Chrono-pharmaceutical approaches to optimize dosing regimens based on the circadian clock machinery

Daily rhythmic variations in biological functions affect the efficacy and/or toxicity of drugs: a large number of drugs cannot be expected to exhibit the same potency at different administration times. The “circadian clock” is an endogenous timing system that broadly regulates metabolism, physiology and behavior. In mammals, this clock governs the oscillatory expression of the majority of genes with a period length of approximately 24 h. Genetic studies have revealed that molecular components of the circadian clock regulate the expression of genes responsible for the sensitivity to drugs and their disposition. The circadian control of pharmacodynamics and pharmacokinetics enables ‘chrono-pharmaceutical’ applications, namely drug administration at appropriate times of day to optimize the therapeutic index (efficacy vs. toxicity). On the other hand, a variety of pathological conditions also exhibit marked day-night changes in symptom intensity. Currently, novel therapeutic approaches are facilitated by the development of chemical compound targeted to key proteins that cause circadian exacerbation of disease events. This review presents an overview of the current understanding of the role of the circadian biological clock in regulating drug efficacy and disease conditions, and also describes the importance of identifying the difference in the circadian machinery between diurnal and nocturnal animals to select the most appropriate times of day to administer drugs in humans.

Longitudinal symptom and clinical outcome analysis of hospitalized COVID-19 patients

COVID-19 pandemics increased patient hospitalization impacting the hospital operations and patient care beyond COVID-19 patients. Although longitudinal symptom analysis may provide prognostic utility about clinical outcomes and critical hospitalization events of COVID-19 patients, such analysis is still missing. Here, we have analyzed over 10,000 hospitalized COVID-19 patients in the Houston Methodist Hospital at the Texas Medical Center from the beginning of pandemics till April of 2020. Our study used statistical and regression analysis over symptoms grouped into symptom groups based on their anatomical locations. Symptom intensity analysis indicated that symptoms peaked at the time of admission and subsided within the first week of hospitalization for most of the patients. Patients surviving the infection (n=9,263), had faster remission rates, usually within the first days of hospitalization compared to sustained symptom for the deceased patient group (n=1,042). The latter had also a longer hospitalization stay and more comorbidities including diabetes, cardiovascular, and kidney disease. Inflammation-associated systemic symptoms (Systemic) such as fever and chills, and lower respiratory system specific symptoms (Lower Respiratory System) such as shortness of breath and pneumonia, were the most informative for the analysis of longitudinal symptom dynamics. Our results suggest that the symptom remission rate could possess prognostic utility in evaluating patient hospitalization stay and clinical outcomes early in hospitalization. We believe knowledge and information about symptom remission rates can be used to improve hospital operations and patient care by using common and relatively easy to process source of information.

Characteristics of Adverse Events in Bee Venom Therapy Reported in South Korea: A Survey Study

This study was aimed at investigating Korean patients’ experience with bee venom therapy (BVT) and providing evidence to enhance BVT safety. Thus, an anonymous online survey was conducted between August 22 and 28, 2018. Five hundred respondents who underwent pharmacopuncture (PA) within one year were surveyed (sample error: 95 ± 4.38%). Of these, 32 respondents were excluded and 468 were evaluated. Of the 468, 61 reported experiencing adverse events after PA. The adverse event rate was higher in the BV-PA(Bee venom-Pharmacopuncture) group than in the non-A group; however, intergroup differences were insignificant. There were no significant differences in mild symptom intensity between the BV-PA and non-BV-PA groups (p = 0.572). However, there was a significant intergroup difference in severe symptom intensity (p < 0.001). Additionally, the BV-PA and non-BV-PA groups did not significantly differ in their level of satisfaction either overall or in terms of effectiveness and safety (p = 0.414, p = 0.339, and p = 0.675, respectively). Furthermore, the BV-PA and non-BV-PA groups did not differ regarding intent to re-treat (p = 0.722). Severe adverse events such as anaphylactic shock were not reported; however, BVT practitioners should be cautious when applying it.

Relationships Between Cardiovascular Autonomic Profile and Work Ability in Patients With Pure Autonomic Failure

Pure autonomic failure (PAF) is a rare disorder belonging to the group of synucleinopathies, characterized by autonomic nervous system degeneration. Severe orthostatic intolerance with recurrent syncope while standing are the two most disabling manifestations. Symptoms may start at middle age, thus affecting people at their working age. The aims of this study were to evaluate the autonomic and work ability impairment of a group of PAF patients and assess the relationships between cardiovascular autonomic control and work ability in these patients. Eleven PAF patients (age 57.3 ± 6.7 years), engaged in work activity, participated in the study. They completed the Composite Autonomic Symptom Score (COMPASS-31, range 0 no symptom-100 maximum symptom intensity) and Work Ability questionnaires (Work Ability Index, WAI, range 7–49; higher values indicate better work ability and lower values indicating unsatisfactory or jeopardized work ability). Electrocardiogram, blood pressure and respiratory activity were continuously recorded for 10 min while supine and during 75° head-up tilt (HUT). Autoregressive spectral analysis of cardiac cycle length approximated as the time distance between two consecutive R-wave peaks (RR) and systolic arterial pressure (SAP) variabilities provided the power in the high frequency (HF, 0.15–0.40 Hz) and low frequency (LF, 0.04–0.15 Hz) bands of RR and SAP variabilities. Cardiac sympatho-vagal interaction was assessed by LF to HF ratio (LF/HF), while the LF power of SAP (LFSAP) quantified the vascular sympathetic modulation. Changes in cardiovascular autonomic indexes induced by HUT were calculated as the delta (Δ) between HUT and supine resting positions. Spearman correlation analysis was applied. PAF patients were characterized by a moderate autonomic dysfunction (COMPASS-31 total score 47.08 ± 20.2) and by a reduction of work ability (WAI 26.88 ± 10.72). Direct significant correlations were found between WAI and ΔLFRR (r = 0.66, p = 0.03) and ΔLF/HFRR (r = 0.70, p = 0.02). Results indicate that patients who were better able to modulate heart rate, as revealed by a greater cardiac sympathetic increase and/or vagal withdrawal during the orthostatic stimulus, were those who reported higher values of WAI. This finding could be relevant to propose new strategies in the occupational environment to prevent early retirement or to extend the working life of these patients.

Assessment of the influence of psychosocial factors on musculoskeletal disorder symptom intensity

BACKGROUND: Previous studies have observed that psychosocial factors are associated with an increase in work-related musculoskeletal disorders (WMSDs) in European countries. However, the influence of psychosocial factors on the WMSD symptoms has not been studied in detail. Additionally, working conditions differ between developing and developed countries. OBJECTIVE: In this study, the influence of psychosocial factors on WMSD symptoms among men and women in the footwear industry in northeastern Brazil is investigated. METHODS: A questionnaire survey was conducted to evaluate workers’ perceptions of psychosocial factors and WMSD symptoms. The influence of psychosocial factors on WMSD symptom trends was observed through ordinal logistic regression models. RESULTS: It was found that different psychosocial factors are related to WMSD symptom intensification. Factors such as “job insecurity” and “low social support,” which are not associated with the worsening of WMSD symptoms in developed countries, showed a noticeable influence in the sample analyzed. CONCLUSION: These findings may be associated with differences in working conditions and economic problems in developing countries, suggesting that some psychosocial factors have a different effect on workers’ perceptions in developing countries.

Validity and reliability of the Turkish version of the lymphedema symptom intensity and distress survey

Objectives: This study aims to adapt the Lymphedema Symptom Intensity and Distress Survey- Arm (LSIDS-Arm) into Turkish and to test its validity and reliability. Patients and methods: Between September 2017 and July 2018, this descriptive, methodological study included a total of 186 women (mean age: 55.4±10.2 years; range, 20 to 80 years) who were diagnosed with breast cancer-related lymphedema (BCRL) and followed in the lymphedema outpatient clinic. Data were collected using sociodemographic and clinical features form, LSIDS-Arm, and Functional Assessment of Cancer Treatment-Breast Cancer Scale+4 (FACT-B+4). After the linguistic and content validity of the scale was achieved, confirmatory factor analysis and known-groups validation were utilized to test the construct validity. Reliability of the survey was tested using the Cronbach alpha and Spearman Brown coefficient, item analysis, and parallel forms reliability. Results: All patients completed the questionnaire. After achievement of linguistic and content validity, confirmatory factor analysis results were found to be higher than the accepted value. Known-groups validation revealed a significant difference in the mean scores for the intensity and distress scales between the patients with and without lymphedema. Cronbach alpha for the subscales ranged from 0.61 to 0.86. Parallel forms reliability showed a moderate, significant correlation between subscales of the intensity and distress scales of the survey and the subscales of FACT-B+4. Conclusion: The Turkish version of the survey is valid and reliable and can be used to evaluate symptoms, severity of symptoms, and distress caused by BCRL symptoms in the Turkish women.

Clinical and psychological factors in coronary heart disease patients with statin associated muscle side-effects

Background To compare clinical and psychological factors among patients with self-perceived statin-associated muscle symptoms (SAMS), confirmed SAMS, and refuted SAMS in coronary heart disease patients (CHD). Methods Data were obtained from a cross-sectional study of 1100 CHD outpatients and a study of 71 CHD outpatients attending a randomized, double-blinded, placebo-controlled, crossover study to test effects of atorvastatin 40 mg/day on muscle symptom intensity. Clinical and psychosocial factors were compared between patients with and without SAMS in the cross-sectional study, and between patients with confirmed SAMS and refuted SAMS in the randomized study. Results Bilateral, symmetric muscle symptoms in the lower extremities during statin treatment were more prevalent in patients with confirmed SAMS compared to patients with refuted SAMS (75% vs. 41%, p = 0.01) in the randomized study. No significant differences in psychological factors (anxiety, depression, worry, insomnia, type D personality characteristics) were detected between patients with and without self-perceived SAMS in the cross-sectional study, or between patients with confirmed SAMS and refuted SAMS, in the randomized study. Conclusions Patients with confirmed SAMS more often present with bilateral lower muscle symptoms compared to those with refuted SAMS. Psychological factors were not associated with self-perceived SAMS or confirmed SAMS. A careful pain history and a search for alternative causes of muscle symptoms are likely to promote communication in patients with SAMS, and may reduce the risk for statin discontinuation.

Translation and cross-cultural adaptation of “Trapeziometacarpal Arthrosis Symptoms and Disability—TASD” into Brazilian Portuguese

Background Osteoarthritis is the most common form of hand arthritis and arthritis of the carpometacarpal joint of the thumb is a potentially limiting disease. There is no homogeneity in the evaluation of outcomes for the rhizarthrosis treatment. In an attempt to standardize the evaluation of results, some subjective questionnaires, non-specific, were used to evaluate rhizarthrosis. Trapeziometacarpal Arthrosis Symptoms and Disability (TASD) was described by Becker et al.with the purpose of evaluating symptom intensity and degree of disability, as to compare results after treatment. Our objective is to translate, validate and do the cultural adaptation of the questionnaire TASD into the Brazilian Portuguese. Methods The questionnaire was translated, with reverse translation. The translations were evaluated and synthesized by a committee, arriving at TASD-BR. Thirty-one patients with a diagnosis of rhizarthrosis answered the questionnaire. We evaluated, the internal consistency, reliability, agreement and ceiling and floor effect for validation. Results The questionnaires were translated and adapted according to defined protocols. The internal consistency, through Cronbach's α coefficient for TASD-BR, was 0.927. The questionnaire's reliability, through the Intraclass Correlation Coefficient, was also shown to be quite high, with κ = 0.961 (0.954–0.967). The agreement, measured through the Standard Error Measurement, remained with standardized values below 5%. There was no ceiling and floor effect. Conclusion Through specific methodology we consider TASD-BR translated and valid for the Brazilian Portuguese.

Association of the RASS Score With Intensity of Symptoms, Discomfort, and Communication Capacity in Terminally Ill Cancer Patients Receiving Palliative Sedation: Is RASS an Appropriate Outcome Measure?

BackgroundPalliative sedation is sometimes needed for refractory symptoms, and the Richmond Agitation-Sedation Scale (RASS) is one of the key measures. The primary aim of this study was to explore the association between the RASS score and degree of distress quantified by other measures: Support Team Assessment Schedule, item 2 (STAS), Discomfort Scale for Dementia of Alzheimer Type (Discomfort Scale), and Non-communicative Patient’s Pain Assessment Instrument (NOPPAIN), as well as a communication capacity measured by the Communication Capacity Scale, item 4 (CCS).MethodsThis was a prospective observational study on terminally ill cancer patients who received continuous infusion of midazolam to relieve refractory symptoms in a palliative care unit of a designated cancer hospital. Primarily responsible palliative care physicians rated RASS, Discomfort Scale, NOPPAIN, and CCS just before starting infusion, and 1 hour, 4 hours, 24 hours, and 48 hours after midazolam infusion, and ward nurses rated STAS at the same time. Since the ward nurses regularly evaluated STAS to titrate midazolam during palliative sedation as routine work, we regarded STAS rated by ward nurses as a standard of distress measure.ResultsA total of 249 assessments were performed for 55 patients. The RASS score was moderately to highly associated with symptom intensity measured by STAS, discomfort measured by the Discomfort Scale, and pain measured by NOPPAIN (r = 0.63 to 0.73). On the other hand, communication capacity measured by CCS is not parallel with the RASS score, and demonstrated a valley-shape. In 82 assessments with RASS of -1 to -3, 11 patients (13%) were regarded as having physical symptoms of STAS of 2 or more.ConclusionsRASS can roughly estimate physical distress in patients receiving palliative sedation, but a measure to more precisely quantify the symptom experience is needed.