Fatigue Symptoms Associated With COVID-19 in Convalescent or Recovered COVID-19 Patients; a Systematic Review and Meta-Analysis.

BACKGROUND: The prevalence and prognosis of post-acute stage SARS-CoV-2 infection fatigue symptoms remain largely unknown. AIMS: We performed a systematic review to evaluate the prevalence of fatigue in post-recovery from SARS-CoV-2 infection. METHOD: Medline, Embase, PsycINFO, CINAHL, Web of Science, Scopus, trial registries, Cochrane Central Register of Controlled Trials, and Google Scholar were searched for studies on fatigue in samples that recovered from polymerase chain reaction (PCR) diagnosed COVID-19. English, French, and Spanish studies were included. Meta-analyses were conducted separately for each recruitment setting. RESULTS: We identified 41 studies with 9,362 patients that recovered from COVID-19. Post-COVID-19 patients self-report of fatigue was higher compared to healthy controls (risk ratio (RR) = 3.688, 95%CI [2.502, 5.436], p < .001). Over 50% of patients discharged from inpatient care reported symptoms of fatigue during the first (event rate [ER] = 0.517, 95%CI [0.278, 0.749]) and second month following recovery (ER = 0.527, 95%CI [0.337, 0.709]). Ten percent of the community patients reported fatigue in the first-month post-recovery. Patient setting moderated the association between COVID-19 recovery and fatigue symptoms (R2 = 0.11, p < .001). Female patients recovering from COVID-19 had a greater self-report of fatigue (odds ratio [OR] = 1.782, 95%CI [1.531, 2.870]). Patients recruited through social media had fatigue above 90% across multiple time points. Fatigue was highest in studies from Europe. CONCLUSION: Fatigue is a symptom associated with functional challenges which could have economic and social impacts. Developing long-term planning for fatigue management amongst patients beyond the acute stages of SARS-CoV-2 infection is essential to optimizing patient care and public health outcomes. Further studies should examine the impact of sociodemographic, pandemic-related restrictions and pre-existing conditions on fatigue.

Interaction of tacrolimus through hedgehog signaling pathway: An in vitro evaluation using rat hepatocytes.

Tacrolimus (TAC) is the drug of choice in immunosuppressive therapy for organ transplantation; however, adverse effects are still a major concern. The current study aims to decipher the short-term exposure of TAC on rat hepatocytes in relation to activation of hedgehog (HH) signaling pathway. Time dependent study was conducted using primary rat hepatocytes treated with TAC (36 µM) for 6, 12, 24 and 48 h. Western blot analysis was performed using cell lysate in order to analyze the regulation of HH pathway proteins including HHIP, SMO, PTCH, IHH, SHH, and GLI transcription factors. The study revealed change in protein expression of HH signaling molecules with activation of HH pathway, due to downregulation of HHIP, and enrichment of HH ligands with activation of SMO and GLI transcription factors. It is therefore, concluded that short term TAC exposure leads to upregulation of HH pathway in liver, which may initially act to repair the liver damage but can worsen the condition in case of prolonged immunosuppressive therapy. This insight could lead to understand association of off target effects of immunosuppressive drugs and occurrence of other liver diseases in transplant patients when it comes to long term immunosuppressive therapy. These findings also illuminate a novel direction that use of HH inhibitor might provide a therapeutic strategy for immune suppression related liver disorders.

Fatigue symptoms associated with COVID-19 in convalescent or recovered COVID-19 patients; a systematic review and meta-analysis

BackgroundThe prevalence and prognosis of post-acute stage SARS-CoV-2 infection fatigue symptoms remain largely unknown. AimsWe performed a systematic review to evaluate the prevalence of fatigue in post-recovery from SARS-CoV-2 infection. MethodMedline, Embase, PsycINFO, CINAHL, Web of Science, Scopus, trial registries, Cochrane Central Register of Controlled Trials and Google Scholar were searched for studies on fatigue in samples that recovered from PCR diagnosed COVID-19. English, French and Spanish studies were included. Meta-analyses were conducted separately for each recruitment setting. ResultsWe identified 41 studies with 9362 patients that recovered from COVID-19. Post-COVID-19 patients self-report of fatigue was higher compared to healthy controls (RR = 3.688, 95%CI [2.502, 5.436], p < 0.001). Over 50% of patients discharged from inpatient care reported symptoms of fatigue during the first (ER = 0.517, 95%CI [0.278, 0.749]) and second month following recovery (ER = 0.527, 95%CI [0.337, 0.709]). 10% of the community patients reported fatigue in the first-month post-recovery. Patient setting moderated the association between COVID-19 recovery and fatigue symptoms (R2 = 0.11, p < 0.001). Female patients recovering from COVID-19 had a greater self-report of fatigue (OR = 1.782, 95%CI [1.531, 2.870]). Patients recruited through social media had fatigue above 90% across multiple time points. Fatigue was highest in studies from Europe. ConclusionFatigue is a symptom associated with functional challenges which could have economic and social impacts. Developing long-term planning for fatigue management amongst patients beyond the acute stages of SARS-CoV-2 infection is essential to optimizing patient care and public health outcomes. Further studies should examine the impact of sociodemographic, pandemic-related restrictions and pre-existing conditions on fatigue.

Effect of Short-Term Tacrolimus Exposure on Rat Liver: An Insight into Serum Antioxidant Status, Liver Lipid Peroxidation, and Inflammation.

Tacrolimus (TAC) is an immunosuppressive drug, optimally used for liver, kidney, and heart transplant to avoid immune rejection. In retrospect, a multitude of studies have reported effects of TAC, such as nephrotoxicity, diabetes, and other complications. However, limited information is available regarding short-term exposure of TAC on the liver. Therefore, the present study was designed to unravel the effects of short-term exposure of TAC on a rat model. The animal model was established by TAC administration for 6, 12, 24, and 48 h time points. Liver histopathological changes were observed with PAS-D, reticulin stain, and immunostaining of PCNA and CK-7 coupled with glycogen quantification in a liver homogenate. TUNEL assay was performed to evaluate the DNA damage in the liver. Concentration of GSH and activities of SOD and CAT in the serum were measured to assess the antioxidant status, whereas liver tissue MDA level was measured as a biomarker of oxidative stress. Hepatic gene expression analysis of IL-10, IL-13, SOCS-2, and SOCS-3 was performed by RT-PCR. Results revealed marked changes in liver architecture of all TAC-treated groups, as evidenced by sinusoid dilation, hepatocyte derangement, glycogen deposition, and collapsed reticulin fibers. Significant increase in PCNA and CK-7 immunostaining along with the presence of TUNEL-positive cells was revealed in treatment groups as compared to the control group. Serum antioxidant enzyme status was markedly decreased, whereas the liver MDA level was increased in TAC treatment groups indicating oxidative stress induction. The gene expression profile of cytokines was significantly upregulated in treatment groups highlighting an inflammatory response. In conclusion, results of the current study propose that even a short-term TAC exposure can induce change in antioxidant status and lipid peroxidation. Therefore, these factors should be considered to avoid and minimize immunosuppression-related issues in a prolonged course of treatment.

Liaison psychiatry services in Wales.

Aims and methodRecent funding from Welsh Government for mental health has helped to develop liaison psychiatry services in Wales. Systematic data collection was undertaken to map the liaison psychiatry services in Wales in collaboration with the Royal College of Psychiatrists in Wales and Public Health Wales 1000 Lives Improvement. A questionnaire was designed and circulated to all the health boards in Wales to gather information to map liaison psychiatry services in Wales. Up-to-date information was confirmed in January 2018, via email. RESULTS: Over the past 2 years, liaison psychiatry services have been set up in six out of seven health boards in Wales. Staffing levels have increased and the remit of services has broadened.Clinical implicationsMapping has highlighted that liaison psychiatry services in Wales continue to evolve. It will be important to continue to monitor these developments and their effects. Comparison with services in England will provide a useful comparison of service provision. A particular challenge will be to establish and monitor liaison psychiatry standards in Wales.Declaration of interestNone.

The Mini-Mental State Examination as a diagnostic and screening test for delirium: systematic review and meta-analysis.

OBJECTIVE: To analyse the evidence concerning the accuracy of the Mini-Mental State Examination (MMSE) as a diagnostic and screening test for the presence of delirium in adults. METHOD: Two authors searched MEDLINE, PsychINFO and EMBASE from inception till March 2014. Articles were included that investigated the diagnostic validity of the MMSE to detect delirium against standardised criteria. A diagnostic validity meta-analysis was conducted. RESULTS: Thirteen studies were included representing 2017 patients in medical settings of whom 29.4% had delirium. The meta-analysis revealed the MMSE had an overall sensitivity and specificity estimate of 84.1% and 73.0%, but this was 81.1% and 82.8% in a subgroup analysis involving robust high quality studies. Sensitivity was unchanged but specificity was 68.4% (95% CI = 50.9-83.5%) in studies using a predefined cutoff of <24 to signify a case. In high-risk samples where delirium was present in 25% of patients, then the Positive predictive value and Negative predictive value would be 50.9% (48.3-66.2%) and 93.2% (90.0-96.5%). CONCLUSION: The MMSE cannot be recommended as a case-finding confirmatory test of delirium, but may be used as an initial screen to rule out high scorers who are unlikely to have delirium with approximately 93% accuracy.

Statistical methods in randomised controlled trials for delirium.

OBJECTIVE: The analysis of clinical trials in delirium is typically complicated by treatment dropouts and by the fact that even untreated individuals may have a good prognosis. These features of delirium trials warrant special statistical attention; implications for each stage of a trial planning process are described. METHODS: Choice of outcome, patient sample, and data collection in delirium trials are discussed. Descriptions are given, together with examples, of time-to-event, imputation-based, linear and nonlinear models for the analysis of randomised controlled trials for delirium. RESULTS: Imputation allows evaluation of the plausibility of individual recovery trajectories, but some simple imputations are found to be unsuitable for delirium research. Time-to-event and nonlinear models encourage a global perspective on analysis, which is often preferable to cross-sectional end-of-trial assessments. It is suggested that nonlinear random effects models for longitudinal trajectories are particularly suitable in a delirium context. CONCLUSION: It is hoped that the methods described, and nonlinear models in particular, will play a part in convincing analyses of future delirium research.

A randomized controlled trial of quetiapine versus placebo in the treatment of delirium.

BACKGROUND: Delirium is a commonly occurring complex neuropsychiatric disorder. Evidence for its treatment based on randomized controlled trials (RCTs) is poor. AIMS: To determine the efficacy and acceptability of quetiapine in the treatment of delirium. METHOD: A double-blind, RCT was conducted. A total of 42 patients were randomized to quetiapine or a placebo group. The primary outcome measure was the Delirium Rating Scale Revised 98. Other scales used were the Brief Psychiatric Rating Scale, Mini-Mental State Examination and Clinical Global Improvement. In order to account for missing data, a nonlinear mixed-effects model was used to estimate the difference between the two groups. RESULTS: The quetiapine group improved more rapidly than the placebo group. Specifically, the quetiapine group recovered 82.7% faster (S.E. 37.1%, P=.026) than the placebo group in terms of DRS-R-98 severity score. In terms of the DRS-R-98 noncognitive subscale, the quetiapine group improved 57.7% faster (S.E. 29.2%, P=.048) than the placebo group. CONCLUSIONS: Quetiapine has the potential to more quickly reduce the severity of noncognitive aspects of delirium. This study was underpowered for treatment comparisons at specific points in time but nonetheless detected significant differences when analyzing the whole study period. While it is not possible to draw definitive conclusions, further larger studies exploring the use of quetiapine in other delirium populations seem justified. Larger increments in the dose of quetiapine may yield even stronger results.

Drug treatment of delirium: past, present and future.

OBJECTIVE: The aim of this review was to summarize and critically evaluate the current literature regarding the safety and efficacy of drug therapy in delirium. We also identified recent research developments and highlighted some ongoing clinical trials to explore future directions in drug treatment and prevention of delirium. METHODS: We conducted a literature search of Medline, Embase, PsychInfo, and Cochrane Review databases, which included both prospective and retrospective clinical trials and case studies on delirium and drug therapy in adult patients up to March 2008. Abstracts from recent topical conferences were also reviewed. Ongoing delirium drug studies were identified via the WHO International Clinical Trials Registry Platform Search Portal, accessed March 12, 2008. RESULTS: The evidence base for effective drug treatment of delirium is restricted by limitations in many of the studies conducted to date. However, there has been an increase in the quantity and quality of delirium drug studies in recent years; preliminary reports and ongoing studies add to this trend. Although efficacy rates between typical and atypical antipsychotic agents are similar, the latter are associated with fewer extrapyramidal side effects. Prophylactic interventions with antipsychotic and cholinesterase inhibitors in high-risk patients provide an opportunity to improve postoperative patient care. Alternative techniques and medication opportunities could be explored in attempts to minimize drug induced delirium potential. CONCLUSIONS: Appropriate drug therapy should be considered part of systematic approaches to delirium treatment and prevention. There is a need for well-designed randomized, double-blind placebo-controlled trials investigating the drug management of various aspects of delirium, including delineating treatment by delirium subtype, dose ranging studies, and optimal duration of therapy.