and type 2 diabetes (T2D) risk may also vary depending on ethnicity. We conducted a meta-analysis to investigate whether the association between BMI and the risk of T2D differs across ethnic groups. Methods MEDLINE, EMBASE and Web of Science were searched up to July 2020. We included prospective cohort studies of &gt;2 years, which investigated the association between BMI and T2D incidence among adults of a specified ethnicity. Linear and non-linear dose-response meta-analyses were performed using random effects models, with subgroup analyses by ethnicity. The heterogeneity among studies was estimated using the Cochran Q test and I2 statistic. Study quality was assessed with the Newcastle-Ottawa Scale. Results 54 studies were included. Cohorts were stratified into the following ethnic subgroups: AC (N = 67,453), EA (N = 1,012,135), European (N = 206,424), Indigenous (N = 10,533), Latin American (LA) (N = 4,669), SA (N = 9,395), and Southeast Asian (SEA) (N = 51,129). Linear dose-response associations between 1 kg/m2 increase in BMI and T2D were observed for the SEA (RR = 1.26; 95% CI, 1.10, 1.30) and SA (RR = 1.11; 95% CI: 1.04, 1.19) subgroups with no evidence of departure from linearity. Associations departed from linearity for all other subgroups. At a BMI level of 30 kg/m2, the non-linear dose-response curves for each of the other subgroups displayed the following risk ratios; AC: RR = 3.13 (95% CI, 1.95, 5.02), EA: RR = 2.39 (95% CI, 1.96, 2.92), European: RR = 7.41 (95% CI, 3.88, 14.18), Indigenous: RR = 8.15 (95% CI, 6.07; 10.95), and LA: RR = 12.82 (95% CI, 5.50, 29.92). For all subgroups, there was a high degree of interstudy heterogeneity (I2 &gt; 75%). Conclusions Our findings indicated that the association between BMI and the risk of T2D differs across ethnic groups, suggesting that ethnic-specific BMI cut-offs could be helpful in identifying cardiometabolic risk profiles across different populations. Funding Sources Canadian Institutes for Health Research.

Neuromodulators enable overlapping synaptic memory regimes and nonlinear transition dynamics in recurrent neural networks

Mood, arousal, and other internal neural states can drastically alter behavior, even in identical external circumstances - the proverbial glass half full or empty. Neuromodulators are critical in controlling these internal neural states, and aberrations in neuromodulatory processes are linked to various neuropsychiatric disorders. To study how neuromodulators influence neural behavior, we modeled neuromodulation as a multiplicative factor acting on synaptic transmission between neurons in a recurrent neural network. We found this simple mechanism could vastly increase the computational capability and flexibility of a neural network by enabling overlapping storage of synaptic memories able to drive diverse, even diametrically opposed, behaviors. We analyzed how local or cell-type specific neuromodulation changes network activity to support such behaviors and reproduced experimental findings of Drosophila starvation behavior. We revealed that circuits have idiosyncratic, non-linear dose-response properties that can be different for chemical versus electrical modulation. Our findings help explain how neuromodulation "unlocks" specific behaviors with important implications for neuropsychiatric therapeutics.