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The New England Journal of Medicine Dec 2023The efficacy of simvastatin in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The efficacy of simvastatin in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear.
METHODS
In an ongoing international, multifactorial, adaptive platform, randomized, controlled trial, we evaluated simvastatin (80 mg daily) as compared with no statin (control) in critically ill patients with Covid-19 who were not receiving statins at baseline. The primary outcome was respiratory and cardiovascular organ support-free days, assessed on an ordinal scale combining in-hospital death (assigned a value of -1) and days free of organ support through day 21 in survivors; the analyis used a Bayesian hierarchical ordinal model. The adaptive design included prespecified statistical stopping criteria for superiority (>99% posterior probability that the odds ratio was >1) and futility (>95% posterior probability that the odds ratio was <1.2).
RESULTS
Enrollment began on October 28, 2020. On January 8, 2023, enrollment was closed on the basis of a low anticipated likelihood that prespecified stopping criteria would be met as Covid-19 cases decreased. The final analysis included 2684 critically ill patients. The median number of organ support-free days was 11 (interquartile range, -1 to 17) in the simvastatin group and 7 (interquartile range, -1 to 16) in the control group; the posterior median adjusted odds ratio was 1.15 (95% credible interval, 0.98 to 1.34) for simvastatin as compared with control, yielding a 95.9% posterior probability of superiority. At 90 days, the hazard ratio for survival was 1.12 (95% credible interval, 0.95 to 1.32), yielding a 91.9% posterior probability of superiority of simvastatin. The results of secondary analyses were consistent with those of the primary analysis. Serious adverse events, such as elevated levels of liver enzymes and creatine kinase, were reported more frequently with simvastatin than with control.
CONCLUSIONS
Although recruitment was stopped because cases had decreased, among critically ill patients with Covid-19, simvastatin did not meet the prespecified criteria for superiority to control. (REMAP-CAP ClinicalTrials.gov number, NCT02735707.).
Topics: Humans; Bayes Theorem; COVID-19; COVID-19 Drug Treatment; Critical Illness; Hospital Mortality; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Simvastatin; Treatment Outcome
PubMed: 37888913
DOI: 10.1056/NEJMoa2309995 -
JAMA Nov 2023The efficacy of vitamin C for hospitalized patients with COVID-19 is uncertain.
IMPORTANCE
The efficacy of vitamin C for hospitalized patients with COVID-19 is uncertain.
OBJECTIVE
To determine whether vitamin C improves outcomes for patients with COVID-19.
DESIGN, SETTING, AND PARTICIPANTS
Two prospectively harmonized randomized clinical trials enrolled critically ill patients receiving organ support in intensive care units (90 sites) and patients who were not critically ill (40 sites) between July 23, 2020, and July 15, 2022, on 4 continents.
INTERVENTIONS
Patients were randomized to receive vitamin C administered intravenously or control (placebo or no vitamin C) every 6 hours for 96 hours (maximum of 16 doses).
MAIN OUTCOMES AND MEASURES
The primary outcome was a composite of organ support-free days defined as days alive and free of respiratory and cardiovascular organ support in the intensive care unit up to day 21 and survival to hospital discharge. Values ranged from -1 organ support-free days for patients experiencing in-hospital death to 22 organ support-free days for those who survived without needing organ support. The primary analysis used a bayesian cumulative logistic model. An odds ratio (OR) greater than 1 represented efficacy (improved survival, more organ support-free days, or both), an OR less than 1 represented harm, and an OR less than 1.2 represented futility.
RESULTS
Enrollment was terminated after statistical triggers for harm and futility were met. The trials had primary outcome data for 1568 critically ill patients (1037 in the vitamin C group and 531 in the control group; median age, 60 years [IQR, 50-70 years]; 35.9% were female) and 1022 patients who were not critically ill (456 in the vitamin C group and 566 in the control group; median age, 62 years [IQR, 51-72 years]; 39.6% were female). Among critically ill patients, the median number of organ support-free days was 7 (IQR, -1 to 17 days) for the vitamin C group vs 10 (IQR, -1 to 17 days) for the control group (adjusted proportional OR, 0.88 [95% credible interval {CrI}, 0.73 to 1.06]) and the posterior probabilities were 8.6% (efficacy), 91.4% (harm), and 99.9% (futility). Among patients who were not critically ill, the median number of organ support-free days was 22 (IQR, 18 to 22 days) for the vitamin C group vs 22 (IQR, 21 to 22 days) for the control group (adjusted proportional OR, 0.80 [95% CrI, 0.60 to 1.01]) and the posterior probabilities were 2.9% (efficacy), 97.1% (harm), and greater than 99.9% (futility). Among critically ill patients, survival to hospital discharge was 61.9% (642/1037) for the vitamin C group vs 64.6% (343/531) for the control group (adjusted OR, 0.92 [95% CrI, 0.73 to 1.17]) and the posterior probability was 24.0% for efficacy. Among patients who were not critically ill, survival to hospital discharge was 85.1% (388/456) for the vitamin C group vs 86.6% (490/566) for the control group (adjusted OR, 0.86 [95% CrI, 0.61 to 1.17]) and the posterior probability was 17.8% for efficacy.
CONCLUSIONS AND RELEVANCE
In hospitalized patients with COVID-19, vitamin C had low probability of improving the primary composite outcome of organ support-free days and hospital survival.
TRIAL REGISTRATION
ClinicalTrials.gov Identifiers: NCT04401150 (LOVIT-COVID) and NCT02735707 (REMAP-CAP).
Topics: Humans; Female; Middle Aged; Male; COVID-19; Ascorbic Acid; Critical Illness; Hospital Mortality; Bayes Theorem; Randomized Controlled Trials as Topic; Vitamins; Sepsis
PubMed: 37877585
DOI: 10.1001/jama.2023.21407 -
Frontiers in Psychology 2023
PubMed: 37655193
DOI: 10.3389/fpsyg.2023.1267023 -
Medicines (Basel, Switzerland) Sep 2023Gabapentin (GBP)-induced movement disorders (MDs) are under-recognized adverse drug reactions. They are commonly not discussed with patients, and their sudden occurrence... (Review)
Review
BACKGROUND
Gabapentin (GBP)-induced movement disorders (MDs) are under-recognized adverse drug reactions. They are commonly not discussed with patients, and their sudden occurrence can lead to misdiagnosis. This literature review aims to evaluate the clinical-epidemiological profile, pathological mechanisms, and management of GBP-associated MD.
METHODS
Two reviewers identified and assessed relevant reports in six databases without language restriction between 1990 and 2023.
RESULTS
A total of 99 reports of 204 individuals who developed a MD associated with GBP were identified. The MDs encountered were 135 myoclonus, 22 dyskinesias, 7 dystonia, 3 akathisia, 3 stutterings, 1 myokymia, and 1 parkinsonism. The mean and median ages were 54.54 (SD: 17.79) and 57 years (age range: 10-89), respectively. Subjects were predominantly male (53.57%). The mean and median doses of GBP when the MD occurred were 1324.66 (SD: 1117.66) and 1033 mg/daily (GBP dose range: 100-9600), respectively. The mean time from GBP-onset to GBP-associated MD was 4.58 weeks (SD: 8.08). The mean recovery time after MD treatment was 4.17 days (SD: 4.87). The MD management involved GBP discontinuation. A total of 82.5% of the individuals had a full recovery in the follow-up period.
CONCLUSIONS
Myoclonus (GRADE A) and dyskinesia (GRADE C) were the most common movement disorders associated with GBP.
PubMed: 37755242
DOI: 10.3390/medicines10090052 -
Diagnostics (Basel, Switzerland) Nov 2023Stuttering is a widespread speech disorder affecting people globally, and it impacts effective communication and quality of life. Recent advancements in artificial... (Review)
Review
Stuttering is a widespread speech disorder affecting people globally, and it impacts effective communication and quality of life. Recent advancements in artificial intelligence (AI) and computational intelligence have introduced new possibilities for augmenting stuttering detection and treatment procedures. In this systematic review, the latest AI advancements and computational intelligence techniques in the context of stuttering are explored. By examining the existing literature, we investigated the application of AI in accurately determining and classifying stuttering manifestations. Furthermore, we explored how computational intelligence can contribute to developing innovative assessment tools and intervention strategies for persons who stutter (PWS). We reviewed and analyzed 14 refereed journal articles that were indexed on the from 2019 onward. The potential of AI and computational intelligence in revolutionizing stuttering assessment and treatment, which can enable personalized and effective approaches, is also highlighted in this review. By elucidating these advancements, we aim to encourage further research and development in this crucial area, enhancing in due course the lives of PWS.
PubMed: 38066778
DOI: 10.3390/diagnostics13233537 -
Journal of Speech, Language, and... Sep 2023Repetitive negative thinking (RNT) is the process of engaging in negatively valenced and habitual thought patterns. RNT is strongly associated with mental health...
PURPOSE
Repetitive negative thinking (RNT) is the process of engaging in negatively valenced and habitual thought patterns. RNT is strongly associated with mental health conditions and often affects quality of life. This study explored RNT in older school-age children and adolescents who stutter to quantify the relationship between RNT and self-reported anxiety characteristics. An additional aim was to describe how individual differences in an adolescent's goal when speaking influences the frequency they engage in RNT.
METHOD
Ninety-nine children and adolescents who stutter aged 9-18 years completed a measurement of the frequency/severity of RNT, a screener of anxiety characteristics, and a measure of adverse impact related to stuttering. Children aged 10 years and above also answered questions about their goal when speaking.
RESULTS
Individual differences in RNT significantly predicted Overall Assessment of the Speaker's Experience of Stuttering (OASES) Total Scores more so than a child or adolescent's age. Higher generalized or social anxiety scores were significantly correlated with more frequent RNT and higher OASES Total Scores. Individual differences in goal when speaking (i.e., whether or not to stutter openly) were found to predict RNT. Finally, 22 children and adolescents (22.2%) also screened positive for generalized anxiety disorder and 32 (32.3%) screened positive for social anxiety disorder.
DISCUSSION
These data provide strong evidence that (a) many children and adolescents who stutter engage in RNT; (b) children and adolescents who engage more frequently in RNT or who have higher OASES Total Scores may be at increased risk for more characteristics of generalized or social anxiety; and (c) individual differences in goal when speaking can predict the degree to which an adolescent engages in RNT.
SUPPLEMENTAL MATERIAL
https://doi.org/10.23641/asha.23713296.
Topics: Child; Humans; Adolescent; Aged; Stuttering; Pessimism; Quality of Life; Anxiety; Anxiety Disorders; Surveys and Questionnaires
PubMed: 37494925
DOI: 10.1044/2023_JSLHR-23-00147 -
Current Research in Neurobiology 2023Childhood-onset fluency disorder, commonly referred to as stuttering, affects over 70 million adults worldwide. While stuttering predominantly initiates during childhood... (Review)
Review
Childhood-onset fluency disorder, commonly referred to as stuttering, affects over 70 million adults worldwide. While stuttering predominantly initiates during childhood and is more prevalent in males, it presents consistent symptoms during conversational speech. Despite these common clinical manifestations, evidence suggests that stuttering, may arise from different etiologies, emphasizing the need for personalized therapy approaches. Current research models often regard the stuttering population as a singular, homogenous group, potentially overlooking the inherent heterogeneity. This perspective consolidates both historical and recent observations to emphasize that stuttering is a heterogeneous condition with diverse causes. As such, it is crucial that both therapeutic research and clinical practices consider the potential for varied etiologies leading to stuttering. Recognizing stuttering as a spectrum disorder embraces its inherent variability, allowing for a more nuanced categorization of individuals based on the underlying causes. This perspective aligns with the principles of precision medicine, advocating for tailored treatments for distinct subgroups of people who stutter, ultimately leading to personalized therapeutic approaches.
PubMed: 38020803
DOI: 10.1016/j.crneur.2023.100116 -
Frontiers in Immunology 2023Rac GTPases are required for neutrophil adhesion and migration, and for the neutrophil effector responses that kill pathogens. These Rac-dependent functions are impaired...
Rac GTPases are required for neutrophil adhesion and migration, and for the neutrophil effector responses that kill pathogens. These Rac-dependent functions are impaired when neutrophils lack the activators of Rac, Rac-GEFs from the Prex, Vav, and Dock families. In this study, we demonstrate that Tiam1 is also expressed in neutrophils, governing focal complexes, actin cytoskeletal dynamics, polarisation, and migration, in a manner depending on the integrin ligand to which the cells adhere. Tiam1 is dispensable for the generation of reactive oxygen species but mediates degranulation and NETs release in adherent neutrophils, as well as the killing of bacteria. , Tiam1 is required for neutrophil recruitment during aseptic peritonitis and for the clearance of during pulmonary infection. However, Tiam1 functions differently to other Rac-GEFs. Instead of promoting neutrophil adhesion to ICAM1 and stimulating β2 integrin activity as could be expected, Tiam1 restricts these processes. In accordance with these paradoxical inhibitory roles, Tiam1 limits the fMLP-stimulated activation of Rac1 and Rac2 in adherent neutrophils, rather than activating Rac as expected. Tiam1 promotes the expression of several regulators of small GTPases and cytoskeletal dynamics, including αPix, Psd4, Rasa3, and Tiam2. It also controls the association of Rasa3, and potentially αPix, Git2, Psd4, and 14-3-3ζ/δ, with Rac. We propose these latter roles of Tiam1 underlie its effects on Rac and β2 integrin activity and on cell responses. Hence, Tiam1 is a novel regulator of Rac-dependent neutrophil responses that functions differently to other known neutrophil Rac-GEFs.
Topics: Humans; Neutrophils; Integrins; rac GTP-Binding Proteins; 14-3-3 Proteins; CD18 Antigens
PubMed: 38077328
DOI: 10.3389/fimmu.2023.1223653