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Background Relative measures, including risk ratios (RRs) and odds ratios (ORs), are reported in many epidemiological studies. RRs represent how many times a condition is likely to develop when exposed to a risk factor. The upper limit of RRs is the multiplicative inverse of the baseline incidence. Ignoring the upper limits of RRs can lead to reporting exaggerated relative effect sizes. Objectives This study aims to demonstrate the importance of such upper limits for effect size reporting via equations, examples, and simulations and provide recommendations for the reporting of relative measures. Methods Equations to calculate RRs and their 95% confidence intervals (CIs) were listed. We performed simulations with 10,000 simulated subjects and three population variables: proportions at risk (0.05, 0.1, 0.3, 0.5, and 0.8), baseline incidence (0.05, 0.1, 0.3, 0.5, and 0.8), and RRs (0.5, 1.0, 5.0, 10.0, and 25.0). Subjects were randomly assigned with a risk based on the set of proportions-at-risk values. A disease occurred based on the baseline incidence among those not at risk. The incidence of those at risk was the product of the baseline incidence and the RRs. The 95% CIs of RRs were calculated according to Altman. Results The calculation of RR 95% CIs is not connected to the RR upper limits in equations. The RRs in the simulated populations at risk could reach the upper limits of RRs: multiplicative inverse of the baseline incidence. The upper limits to the derived RRs were around 1.25, 2, 3.3, 10, and 20, when the assumed baseline incidence rates were 0.8, 0.5, 0.3, 0.2, and 0.05, respectively. We demonstrated five scenarios in which the RR 95% CIs might exceed the upper limits. Conclusions Statistical significance does not imply the RR 95% CIs not exceeding the upper limits of RRs. When reporting RRs or ORs, the RR upper limits should be assessed. The rate ratio is also subject to a similar upper limit. In the literature, ORs tend to overestimate effect sizes. It is recommended to correct ORs that aim to approximate RRs assuming outcomes are rare. A reporting guide for relative measures, RRs, ORs, and rate ratios, is provided. Researchers are recommended to report whether the 95% CIs of relative measures, RRs, ORs, and rate ratios, overlap with the range of upper limits and discuss whether the relative measure estimates may exceed the upper limits.

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Background: In general, only few studies are dedicated to blood pressure behavior under physical stress in children and adolescents. Even less is published about the blood pressure behavior of young high-performance athletes on the ergometer. For this reason, we evaluated the blood pressure behavior under stress compared to non-athletes in a large collective (n = 739) of young high-performance athletes (age 10-20 years, mean 15.8 years, male 442, female 297) of different sports. A complete echocardiographic examination was available in all athletes. Result: Regardless of gender, the young competitive athletes achieved significantly higher maximum blood pressure values than investastigated populations from previous studies. Based on the data obtained, blood pressure percentiles are now defined explicitly for junior athletes across sports as well as age- and gender-dependent, which did not exist in this form of normal values for the special clientele of young competitive athletes. The echocardiographic examinations demonstrated stress-induced cardiac adaptation adaptations in the majority of athletes, which thus correlate with the comparatively higher stress blood pressures compared to non-athletes. Conclusion: For the first time, blood pressure percentiles for exercise tests on the ergometer for age groups and gender in high performance athletes are defined based on a comparatively large collective of young competitive athletes. Upper limits were determined, in particular for systolic blood pressure under stress, and categorized according to gender and age. Performance diagnosticians and physicians are now enabled to make a more accurate assessment of the corresponding blood pressure regulation of young athletes under exercise conditions.

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Zinc supplementation reduces morbidity, but evidence suggests that excessive intakes can have negative health consequences. Current guidelines of upper limits (ULs) of zinc intake for young children are extrapolated from adult data. This systematic review (PROSPERO; registration no. CRD42020215187) aimed to determine the levels of zinc intake at which adverse effects are observed in young children. Studies reporting potential adverse effects of zinc intake in children aged 0-3 y were identified (from inception to August 2020) in MEDLINE, Embase, and the Cochrane Library, with no limits on study design. Adverse clinical and physical effects of zinc intake were synthesized narratively, and meta-analyses of biochemical outcomes were conducted. Random effects models were used to generate forest plots to examine the evidence by age category, dose, dose duration, chemical formula of zinc, and zinc compared with placebo. The Joanna Briggs Institute Critical Appraisal Checklist, Cochrane Risk of Bias 2, and Grading of Recommendations Assessment, Development, and Evaluation (GRADE) guideline were employed to assess risk of bias and to appraise the certainty of evidence. Fifty-eight studies assessed possible adverse effects of zinc doses ranging from 3 to 70 mg/d. Data from 39 studies contributed to meta-analyses. Zinc supplementation had an adverse effect on serum ferritin, plasma/serum copper concentration, serum transferrin receptor, hemoglobin, hematocrit, and the odds of anemia in ≥1 of the subgroups investigated. Lactulose:mannitol ratio was improved with zinc supplementation, and no significant effect was observed on C-reactive protein, erythrocyte superoxide dismutase, zinc protoporphyrin, blood cholesterol, and iron deficiency anemia. The certainty of the evidence, as assessed using GRADE, was very low to moderate. Although possible adverse effects of zinc supplementation were observed in some subgroups, it is unclear whether these findings are clinically important. The synthesized data can be used to undertake a dose-response analysis to update current guidelines of ULs of zinc intake for young children.

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Background & Aims: Psychological and life stressors may impact autoimmune hepatitis (AIH) disease activity and increase relapse risk. Mindfulness-based stress reduction (MBSR) is a validated course that reduces stress reactivity, and improves stress and emotion regulation. This single-arm exploratory pilot study of adult patients with AIH aimed to define the impact of an 8-week MBSR program on quality of life, disease activity, and cytokine mediators. Methods: The perceived stress survey-10 (PSS) and the brief self-control scale (BSCS) measured subjective distress and self-control. Serum alanine aminotransferase (ALT) and cytokine levels were measured, and immunosuppressant doses recorded. Results: Seventeen patients completed the MBSR program. Post-MBSR, 71% (n = 12) showed PSS score improvement at 8 weeks vs. baseline (median 15 vs. 21, p = 0.02). At 12 months, PSS improvement persisted vs. baseline (median 15 vs. 21, p = 0.02). Post-MBSR, 71% (n = 12) showed BSCS score improvement at 8 weeks vs. baseline (median 4.1 vs. 3.8, p = 0.03). At 12 months, the median BSCS score remained significant (3.9 vs. 3.8, p = 0.03). After the 8-week MBSR, the 35% of patients with ALT >34 U/L had a median ALT reduction (44.5 vs. 71.5 U/L, p = 0.06), whereas the 71% of patients on prednisone had significant dose reductions (5.75 vs. 10 mg, p = 0.02) which persisted at 12 months vs. baseline (3.75 vs. 10 mg, p = 0.02) without a compensatory increase in steroid-sparing dosing. Significant improvement was noted in peripheral blood cytokine levels (IL-6, IL-8, IL-10, IL-17, IL-23, and sCD74/MIF ratio) from baseline to 8 weeks. Conclusions: MBSR significantly improved perceived stress and self-control scores while decreasing ALT levels, steroid requirements, and inflammatory cytokine levels in this pilot study in adult AIH. Stress modification may impact quality of life and disease activity, and should be further evaluated as an intervention in AIH. Clinical Trials registration: This study is registered at ClinicalTrials.gov (NCT02950077). Lay summary: Autoimmune hepatitis can reduce quality of life and mental health, while stress may impact autoimmune hepatitis itself. We piloted mindfulness-based stress reduction as a strategy to reduce stress in adult patients with autoimmune hepatitis and found that the intervention reduced perceived stress and may have also impacted the disease by improving inflammation and medication needs. Stress reduction should be further studied to improve quality of life and possibly to impact disease activity in autoimmune hepatitis.

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Vitamin A deficiency is a major health risk for infants and children in low- and middle-income countries. This scoping review identified, quantified, and mapped research for use in updating nutrient requirements and upper limits for vitamin A in children aged 0 to 48 months, using health-based or modelling-based approaches. Structured searches were run on Medline, EMBASE, and Cochrane Central, from inception to 19 March 2021. Titles and abstracts were assessed independently in duplicate, as were 20% of full texts. Included studies were tabulated by question, methodology and date, with the most relevant data extracted and assessed for risk of bias. We found that the most recent health-based systematic reviews and trials assessed the effects of supplementation, though some addressed the effects of staple food fortification, complementary foods, biofortified maize or cassava, and fortified drinks, on health outcomes. Recent isotopic tracer studies and modelling approaches may help quantify the effects of bio-fortification, fortification, and food-based approaches for increasing vitamin A depots. A systematic review and several trials identified adverse events associated with higher vitamin A intakes, which should be useful for setting upper limits. We have generated and provide a database of relevant research. Full systematic reviews, based on this scoping review, are needed to answer specific questions to set vitamin A requirements and upper limits.

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Objective:To investigate the pathological characteristics in chronic HBV infection patients with different upper limits of alanine aminotransferase (ALT) normal values and the influencing factors of liver tissue injury.Methods:The clinical data of 667 chronic HBV infection patients with ALT<40 U/L and HBV DNA loads >30 IU/mL who received liver biopsy in Zhenhai District Hospital of Traditional Chinese Medicine and Hwa Mei Hospital from January 2014 to December 2020 were retrospectively analyzed. The enrolled patients were divided into ALTⅠ group (<30 U/L for males, <19 U/L for females), ALTⅡ group (≥30 U/L and <35 U/L for males, ≥19 U/L and <25 U/L for females) and ALT Ⅲ group (≥35 U/L and <40 U/L for males, ≥25 U/L and <40 U/L for females). According to the degree of liver inflammation (G) and fibrosis stage (S), the enrolled patients were divided into non-significant damage group (G<2 and S<2) and significant damage group (≥G2 or/and ≥S2). Ridit analysis was used to compare the G/S composition ratio among three ALT groups, Logistic regression was used to analyze the risk factors of liver injury, the receiver operating characteristic curve (ROC) and the area under the curve (AUC) were used to analyze the optimal diagnostic threshold of ALT.Results:There were significant differences in the composition ratio of G and S among the three ALT groups( χ2=13.926 and 14.702, both P<0.001). The constituent ratios of significant liver pathological damage in the three groups of ALT levels were 26.05% (99/380), 32.03% (41/128) and 46.54% (74/159), respectively( χ2=21.596, P<0.001). Multivariate logistic regression analysis showed that high white/globulin ratio and PLT counts( OR=0.246 and 0.986, both P<0.001)were the protective factors for liver tissue injury; while negative HBcAg staining and elevated ALT and GGT levels ( OR=3.797, 1.053 and 1.013, P<0.001 or <0.05) were the risk factors of liver injury. ROC curve demonstrated the ALT threshold of liver tissue damage in male and female patients were 25.6 U/L and 25.5 U/L. Conclusions:In chronic HBV infection patients with normal ALT, with the increase of ALT level, the degree of liver tissue pathological damage may become more severe. The study demonstrates that it is necessary to lower the ALT threshold for protecting patients from liver tissue pathological damage.

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Coronavirus disease 2019 (COVID-19), an infection caused by severe acute respiratory syndrome coronavirus-type 2 (SARS-CoV-2), has emerged as a serious threat to public health. Liver transplant (LT) recipients may be at increased risk of acquisition of SARS-CoV-2 infection and higher morbidity and mortality due to constant contact with health-care services, the use of immunosuppressants and frequent comorbidities. In the first part of this review we discuss (1) the epidemiology and risk factors for SARS-CoV-2 infection in LT recipients; (2) the clinical and laboratory features of COVID-19 in this specific population, highlighting differences in presenting signs and symptoms with respect to general populations and (3) the natural history and prognostic factors in LT recipients hospitalized with COVID-19, with particular focus on the possible role of immunosuppression. Thereafter, we review the potential therapeutic options for COVID-19 treatment and prevention. Specifically, we give an overview of current practice in immunosuppressant regimen changes, showing the potential benefits of this strategy, and explore safety and efficacy issues of currently approved drugs in LT recipients. The last topic is dedicated to the potential benefits and pitfalls of vaccination.

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We examined international regulatory developments related to the use of proteinogenic amino acids in human nutrition and concluded that the current risk-assessment practices tend to focus exclusively on setting maximum daily limits. In this brief review we argue that controlling the standards of purity and ingredient quality are the key safety issues that should be considered during risk assessment. Moreover, if maximum intake limits on amino acids are implemented, they should be defined using a well-established rationale for the health risks associated with high intakes. This would avoid setting limits that are so low that they render the dietary supplements ineffective and which, therefore, could mislead the consumer. We further suggest that there should be greater regional concordance in how the use of amino acids as ingredients is regulated and use the capacity of industry to oversee pre-competitive issues, such as standards of purity and scientific research on the safety of generic ingredients. Our arguments are based on clinical safety scientific research and oversights of amino acid purity standards conducted in the last decade by the not-for-profit international association, the International Council on Amino Acid Science.

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Excessive micronutrient intake causes a variety of adverse health effects, depending on dose and duration. The risk of excess intake carries significant implications for micronutrient delivery interventions, particularly when such programs are overlapping. To minimize risk and provide public health guidance, several countries and the Food and Agriculture Organization of the United Nations/World Health Organization have set upper intake levels (ULs) for various life-stage populations using the risk assessment framework. However, there is a lack of international consensus on the actual ULs due to variability in application of this framework and a scarcity of evidence from which to draw upon, especially for children. Often ULs for children are established through a downward weight-based extrapolation from adult ULs, which is not always appropriate. The published ULs of nine organizations are compared, recent population nutrient intake evidence is presented, and the toxic effects of key minerals and vitamins are reviewed. Finally, the evidence for toxicity and setting of ULs for each nutrient is discussed including a comment on our degree of confidence in the strength of existing individual ULs. Challenges with risk assessment and opportunities for strengthening the definition of ULs are discussed.

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Maximal physical performances are powerful and accurate biomarkers in the understanding of age-related changes during the aging process. Previous studies have characterized age-related changes from Caenorhabditis elegans to Homo sapiens. We characterized changes in this pattern for H. sapiens, decade by decade, from 1970 to 2017. Using 286,916 performances related to age from the world's best performances in each age group, we measured the relative change of 10 different running and jumping events for both women and men. We compared the change in sexual dimorphism with age and showed that the gender gap in maximal performance regarding age increases gradually, especially after the age of 50. Between 1970 and 2017, the performances for all age groups in all events have slightly progressed. However, during the last decades, the relative progression of the best performances for all age groups has decreased in both range and frequency, suggesting that age-related maximal physical performances for H. sapiens are reaching their physiological limits.

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To assess the efficacy and short-term outcomes of adherence to statin therapy among coronary heart disease (CHD) patients following their hospital discharge, we enrolled 615 CHD patients who were prescribed statins from The First Affiliated Hospital of Chongqing Medical University in China between February 1st and October 31st of 2013. Statin adherence was evaluated by identifying the proportion of patients who remained adherent or became non-adherent to statin therapy over 4-8 months post-discharge from the hospital. The composite outcomes included all-cause mortality and re-hospitalization with cardiovascular disease. We found that 15.9% patients were non-adherent to their statin therapies and that coronary artery stenosis<75% (OR = 3.433, 95% CI: 2.191-5.380, p < 0.001) and adverse effects (OR = 2.542, 95% CI: 1.327-4.869, p = 0.005) both clearly contributed to poor adherence. The primary self-reported reasons for non-adherence included a lack of knowledge about the benefits of statin therapy (36.7%), the treatment being halted at the advice of their doctor (19.4%), and the difficulty in obtaining statins (12.2%). Non-adherence to statin therapy was significantly associated with an increased risk of cardiovascular events (OR = 1.741, 95% CI: 1.035-2.929, p = 0.037). In conclusion, CHD patients with moderate stenosis or adverse effects tended to have poor statin adherence, and this was significantly associated with increased cardiovascular events. We should strengthen education of the importance of statin therapy for both patients and doctors and facilitate the ability of patients to obtain their statin medication. Clinical Study Register Code: ChiCTR-EPC-16007839.

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Echoing scientific and industrial progress, the Twentieth century was an unprecedented period of improvement for human capabilities and performances, with a significant increase in lifespan, adult height, and maximal physiological performance. Analyses of historical data show a major slow down occurring in the most recent years. This triggered large and passionate debates in the academic scene within multiple disciplines; as such an observation could be interpreted as our upper biological limits. Such a new phase of human history may be related to structural and functional limits determined by long term evolutionary constraints, and the interaction between complex systems and their environment. In this interdisciplinary approach, we call into question the validity of subsequent forecasts and projections through innovative and related biomarkers such as sport, lifespan, and height indicators. We set a theoretical framework based on biological and environmental relevance rather than using a typical single-variable forecasting approach. As demonstrated within the article, these new views will have major social, economical, and political implications.

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The control of risk and harm in human research often calls for the establishment of upper limits of risk of pain, suffering, and distress that investigators must not exceed. Such upper limits are uncommon in animal research, in which limits of acceptability are usually left to the discretion of individual investigators, institutions, national inspectors, or ethics review committees. We here assess the merits of the European Directive 2010/63/EU on the Protection of Animals Used for Scientific Purposes and its accompanying instruments, such as guides and examples. These documents present a body of legislation governing animal research in the European Union. We argue that the directive supplies a promising approach, but one in need of revision. We interpret the directive's general conception of upper limits and show its promise for the establishment of high-quality policies. We provide a moral rationale for such policies, address the problem of justified exceptions to established upper limits, and show when causing harm is and is not wrongful. We conclude that if the standards we propose for improving the directive are not realized in the review of research protocols, loose and prejudicial risk-benefit assessments may continue to be deemed sufficient to justify morally questionable research. However, a revised EU directive and accompanying instruments could have a substantial influence on the ethics of animal research worldwide, especially in the development of morally sound legal frameworks.

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2-Phosphonomethyl pentanedioic acid (2-PMPA) is a potent and selective inhibitor of glutamate carboxypeptidase-II, an enzyme which catabolizes the abundant neuropeptide N-acetyl-aspartyl-glutamate (NAAG) to N-acetylaspartate (NAA) and glutamate. 2-PMPA demonstrates robust efficacy in numerous animal models of neurological disease, however its pharmacokinetics has not yet been fully described. 2-PMPA is a highly polar compound with multiple negative charges causing significant challenges for analysis in biological matrices. Here we report a derivatization method for the acidic groups that involved protein precipitation with acetonitrile followed by reaction with N-tert-butyldimethysilyl-N-methyltrifluoroacetamide (MTBSTFA). The silylated analyte with transitions (683→551.4) and the internal standard (669→537.2) were monitored by tandem mass spectrometry with electrospray positive ionization mode. The method was subsequently used to evaluate 2-PMPA pharmacokinetics in rats. Intraperitoneal administration of 100mg/kg 2-PMPA resulted in maximum concentration in plasma of 275µg/mL at 0.25h. The half-life, area under the curve, apparent clearance, and volume of distribution were 0.64h, 210µg×h/mL, 7.93mL/min/kg, and 0.44L/kg, respectively. The tissue/plasma ratios in brain, sciatic nerve and dorsal root ganglion were 0.018, 0.120 and 0.142, respectively. In summary, a sensitive analytical method for 2-PMPA is reported that can be employed for similarly charged molecules.

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For stratified 2 × 2 tables, standard approximate confidence limits can perform poorly from a strict frequentist perspective, even for moderate-sized samples, yet they are routinely used. In this paper, I show how to use importance sampling to compute highly accurate limits in reasonable time. The methodology is very general and simple to implement, and orders of magnitude are faster than existing alternatives.

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AIM: To investigate whether the disease progression of chronic hepatitis C patients with normal alanine aminotransferase (ALT) levels differs by ALT levels. METHODS: A total of 232 chronic hepatitis C patients with normal ALT (< 40 IU/L) were analyzed. The patients were divided into "high-normal" and "low-normal"ALT groups after determining the best predictive cutoff level associated with disease progression for each gender. The incidence of disease progression, as defined by the occurrence of an increase of ≥ 2 points in the Child-Pugh score, spontaneous bacterial peritonitis, bleeding gastric or esophageal varices, hepatic encephalopathy, the development of hepatocellular carcinoma, or death related to liver disease, were compared between the two groups. RESULTS: Baseline serum ALT levels were associated with disease progression for both genders. The best predictive cutoff baseline serum ALT level for disease progression was 26 IU/L in males and 23 IU/L in females. The mean annual disease progression rate was 1.2% and 3.9% for male patients with baseline ALT levels ≤ 25 IU/L (low-normal) and > 26 IU/L (high-normal), respectively (P = 0.043), and it was 1.4% and 4.8% for female patients with baseline ALT levels ≤ 22 IU/L (low-normal) and > 23 IU/L (high-normal), respectively (P = 0.023). ALT levels fluctuated during the follow-up period. During the follow-up, more patients with "high-normal" ALT levels at baseline experienced ALT elevation (> 41 IU/L) than did patients with "low-normal" ALT levels at baseline (47.7% vs 27.9%, P = 0.002). The 5 year cumulative incidence of disease progression was significantly lower in patients with persistently "low-normal" ALT levels than "high-normal" ALT levels or those who exhibited an ALT elevation > 41 U/L during the follow-up period (0%, 8.3% and 34.3%, P < 0.001). CONCLUSION: A "high normal" ALT level in chronic hepatitis C patients was associated with disease progression, suggesting that the currently accepted normal threshold of serum ALT should be lowered.

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