Sex differences in the global burden of multidrug- resistant tuberculosis without extensive drug resistance in the general population and people living with HIV/AIDS, 1990-2019.

OBJECTIVE: Currently, human immunodeficiency virus (HIV) and multi-drug resistant tuberculosis (MDR-TB) without extensive drug resistance (XDR) are significant challenges in terms of the global burden of disease. This study aimed to evaluate the trends of the global burden of MDR-TB without XDR and HIV/AIDS-MDR-TB without XDR, focusing on differences in socioeconomic status and sex for 204 countries and territories across periods from 1990 to 2019. MATERIALS AND METHODS: Data from the Global Burden of Disease (GBD) 2019 study were obtained to construct a separate index measuring the burden of MDR-TB without XDR and HIV/AIDS-MDR-TB without XDR. Incidence, prevalence, mortality, and disability-adjusted life years (DALYs) were calculated for each case and group. A population-attributable fraction approach was used to assess mortality and incidence of HIV/AIDS and MDR-TB coinfection. 95% uncertainty intervals (UIs) were presented for all measures. RESULTS: Our global estimates suggest that there were approximately 450,000 (95% UI 247,000-785,000) incident cases of MDR-TB without XDR and 109,000 (43,000-210,000) deaths caused by MDR-TB without XDR among individuals who were HIV-negative in 2019. For HIV-positive individuals, the corresponding figures were approximately 47,000 (33,000-67,000) incident cases of MDR-TB and 19,000 (8,000-36,000) deaths due to MDR-TB in the same year. In 2019, higher numbers of incident cases and deaths were observed in males compared to females among individuals who were HIV-negative. Conversely, for HIV-positive individuals, females had higher numbers of incident cases and deaths compared to males. Specifically, the estimated numbers for incident cases were 23,000 (15,000-33,000) for females and 24,000 (17,000-35,000) for males, while the estimated numbers for deaths were 9,600 (4,000-17,900) for females and 9,800 (4,100-18,500) for males. Male-to-female ratios have remained above 1.0 from 1990 to 2019 in both incident cases and number of deaths for HIV-negative individuals. However, for HIV and MDR-TB coinfection, both ratios were below 1.0 in most of the time series. CONCLUSIONS: Males had more cases and deaths due to MDR-TB without XDR than females in HIV-negative patients, while females faced a higher incidence and mortality in HIV/AIDS-MDR-TB without XDR. Interventions are needed to deal with such factors, which increase the burden of coinfection among females across the world.

The global burden of sudden infant death syndrome from 1990 to 2019: a systematic analysis from the Global Burden of Disease study 2019.

BACKGROUND: Sudden infant death syndrome (SIDS) still remains one of the leading causes of infant death worldwide, especially in high-income countries. To date, however, there is no detailed information on the global health burden of SIDS. AIMS: To characterize the global disease burden of SIDS and its trends from 1990 to 2019 and to compare the burden of SIDS according to the socio-demographic index (SDI). DESIGN: Systematic analysis based on the Global Burden of Disease (GBD) 2019 data. METHODS: Epidemiological data of 204 countries from 1990 to 2019 were collected via various methods including civil registration and vital statistics in the original GBD study. Estimates for mortality and disease burden of SIDS were modeled. Crude mortality and mortality rates per 100 000 population were analyzed. Disability-adjusted life years (DALYs) and DALY rates were also assessed. RESULTS: In 2019, mortality rate of SIDS accounted for 20.98 [95% Uncertainty Interval, 9.15-46.16] globally, which was a 51% decrease from 1990. SIDS was most prevalent in Western sub-Saharan Africa, High-income North America and Oceania in 2019. The burden of SIDS was higher in males than females consistently from 1990 to 2019. Higher SDI and income level was associated with lower burden of SIDS; furthermore, countries with higher SDI and income had greater decreases in SIDS burden from 1990 to 2019. CONCLUSIONS: The burden of SIDS has decreased drastically from 1990 to 2019. However, the improvements have occurred disproportionately between regions and SDI levels. Focused preventive efforts in under-resourced populations are needed.

Neuropsychological adverse drug reactions of Remdesivir: analysis using VigiBase, the WHO global database of individual case safety reports.

OBJECTIVE: Although remdesivir (GS-5734) has recently demonstrated clinical benefits against the pandemic outbreak of coronavirus disease 2019 (COVID-19), neuropsychological adverse reactions (ADRs) remain to be examined in real-world settings. Therefore, we aimed to identify and characterize the neuropsychological ADRs associated with remdesivir use. MATERIALS AND METHODS: We obtained data for this international pharmacovigilance cohort study from individual case safety reports (ICSRs) in a World Health Organization database (VigiBase) from the first report on remdesivir on February 17, 2020, until August 30, 2020 (n=1,403,532). ADRs reported to be relevant to remdesivir were compared with the full database by using a Bayesian neural network method to calculate the information component (IC). RESULTS: A total of 2,107 reported cases of neuropsychological ADRs suspected to be associated with remdesivir were identified from among all ICSRs in the database during the observation period. Although 108 neuropsychological ADRs (64 neurologic events and 44 psychologic events) were reported in association with the medication, no statistically significant pharmacovigilance signal could be detected; the IC025 value was negative for all of the neuropsychological dysfunctions (anxiety [n=13, 0.62%], seizures [n=12, 0.57%], lethargy [n=6, 0.28%], agitation [n=5, 0.25%], cerebral infarction [n=3, 0.14%], ischemic stroke [n=3, 0.14%], and hemiparesis [n=3, 0.14%]). CONCLUSIONS: Our study demonstrates that remdesivir, a novel drug applied to the treatment of COVID-19, does not have a significant association with adverse neurologic or psychiatric reactions in the real-world setting.

Efficacy and safety of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) monotherapy for advanced EGFR-mutated non-small cell lung cancer: systematic review and meta-analysis.

OBJECTIVE: It is controversial whether there is efficacy or safety benefit of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) in advanced EGFR-mutated non-small cell lung cancer (NSCLC) compared to standard chemotherapy. We aim to assess the efficacy and safety of EGFR-TKIs compared to other chemotherapeutics in EGFR-mutated NSCLC. MATERIALS AND METHODS: Up to April 27th, 2020, PubMed, Embase, Medline, Scopus, Cochrane library, and ClinicalTrials.gov were searched for articles or trials meeting the inclusion criteria. After filtering, 230 eligible studies were initially identified. Data extraction followed PRISMA and included outcomes were progression-free survival (PFS), overall survival (OS), and severe adverse events (SAEs). Direct and indirect meta-analyses were generated in the context of log-linear mixed-effects models, with fixed effects for each relative comparison and random effects for each study. RESULTS: The results showed that EGFR-TKI therapy had improved PFS with a hazard ratio (HR) of 0.40 (95% CI: 0.36-0.44, p<0.001) compared to standard chemotherapy. Nevertheless, the EGFR-TKIs showed no benefit on OS (HR: 0.96, 95% CI: 0.83-1.10, p=0.556). In the analysis of adverse events, EGFR-TKIs had fewer SAEs than standard chemotherapy (HR: 0.29, 95% CI: 0.26-0.33, p<0.001). CONCLUSIONS: Our systemic review indicates that EGFR-TKI therapy has improved PFS, and reduced SAEs compared to standard chemotherapy in advanced EGFR-mutated NSCLC.

Suicide associated with COVID-19 infection: an immunological point of view.

OBJECTIVE: Coronavirus disease 2019 (COVID-19) is a pandemic and leading cause of death. Beyond the deaths directly caused by the virus and the suicides related to the psychological response to the dramatic changes as socioeconomic related to the pandemic, there might also be suicides related to the inflammatory responses of the infection. Infection induces inflammation as a cytokine storm, and there is an increasing number of studies that report a relationship between infection and suicide. MATERIALS AND METHODS: We searched the World Health Organization status report and the PubMed database for keywords (COVID-19, suicide, infection, inflammation, cytokines), and reviewed five cytokine pathways between suicide and inflammation using two meta-analyses and two observational studies starting from November 31, 2020, focusing on the relationship between suicide and inflammation by infection. First, we discussed existing evidence explaining the relationship between suicidal behaviors and inflammation. Second, we summarized the inflammatory features found in COVID-19 patients. Finally, we highlight the potential for these factors to affect the risk of suicide in COVID-19 patients. RESULTS: Patients infected with COVID-19 have high amounts of IL-1ß, IFN-γ, IP10, and MCP1, which may lead to Th1 cell response activation. Also, Th2 cytokines (e.g., IL-4 and IL-10) were increased in COVID-19 infection. In COVID-19 patients, neurological conditions, like headache, dizziness, ataxia, seizures, and others have been observed. CONCLUSIONS: COVID-19 pandemic can serve as a significant environmental factor contributing directly to increased suicide risk; the role of inflammation by an infection should not be overlooked.

Empirical assessment of biases in cerebrospinal fluid biomarkers of Alzheimer's disease: an umbrella review and re-analysis of data from meta-analyses.

OBJECTIVE: Alzheimer's disease (AD) is a leading cause of years lived with disability in older age, and several cerebrospinal fluid (CSF) markers have been proposed in individual meta-analyses to be associated with AD but field-wide evaluation and scrutiny of the literature is not available. MATERIALS AND METHODS: We performed an umbrella review for the reported associations between CSF biomarkers and AD. Data from available meta-analyses were reanalyzed using both random and fixed effects models. We also estimated between-study heterogeneity, small-study effects, excess significance, and prediction interval. RESULTS: A total of 38 meta-analyses on CSF markers from 11 eligible articles were identified and reanalyzed. In 14 (36%) of the meta-analyses, the summary estimate and the results of the largest study showed non-concordant results in terms of statistical significance. Large heterogeneity (I2≥75%) was observed in 73% and small-study effects under Egger's test were shown in 28% of CSF biomarkers. CONCLUSIONS: Our results suggest that there is an excess of statistically significant results and significant biases in the literature of CSF biomarkers for AD. Therefore, the results of CSF biomarkers should be interpreted with caution.

Risk factors of COVID-19 mortality: a systematic review of current literature and lessons from recent retracted articles.

OBJECTIVE: Recently, two influential articles that reported the association of (hydroxy)chloroquine or angiotensin converting enzyme (ACE) inhibitors and coronavirus disease 2019 (COVID-19) mortality were retracted due to significant methodological issues. Therefore, we aimed to analyze the same clinical issues through an improved research method and to find out the differences from the retracted papers. We systematically reviewed pre-existing literature, and compared the results with those of the retracted papers to gain a novel insight. MATERIALS AND METHODS: We extracted common risk factors identified in two retracted papers, and conducted relevant publication search until June 26, 2020 in PubMed. Then, we analyzed the risk factors for COVID-19 mortality and compared them to those of the retracted papers. RESULTS: Our systematic review demonstrated that most demographic and clinical risk factors for COVID-19 mortality were similar to those of the retracted papers. However, while the retracted paper indicated that both (hydroxy)chloroquine monotherapy and combination therapy with macrolide were associated with higher risk of mortality, our study showed that only combination therapy of hydroxychloroquine and macrolide was associated with higher risk of mortality (odds ratio 2.33; 95% confidence interval 1.63-3.34). In addition, our study demonstrated that use of ACE inhibitors or angiotensin receptor blockers (ARBs) was associated with reduced risk of mortality (0.77; 0.65-0.91). CONCLUSIONS: When analyzing the same clinical issues with the two retracted papers through a systematic review of randomized controlled trials and relevant cohort studies, we found out that (hydroxy)chloroquine monotherapy was not associated with higher risk of mortality, and that the use of ACE inhibitors or ARBs was associated with reduced risk of mortality in COVID-19 patients.

Antipsychotic use and risk of life-threatening medical events: umbrella review of observational studies.

OBJECTIVE: To quantify the risk of hip fracture, thromboembolism, stroke, myocardial infarction, pneumonia and sudden cardiac death associated with exposure to antipsychotics. METHODS: Systematic searches were conducted in Medline, Embase and PsycINFO from inception until 30/07/2018 for systematic reviews of observational studies. AMSTAR-2 was used for the quality assessment of systematic reviews, while the strength of associations was measured using GRADE and quantitative umbrella review criteria (URC). RESULTS: Sixty-eight observational studies from six systematic reviews were included. The association between antipsychotic exposure and pneumonia was the strongest [URC = class I; GRADE = low quality; odds ratio (OR) = 1.84, 95% confidence interval (CI) = 1.62-2.09; participants = 28 726; age = 76.2 ± 12.3 years], followed by the association with hip fracture (URC = class II; GRADE = low quality; OR = 1.57, 95% CI = 1.42-1.74; participants = 5 288 118; age = 55.4 ± 12.5 years), and thromboembolism (URC = class II; GRADE = very low quality; OR = 1.55, 95% CI = 1.31-1.83; participants = 31 417 175; age = 55.5 ± 3.2 years). The association was weak for stroke (URC = class III; GRADE = very low quality; OR = 1.45, 95% CI = 1.24-1.70; participants = 65 700; age = 68.7 ± 13.8 years), sudden cardiac death (URC = class III; GRADE = very low quality; OR = 2.24, 95% CI = 1.45-3.46; participants = 77 488; age = 52.2 ± 6.2 years) and myocardial infarction (URC = class III; GRADE = very low quality; OR = 2.21, 95% CI = 1.41-3.46; participants = 399 868; age = 74.1 ± 9.3 years). CONCLUSION: The most robust results were found for the risk of pneumonia, followed by the risk of hip fracture and thromboembolism. For stroke, sudden cardiac death and myocardial infarction, the strength of association was weak. The observational nature of the primary studies may represent a source of bias.

Association between happiness and psychopathology in an elderly regional rural population in Crete.

Research has shown that socio-demographic profile and psychopathology symptoms are related to levels of happiness in old age. The aims of this cross-sectional study were: 1) to investigate the effect of recent stressful life events and socio-demographic factors on psychopathological symptoms in elderly residents in mountain regions of Crete, Greece and 2) to explore the mechanism which underlies the relationship between socio-demographic factors and psychopathological symptoms, with levels of happiness in old age. To this end, we used the nine psychopathology dimensions of symptoms as defined in the Symptom Checklist-90-R (SCL-90), while the Holmes and Rahe stress inventory was administered to quantify the stressful life events. A sample of 205 elderly men and women (age=77.1±6.7 years) living in 10 remote rural and isolated villages participated in this study. Data was collected through questionnaires completed upon individual meetings with each participant, with the interviewer's assistance. Each questionnaire included the two aforesaid scales alongside questions on individual socio-demographic characteristics. Analysis of variance was applied to detect socio-demographic factors that have a significant effect on specific psychopathological symptoms. Then, path analysis was applied to quantify the direct and indirect effect of the selected socio-demographic factors on happiness levels. Stressful life events were found to have no statistically significant effect on the presence of specific symptoms (somatization, psychoticism, anxiety) in elderly adults. Furthermore, certain socio-demographic factors (marital status, smoking, family income and social activity) were found to influence happiness, which varied according to the level of psycho-emotional tension. The results suggest that somatization, psychoticism, and phobic anxiety symptoms are psychic reactions independent of recent stressful life events. Our study,despite its regional character, may contribute in the development of appropriate clinical assessment tools and interventions, helping primary care practitioners to approach elderly people living in remote villages in a more appropriate and holistic manner, improving thereby the effectiveness of their interventions.

Association of insomnia severity with well-being, quality of life and health care costs: A cross-sectional study in older adults with chronic pain (PainS65+).

BACKGROUND: Insomnia is one of the most common complaints in chronic pain. This study aimed to evaluate the association of insomnia with well-being, quality of life and health care costs. METHODS: The sample included 2790 older individuals (median age = 76; interquartile range [IQR] = 70-82) with chronic pain. The participants completed a postal survey assessing basic demographic data, pain intensity and frequency, height, weight, comorbidities, general well-being, quality of life and the insomnia severity index (ISI). Data on health care costs were calculated as costs per year (€ prices) and measured in terms of outpatient and inpatient care, pain drugs, total drugs and total health care costs. RESULTS: The overall fraction of clinical insomnia was 24.6% (moderate clinical insomnia: 21.9% [95% CI: 18.8-23.3]; severe clinical insomnia: 2.7% [95% CI: 1.6-3.2]). Persons who reported clinical insomnia were more likely to experience pain more frequently with higher pain intensity compared to those reported no clinically significant insomnia. Mean total health care costs were € 8469 (95% CI: €4029-€14,271) for persons with severe insomnia compared with € 4345 (95% CI: €4033-€4694) for persons with no clinically significant insomnia. An association between severe insomnia, well-being, quality of life, outpatient care, total drugs costs and total health care costs remained after controlling for age, sex, pain intensity, frequency, body mass index and comorbidities using linear regression models. CONCLUSIONS: Our results determine an independent association of insomnia with low health-related quality of life and increased health care costs in older adults with chronic pain. SIGNIFICANCE: The concurrence and the severity of insomnia among older adults with chronic pain were associated with decreased well-being and quality of life, and increased health care costs to society.

Does psychotherapy work? An umbrella review of meta-analyses of randomized controlled trials.

OBJECTIVE: To map and evaluate the evidence across meta-analyses of randomized controlled trials (RCTs) of psychotherapies for various outcomes. METHODS: We identified 173 eligible studies, including 247 meta-analyses that synthesized data from 5157 RCTs via a systematic search from inception to December 2016 in the PubMed, PsycINFO and Cochrane Database of Systematic Reviews. We calculated summary effects using random-effects models, and we assessed between-study heterogeneity. We estimated whether large studies had significantly more conservative results compared to smaller studies (small-study effects) and whether the observed positive studies were more than expected by chance. Finally, we assessed the credibility of the evidence using several criteria. RESULTS: One hundred and ninety-nine meta-analyses were significant at P-value ≤ 0.05, and almost all (n = 196) favoured psychotherapy. Large and very large heterogeneity was observed in 130 meta-analyses. Evidence for small-study effects was found in 72 meta-analyses, while 95 had evidence of excess of significant findings. Only 16 (7%) provided convincing evidence that psychotherapy is effective. These pertained to cognitive behavioural therapy (n = 6), meditation therapy (n = 1), cognitive remediation (n = 1), counselling (n = 1) and mixed types of psychotherapies (n = 7). CONCLUSIONS: Although almost 80% meta-analyses reported a nominally statistically significant finding favouring psychotherapy, only a few meta-analyses provided convincing evidence without biases.

Prevalence of different pain categories based on pain spreading on the bodies of older adults in Sweden: a descriptive-level and multilevel association with demographics, comorbidities, medications, and certain lifestyle factors (PainS65+).

BACKGROUND AND OBJECTIVE: There is limited knowledge about the prevalence of pain and its relation to comorbidities, medication, and certain lifestyle factors in older adults. To address this limitation, this cross-sectional study examined the spreading of pain on the body in a sample of 6611 subjects ≥65 years old (mean age = 75.0 years; standard deviation [SD] = 7.7) living in southeastern Sweden. METHODS: Sex, age, comorbidities, medication, nicotine, alcohol intake, and physical activity were analyzed in relation to the following pain categories: local pain (LP) (24.1%), regional pain medium (RP-Medium) (20.3%), regional pain heavy (RP-Heavy) (5.2%), and widespread pain (WSP) (1.7%). RESULTS: RP-Medium, RP-Heavy, and WSP were associated more strongly with women than with men (all p<0.01). RP-Heavy was less likely in the 80-84 and >85 age groups compared to the 65-69 age group (both p<0.01). Traumatic injuries, rheumatoid arthritis/osteoarthritis, and analgesics were associated with all pain categories (all p<0.001). An association with gastrointestinal disorders was found in LP, RP-Medium, and RP-Heavy (all p<0.01). Depressive disorders were associated with all pain categories, except for LP (all p<0.05). Disorders of the central nervous system were associated with both RP-Heavy and WSP (all p<0.05). Medication for peripheral vascular disorders was associated with RP-Medium (p<0.05), and hypnotics were associated with RP-Heavy (p<0.01). CONCLUSION: More than 50% of older adults suffered from different pain spread categories. Women were more likely to experience greater spreading of pain than men. A noteworthy number of common comorbidities and medications were associated with increased likelihood of pain spread from LP to RP-Medium, RP-Heavy, and WSP. Effective management plans should consider these observed associations to improve functional deficiency and decrease spreading of pain-related disability in older adults.

The impact of depression and cardiophobia on quality of life in patients with essential hypertension.

Patients with chronic conditions like hypertension may experience many negative emotions which endorse the development of anxiety and depression symptomatology, thus they increase their risk for poor quality of life. Several studies have shown an association between symptoms of psychological distress and hypertension. In this study we aimed to quantify the link between depression, cardiophobia and quality of life in hypertensive patients. A cross-sectional design was employed. A sample of 197 hypertensive patients (89 men-108 women, mean age 53 years, SD=12 ranged 25-78) from a university outpatient hypertension clinic in Greece participated. Ninety-four (47.7%) of the participants suffered from essential grade I hypertension; 68 (34.5%) were grade II; 16 (8.1%) were categorized as grade III, while only 11 (5.6%) patients were recorded as normotensives with high normal values. The questionnaires included: (a) question for the recording of social-demographic characteristics and clinical features, (b) The Short Form (SF-36) Health Survey, (c) The Beck Depression Inventory -I, and (d) The Cardiac Anxiety Questionnaire. There were no significant differences between the two genders with exception of marital status (p=0.010), dyslipidemia (p=0.050), grade of hypertension (p=0.014), cardiac left ventricular hypertrophy (p=0.004), renal failure (p=0.043) and stroke (p=0.024). Lower levels of quality of life and higher levels of depression and cardiophobia were observed compared to the general population. There were no significant differences on psychological measures between the two sexes (p>0.05). Cardiophobia was positively related to depressive symptomatology (r=0.533, p=0.000) while negatively to both physical and mental health summary measures of SF-36 health survey (r=-0.467, p=0.000 r=-0.537, p=0.000 respectively). Multiple linear regression models found that for psychical health depression and cardiac anxiety, avoidance activities had an influence on levels of quality of life in hypertensive patients, after controlling for age and other socio-demographic variables and clinical characteristics (Beta=-0.133, p=0.007, Beta=-0.364 p=0.000 and Beta=-0.167 p=0.006, respectively). For mental component summary depression and cardiophobia, heart focused attention had also impact on mental health in hypertensives (Beta=-0.438, p=0.016, Beta=-0.564, p=0.000 and Beta=-0.223, p=0.037, respectively) after adjustments. Heart focused anxiety symptoms-as avoidance activities and/or attention and monitoring cardiac activity, are related to hypertensive patients' present deteriorated depressive symptoms and levels of quality of life. Both depressive symptomatology and heart focused anxiety may be a mechanism partly responsible for hypertensive patients' present impaired levels of quality of life.