Nutritional epidemiology employs observational data to discover associations between diet and disease risk. However, existing analytic methods of dietary data are often sub-optimal, with limited ...incorporation and analysis of the correlations between the studied variables and nonlinear behaviours in the data. Machine learning (ML) is an area of artificial intelligence that has the potential to improve modelling of nonlinear associations and confounding which are found in nutritional data. These opportunities notwithstanding, the applications of ML in nutritional epidemiology must be approached cautiously to safeguard the scientific quality of the results and provide accurate interpretations. Given the complex scenario around ML, judicious application of such tools is necessary to offer nutritional epidemiology a novel analytical resource for dietary measurement and assessment and a tool to model the complexity of dietary intake and its relation to health. This work describes the applications of ML in nutritional epidemiology and provides guidelines to avoid common pitfalls encountered in applying predictive statistical models to nutritional data. Furthermore, it helps unfamiliar readers better assess the significance of their results and provides new possible future directions in the field of ML in nutritional epidemiology.
The comet assay is a widely used test for the detection of DNA damage and repair activity. However, there are interlaboratory differences in reported levels of baseline and induced damage in the same ...experimental systems. These differences may be attributed to protocol differences, although it is difficult to identify the relevant conditions because detailed comet assay procedures are not always published. Here, we present a Consensus Statement for the Minimum Information for Reporting Comet Assay (MIRCA) providing recommendations for describing comet assay conditions and results. These recommendations differentiate between 'desirable' and 'essential' information: 'essential' information refers to the precise details that are necessary to assess the quality of the experimental work, whereas 'desirable' information relates to technical issues that might be encountered when repeating the experiments. Adherence to MIRCA recommendations should ensure that comet assay results can be easily interpreted and independently verified by other researchers.
Abstract
The pathophysiology of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and especially of its complications is still not fully ...understood. In fact, a very high number of patients with COVID-19 die because of thromboembolic causes. A role of plasminogen, as precursor of fibrinolysis, has been hypothesized. In this study, we aimed to investigate the association between plasminogen levels and COVID-19-related outcomes in a population of 55 infected Caucasian patients (mean age: 69.8 ± 14.3, 41.8% female). Low levels of plasminogen were significantly associated with inflammatory markers (CRP, PCT, and IL-6), markers of coagulation (D-dimer, INR, and APTT), and markers of organ dysfunctions (high fasting blood glucose and decrease in the glomerular filtration rate). A multidimensional analysis model, including the correlation of the expression of coagulation with inflammatory parameters, indicated that plasminogen tended to cluster together with IL-6, hence suggesting a common pathway of activation during disease’s complication. Moreover, low levels of plasminogen strongly correlated with mortality in COVID-19 patients even after multiple adjustments for presence of confounding. These data suggest that plasminogen may play a pivotal role in controlling the complex mechanisms beyond the COVID-19 complications, and may be useful both as biomarker for prognosis and for therapeutic target against this extremely aggressive infection.
The comet assay is a well-accepted biomonitoring tool to examine the effect of dietary, lifestyle, environmental and occupational exposure on levels of DNA damage in human cells. With such a wide ...range of determinants for DNA damage levels, it becomes challenging to deal with confounding and certain factors are inter-related (e.g. poor nutritional intake may correlate with smoking status). This review describes the effect of intrinsic (i.e. sex, age, tobacco smoking, occupational exposure and obesity) and extrinsic (season, environmental exposures, diet, physical activity and alcohol consumption) factors on the level of DNA damage measured by the standard or enzyme-modified comet assay. Although each factor influences at least one comet assay endpoint, the collective evidence does not indicate single factors have a large impact. Thus, controlling for confounding may be necessary in a biomonitoring study, but none of the factors is strong enough to be regarded a priori as a confounder. Controlling for confounding in the comet assay requires a case-by-case approach. Inter-laboratory variation in levels of DNA damage and to some extent also reproducibility in biomonitoring studies are issues that have haunted the users of the comet assay for years. Procedures to collect specimens, and their storage, are not standardized. Likewise, statistical issues related to both sample-size calculation (before sampling of specimens) and statistical analysis of the results vary between studies. This review gives guidance to statistical analysis of the typically complex exposure, co-variate, and effect relationships in human biomonitoring studies.
The comet assay is widely used in human biomonitoring to measure DNA damage as a marker of exposure to genotoxic agents or to investigate genoprotective effects. Studies often involve small numbers ...of subjects, and design may be sub-optimal in other respects. In addition, comet assay protocols in use in different laboratories vary significantly. In spite of these difficulties, it is appropriate to carry out a pooled analysis of all available comet assay biomonitoring data, in order to establish baseline parameters of DNA damage, and to investigate associations between comet assay measurements and factors such as sex, age, smoking status, nutrition, lifestyle, etc. With this as its major objective, the ComNet project has recruited almost 100 research groups willing to share datasets. Here we provide a background to this project, discussing the history of the comet assay and practical issues that can critically affect its performance. We survey its diverse applications in biomonitoring studies, including environmental and occupational exposure to genotoxic agents, genoprotection by dietary and other factors, DNA damage associated with various diseases, and intrinsic factors that affect DNA damage levels in humans. We examine in depth the quality of data from a random selection of studies, from an epidemiological and statistical point of view.
•Micronuclei (MNi) are a biomarker of chromosomal damage and instability in humans.•Causes and consequences of MNi formation can be elucidated using molecular probes.•Chromosomes trapped in MNi can ...be shattered and become hypermutated.•DNA leaking from disrupted MNi is sensed by cGAS-STING and causes inflammation.•Association of MNi with many diseases has increased interest in their use in clinics.
Micronuclei (MNi) are among the most widely studied biomarkers of DNA damage and chromosomal instability in humans. They originate from chromosome fragments or intact chromosomes that are not included in daughter nuclei during mitosis. The main reasons for their formation are a lack of functional centromere in the chromosome fragments or whole chromosomes or defects in one or more of the proteins of the mitotic system that, consequently, fails to segregate chromosomes properly. Assays have been developed to measure MNi in peripheral blood lymphocytes, red blood cells as well as various types of epithelial cells such as buccal, nasal, urothelial and cervical cells. Some of the assays have been further developed into micronucleus (MN) cytome assays to include additional nuclear anomalies, cell death and nuclear division biomarkers. In addition, the use of molecular probes has been adopted widely for the purpose of understanding the mechanistic origin of MNi. MN assays in humans are used for the purpose of investigating the genotoxic effects of adverse environmental, life-style and occupational factors, genetic susceptibility to DNA damage, and for determining risk of accelerated aging and diseases affected by genomic instability such as developmental defects and cancer. The emerging new knowledge showing that chromosomes trapped in MNi can undergo a high rate of fragmentation and become massively re-arranged have highlighted the possibility that MN formation is not only a biomarker of induced DNA damage but also a mechanism that drives hypermutation. Furthermore, another line of recent research showed that DNA and chromatin leaking from disrupted MNi triggers the innate immune cGAS-STING mechanism that promotes inflammation which can cause a wide-range of age-related diseases if left unresolved. For these reasons, MN assays in humans have become an increasingly important biomarker of disease initiation and progression across all life-stages.
S100B is a calcium-binding protein secreted in central nervous system from astrocytes and other glia cells. High blood S100B levels have been linked to brain damage and psychiatric disorders. S100B ...levels have been reported to be higher in schizophrenics than healthy controls. To quantify the relationship between S100B blood levels and schizophrenia a systematic literature review of case-control studies published on this topic within July 3rd 2014 was carried out using three bibliographic databases: Medline, Scopus and Web of Science. Studies reporting mean and standard deviation of S100B blood levels both in cases and controls were included in the meta-analysis. The meta-Mean Ratio (mMR) of S100B blood levels in cases compared to controls was used as a measure of effect along with its 95% Confidence Intervals (CI). 20 studies were included totaling for 994 cases and 785 controls. Schizophrenia patients showed 76% higher S100B blood levels than controls with mMR = 1.76 95% CI: 1.44-2.15. No difference could be found between drug-free patients with mMR = 1.84 95%CI: 1.24-2.74 and patients on antipsychotic medication with mMR = 1.75 95% CI: 1.41-2.16). Similarly, ethnicity and stage of disease didn't affect results. Although S100B could be regarded as a possible biomarker of schizophrenia, limitations should be accounted when interpreting results, especially because of the high heterogeneity that remained >70%, even after carrying out subgroups analyses. These results point out that approaches based on traditional categorical diagnoses may be too restrictive and new approaches based on the characterization of new complex phenotypes should be considered.
Background and objectives
The identification of predictors of response to antiCGRP mAbs could favor tailored therapies and personalized treatment plans. This study is aimed at investigating ...predictors of ≥ 50%, ≥ 75% and 100% response at 24 weeks in patients with high-frequency episodic (HFEM: 8–14 days/month) or chronic migraine (CM).
Methods
This is a large, multicenter, cohort, real-life study. We considered all consecutive adult patients affected by HFEM or CM who were prescribed antiCGRP mAbs for ≥ 24 weeks in 20 headache centers. Patients were interviewed face-to-face using a shared semi-structured questionnaire carefully exploring socio-demographic and clinical characteristics. Patients received subcutaneous erenumab (70 mg or140 mg, monthly), galcanezumab (120 mg monthly, following a 240 mg loading dose), or fremanezumab (225 mg, monthly or 675 mg, quarterly) according to drug market availability, physician’s choice, or patient’s preference. The primary endpoint of the study was the assessment of ≥ 50% response predictors at 24 weeks. Secondary endpoints included ≥ 75% and 100% response predictors at 24 weeks.
Results
Eight hundred sixty-four migraine patients had been treated with antiCGRP mAbs for ≥ 24 weeks (erenumab: 639 pts; galcanezumab: 173 pts; fremanezumab: 55 pts). The ≥50% response (primary endpoint) in HFEM was positively associated with unilateral pain (UP) + unilateral cranial autonomic symptoms (UAs) (OR:4.23, 95%CI:1.57–11.4;
p
= 0.004), while in CM was positively associated with UAs (OR:1.49, 95%CI:1.05–2.11;
p
= 0.026), UP + UAs (OR:1.90, 95%CI:1.15–3.16;
p
= 0.012), UP + allodynia (OR:1.71, 95%CI:1.04–2.83;
p
= 0.034), and negatively associated with obesity (OR:0.21, 95%CI:0.07–0.64;
p
= 0.006). The 75% response (secondary endpoint) was positively associated with UP + UAs in HFEM (OR:3.44, 95%CI:1.42–8.31;
p
= 0.006) and with UP + UAs (OR:1.78, 95%CI:1.14–2.80;
p
= 0.012) and UP + allodynia (OR:1.92, 95%CI:1.22–3.06;
p
= 0.005) in CM. No predictor of 100% response emerged in patients with HFEM or CM.
Conclusions
A critical evaluation of headache characteristics indicating peripheral or central sensitization may help in predicting responsiveness to antiCGRP mAbs in HFEM and CM. A more precise pain profiling may represent a steppingstone for a mechanism-based approach and personalized treatment of migraine with compounds targeting specific molecular mechanisms.
Background
Fremanezumab has demonstrated to be effective, safe, and tolerated in the prevention of episodic or chronic migraine (CM) in randomized, placebo-controlled trials (RCTs). Real-life studies ...are needed to explore drug effects in unselected patients in routine circumstances and to provide higher generalizability results. This study explores the effectiveness, safety, and tolerability of fremanezumab in a real-life population of individuals affected by high-frequency episodic (HFEM: 8–14 days/month) or CM.
Methods
This is a 12-week multicenter, prospective, cohort, real-life study. We considered all consecutive patients affected by HFEM or CM visited at 9 Italian headache centers from 28/07/2020 to 11/11/2020. Eligible patients were given subcutaneous fremanezumab at the doses of 225 mg monthly or 675 mg quarterly, according to their preference. Primary study endpoints were the change in monthly migraine days (MMDs) in HFEM and monthly headache days (MHDs) in CM patients at weeks 9–12 compared to baseline. Secondary endpoints encompassed variation in monthly analgesic intake (MAI), Numerical Rating Scale (NRS), HIT-6 and MIDAS scores, and ≥ 50%, ≥ 75% and 100% responder rates at the same time intervals.
Results
Sixty-seventh number migraine patients had received ≥ 1 subcutaneous fremanezumab dose and were considered for safety analysis, while 53 patients completed 12 weeks of treatment and were included also in the effectiveness analysis. Fremanezumab was effective in both HFEM and CM, inducing at week 12 a significant reduction in MMDs (-4.6,
p
< 0.05), MHDs (-9.4,
p
< 0.001), MAI (-5.7,
p
< 0.05; -11.1,
p
< 0.001), NRS (-3.1,
p
< 0.001; -2.5,
p
< 0.001), and MIDAS scores (-58.3,
p
< 0.05; -43.7;
p
< 0.001). HIT-6 was significantly reduced only in HFEM patients (-18.1,
p
< 0.001). Remission from CM to episodic migraine and from MO to no-MO occurred in 75% and 67.7% of the patients. The ≥ 50%, ≥ 75% and 100% responder rates at week 12 were 76.5%, 29.4% and 9.9% in HFEM and 58.3%, 25% and 0% in CM. Younger age emerged as a positive response predictor (OR = 0.91; 95% CI 0.85–0.98,
p
= 0.013). Treatment-emergent adverse events were uncommon (5.7%) and mild. No patient discontinued fremanezumab for any reason.
Conclusions
Fremanezumab seems more effective in real-life than in RCTs. Younger age emerges as a potential response predictor.
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