Cortisol diurnal patterns,associations with depressive symptoms,and the impact of intervention in older adults: Results using modern robust methods aimed at dealing with low power due to violations of standard assumptions

Advances in salivary bioscience enable the widespread integration of biological measures into the behavioral and social sciences. While theoretical integration has progressed, much less attention has focused on analytical strategies and tactics. The statistical literature warns that common methods for comparing groups and studying associations can have relatively poor power compared to more modern robust techniques. Here we illustrate, in secondary data analyses using the USC Well Elderly II study (n = 460, age 60–95, 66% female), that modern robust methods make a substantial difference when analyzing relations between salivary analyte and behavioral data. Analyses that deal with the diurnal pattern of cortisol and the association of the cortisol awakening response with depressive symptoms and physical well-being are reported. Non-significant results become significant when using improved methods for dealing with skewed distributions and outliers. Analytical strategies and tactics that employ modern robust methods have the potential to reduce the probability of both Type I and Type II errors in studies that compare salivary analytes between groups, across time, or examine associations with salivary analyte levels.     

TRAINING LOAD,IMMUNE SYSTEM,UPPER RESPIRATORY SYMPTOMS AND PERFORMANCE IN WELL-TRAINED CYCLISTS THROUGHOUT A COMPETITIVE SEASON

This study aimed to evaluate the leukocyte subset counts, serum immunoglobulin A, performance and upper respiratory symptoms (URS), as well as their interrelationships, of well-trained cyclists for a 29-week training season using monitored loads. The season was divided into three phases: preparatory (nine weeks), first competitive phase (nine weeks) and second competitive phase (11 weeks). The sample consisted of eight well-trained cyclists, aged 18 ± 2 years. Immunological parameters and performance were evaluated during weeks 1 (baseline), 10 (early first competitive phase), 19 (early second competitive phase) and 29 (end of the second competitive phase). The training loads (volume x rating of perceived exertion) were monitored daily while the monitoring of URS was performed every 15 days using the WURSS-44 questionnaire. The data were analyzed using a one-way ANOVA and a Pearson correlation test with the significance level set at p ≤ 0.05. No significant differences were found for training load, leukocyte subset counts or serum immunoglobulin A among the three phases. However, serum immunoglobulin A was 50.9% below the control group values. URS were significantly higher during the preparatory period, and there were significant correlations between URS and training load (strain) in the preparatory period (r = 0.72, p = 0.032) and second competitive phase (r = 0.73, p = 0.036). In conclusion, indicators of training load without a significant change throughout the season did not significantly affect immune parameters measured; however, the increase of strain can cause an increase of upper respiratory symptoms throughout the season, but without loss of performance.     

Pollen allergen reports help to understand preseason symptoms

Early symptoms of pollen allergies arefrequently reported before pollination periodof allergenic plant starts. At northernlatitudes the main concern is Betulaceae-trees(alders, hazel, birches). Pollen allergeninformation, based on the analysis of actualairborne allergen concentrations, beside thetraditional pollen reports, based on pollencounts, has been given in SW Finland since1998. 1–2 weeks before the onset of floweringpollen allergens are detected airborne inquantities high enough to provoke symptoms.Information is given on radio and in localnewspapers. During the first season of the newservice (1998) we carried out a questionnairestudy. The results showed that new informationservice, though not as frequently used as wehad hoped for, was useful to allergic personsfor starting their medication in time. Theyalso received explanation for their earlierinexplicable symptoms. We recommend bothinformation services to be run concurrently togive the best information to the public.     

Proteomic approaches to identify blood-based biomarkers for depression and bipolar disorders

Introduction: Major depressive disorder (MDD) and bipolar disorder (BD) are leading causes of disability worldwide, yet many people remain undiagnosed, are misdiagnosed, and/or ineffectively treated. Diagnosis relies on the clinical assessment of symptoms, and there is currently no molecular or brain-imaging diagnostic test available. Identifying and validating protein biomarkers could provide a more accurate and objective means of diagnosis.

Areas covered: Proteomics is a powerful tool that enables the identification and quantification of novel candidate biomarkers of disease. In this review, we discuss the role of proteomic technologies in biomarker discovery and validation, peripheral blood as a source of protein biomarkers, statistical methods for analyzing proteomic data, and some existing challenges in the field. We also review a selection of previously published studies focused on identifying blood-based diagnostic protein biomarkers of MDD and BD within a ten-year period.

Expert commentary: Proteomic studies have led to the identification of numerous potential biomarkers of MDD and BD. However, clinical validation and translation into clinical practice have not yet been achieved. Conducting large-scale validation studies and addressing various factors that limit the reproducibility of the proteomic findings are key to ensure that robust and reliable biomarker tests are developed and clinically validated.     

Chronic social stress induces DNA methylation changes at an evolutionary conserved intergenic region in chromosome X

Chronic stress resulting from prolonged exposure to negative life events increases the risk of mood and anxiety disorders. Although chronic stress can change gene expression relevant for behavior, molecular regulators of this change have not been fully determined. One process that could play a role is DNA methylation, an epigenetic process whereby a methyl group is added onto nucleotides, predominantly cytosine in the CpG context, and which can be induced by chronic stress. It is unknown to what extent chronic social defeat, a model of human social stress, influences DNA methylation patterns across the genome. Our study addressed this question by using a targeted-capture approach called Methyl-Seq to investigate DNA methylation patterns of the dentate gyrus at putative regulatory regions across the mouse genome from mice exposed to 14 days of social defeat. Findings were replicated in independent cohorts by bisulfite-pyrosequencing. Two differentially methylated regions (DMRs) were identified. One DMR was located at intron 9 of Drosha, and it showed reduced methylation in stressed mice. This observation replicated in one of two independent cohorts. A second DMR was identified at an intergenic region of chromosome X, and methylation in this region was increased in stressed mice. This methylation difference replicated in two independent cohorts and in Major Depressive Disorder (MDD) postmortem brains. These results highlight a region not previously known to be differentially methylated by chronic social defeat stress and which may be involved in MDD.     

The severity of psychiatric disorders

The issue of the severity of psychiatric disorders has great clinical importance. For example, severity influences decisions about level of care, and affects decisions to seek government assistance due to psychiatric disability. Controversy exists as to the efficacy of antidepressants across the spectrum of depression severity, and whether patients with severe depression should be preferentially treated with medication rather than psychotherapy. Measures of severity are used to evaluate outcome in treatment studies and may be used as meaningful endpoints in clinical practice. But, what does it mean to say that someone has a severe illness? Does severity refer to the number of symptoms a patient is experiencing? To the intensity of the symptoms? To symptom frequency or persistence? To the impact of symptoms on functioning or on quality of life? To the likelihood of the illness resulting in permanent disability or death? Putting aside the issue of how severity should be operationalized, another consideration is whether severity should be conceptualized similarly for all illnesses or be disorder specific. In this paper, we examine how severity is characterized in research and contemporary psychiatric diagnostic systems, with a special focus on depression and personality disorders. Our review shows that the DSM‐5 has defined the severity of various disorders in different ways, and that researchers have adopted a myriad of ways of defining severity for both depression and personality disorders, although the severity of the former was predominantly defined according to scores on symptom rating scales, whereas the severity of the latter was often linked with impairments in functioning. Because the functional impact of symptom‐defined disorders depends on factors extrinsic to those disorders, such as self‐efficacy, resilience, coping ability, social support, cultural and social expectations, as well as the responsibilities related to one's primary role function and the availability of others to assume those responsibilities, we argue that the severity of such disorders should be defined independently from functional impairment.     

Early warning biomarkers in major depressive disorder: a strategic approach to a testing question

Purpose: Identification of biomarkers in major depressive disorder (MDD) has proceeded in an extemporised manner. No single biomarker has been identified with utility in screening, diagnosis, prognosis, or monitoring, and screening tests have different characteristics than the other functions. Using chaos, bifurcation, and perturbation (CBP) theories, the aim is to identify biomarkers to aid clinicians in screening for MDD.

Materials and methods: MDD is a complex disorder; consequently, a reductionist approach to characterize the complex system changes found in MDD will be inchoate and unreliable. A holistic approach is used to identify biomarkers reflecting the tipping points seen before the catastrophic bifurcation that results in MDD.

Results: Applying CBP theories revealed skew, resistance to change, flickering, increased variance and autocorrelation as patterns of biomarkers. Integrals and differentials of extracellular and intracellular biomarkers were identified, specifically focussed on hypothalamo-pituitary axis (HPA) dysfunction, metabolic dysfunction, inflammation and mitochondrial oxidative stress, and tryptophan metabolism.

Conclusions: Applying CBP theories to the dysfunctional complex biological systems in MDD led to development of integrals and differentials of biomarkers that can be used in screening for MDD and planning future biomarker research, targeting intracellular and extracellular inflammation, HPA axis dysfunction, and tryptophan metabolism.     

Respiratory symptoms and lung function in taxi drivers and manual workers

The aim of this study, was to determine the prevalence of some respiratory symptoms and possible diseases among taxi drivers and manual workers. This prospective study was performed on 165 Pakistani male drivers, (mean age: 34.5±7.8 years) and 165 Pakistani male manual workers not exposed to dust or fumes, without occupational exposure to driving employed in the Water and Electricity Department and recruited as controls (mean age: 34.6±7.6 years and mean height and weight 169.8±6.0 cm and 71.9±10.9 kg). The data on chronic respiratory symptoms showed that taxi drivers had higher prevalence of symptoms than manual workers, being significantly greater for asthma (RR=1.72; 95% CI=1.00–2.88,P=0.037); allergic rhinitis (RR=2.41; 95% CI=1.46–3.94,P=0.0006); dyspnea (RR=2.13; 95% CI=1.22–3.71,P=0.009); and nasal catarrh (RR=2.19; 95% CI=1.22–3.91,P=0.0106). Thirty percent of taxi drivers and 27% of manual workers were smokers, there was no significant differences in the prevalence of chronic respiratory symptoms between smokers and non-smokers. Lung function parameters in the taxi drivers were significantly lower than in manual workers group (P<0.0001) except PEF parameter. When comparing the measured mean values of lung function parameters in the drivers among smokers and nonsmokers, there was no significant differences between smokers and nonsmokers. Also, a comparison of ventilatory capacity of paired predicted values with measured normal values showed statistically significant differences between predicted and measured values for taxi drivers and manual workers for FVC, FEV₁, FEF_25–75 and PEF parameters except for FEV₁/FVC test in manual workers. In conclusion, the results of the present study provide evidence regarding effects of such as carbon monoxide, nitrogen dioxide, sulfur dioxide and gases exposures on taxi drivers and long-term driving, which may be associated with the development of chronic respiratory symptoms and lung function impairment.     

An update comprehensive review on the status of COVID-19: vaccines,drugs, variants and neurological symptoms

Various recently reported mutant variants, candidate and urgently approved current vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), many current situations with severe neurological damage and symptoms as well as respiratory tract disorders have begun to be reported. In particular, drug, vaccine, and neutralizing monoclonal antibodies (mAbs) have been developed and are currently being evaluated in clinical trials. Here, we review lessons learned from the use of novel mutant variants of the COVID-19 virus, immunization, new drug solutions, and antibody therapies for infections. Next, we focus on the B 1.1.7, B 1.351, P.1, and B.1.617 lineages or variants of concern that have been reported worldwide, the new manifestations of neurological manifestations, the current therapeutic drug targets for its treatment, vaccine candidates and their efficacy, implantation of convalescent plasma, and neutralization of mAbs. We review specific clinical questions, including many emerging neurological effects and respiratory tract injuries, as well as new potential biomarkers, new studies in addition to known therapeutics, and chronic diseases of vaccines that have received immediate approval. To answer these questions, further understanding of the burden kinetics of COVID-19 and its correlation with neurological clinical outcomes, endogenous antibody responses to vaccines, pharmacokinetics of neutralizing mAbs, and action against emerging viral mutant variants is needed.