Characteristics, treatment, and outcomes of Myasthenia Gravis in COVID-19 patients: A systematic review.

OBJECTIVE: Recent studies suggest that the clinical course and outcomes of patients with coronavirus disease 2019 (COVID-19) and myasthenia gravis (MG) are highly variable. We performed a systematic review of the relevant literature with a key aim to assess the outcomes of invasive ventilation, mortality, and hospital length of stay (HLoS) for patients presenting with MG and COVID-19. METHODS: We searched the PubMed, Scopus, Web of Science, and MedRxiv databases for original articles that reported patients with MG and COVID-19. We included all clinical studies that reported MG in patients with confirmed COVID-19 cases via RT-PCR tests. We collected data on patient background characteristics, symptoms, time between MG and COVID-19 diagnosis, MG and COVID-19 treatments, HLoS, and mortality at last available follow-up. We reported summary statistics as counts and percentages or mean±SD. When necessary, inverse variance weighting was used to aggregate patient-level data and summary statistics. RESULTS: Nineteen studies with 152 patients (mean age 54.4 ± 12.7 years; 79/152 [52.0%] female) were included. Hypertension (62/141, 44.0%) and diabetes (30/141, 21.3%) were the most common comorbidities. The mean time between the diagnosis of MG and COVID-19 was7.0 ± 6.3 years. Diagnosis of COVID-19 was confirmed in all patients via RT-PCR tests. Fever (40/59, 67.8%) and ptosis (9/55, 16.4%) were the most frequent COVID-19 and MG symptoms, respectively. Azithromycin and ceftriaxone were the most common COVID-19 treatments, while prednisone and intravenous immunoglobulin were the most common MG treatments. Invasive ventilation treatment was required for 25/59 (42.4%) of patients. The mean HLoS was 18.2 ± 9.9 days. The mortality rate was 18/152 (11.8%). CONCLUSION: This report provides an overview of the characteristics, treatment, and outcomes of MG in COVID-19 patients. Although COVID-19 may exaggerate the neurological symptoms and worsens the outcome in MG patients, we did not find enough evidence to support this notion. Further studies with larger numbers of patients with MG and COVID-19 are needed to better assess the clinical outcomes in these patients.

Corticosteroid therapy for COVID-19: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Corticosteroid treatment is an effective and common therapeutic strategy for various inflammatory lung pathologies and may be an effective treatment for coronavirus disease 2019 (COVID-19). The purpose of this systematic review and meta-analysis of current literature was to investigate the clinical outcomes associated with corticosteroid treatment of COVID-19. METHODS: We systematically searched PubMed, medRxiv, Web of Science, and Scopus databases through March 10, 2021 to identify randomized controlled trials (RCTs) that evaluated the effects of corticosteroid therapies for COVID-19 treatment. Outcomes of interest were mortality, need for mechanical ventilation, serious adverse events (SAEs), and superinfection. RESULTS: A total of 7737 patients from 8 RCTs were included in the quantitative meta-analysis, of which 2795 (36.1%) patients received corticosteroids plus standard of care (SOC) while 4942 (63.9%) patients received placebo and/or SOC alone. The odds of mortality were significantly lower in patients that received corticosteroids as compared to SOC (odds ratio [OR] = 0.85 [95% CI: 0.76; 0.95], P = .003). Corticosteroid treatment reduced the odds of a need for mechanical ventilation as compared to SOC (OR = 0.76 [95% CI: 0.59; 0.97], P = .030). There was no significant difference between the corticosteroid and SOC groups with regards to SAEs and superinfections. CONCLUSION: Corticosteroid treatment can reduce the odds for mortality and the need for mechanical ventilation in severe COVID-19 patients.

Outcomes of acute respiratory distress syndrome in COVID-19 patients compared to the general population: a systematic review and meta-analysis.

INTRODUCTION: Acute respiratory distress syndrome (ARDS) due to coronavirus disease 2019 (COVID-19) often leads to mortality. Outcomes of patients with COVID-19-related ARDS compared to ARDS unrelated to COVID-19 is not well characterized. AREAS COVERED: We performed a systematic review of PubMed, Scopus, and MedRxiv 11/1/2019 to 3/1/2021, including studies comparing outcomes in COVID-19-related ARDS (COVID-19 group) and ARDS unrelated to COVID-19 (ARDS group). Outcomes investigated were duration of mechanical ventilation-free days, intensive care unit (ICU) length-of-stay (LOS), hospital LOS, and mortality. Random effects models were fit for each outcome measure. Effect sizes were reported as pooled median differences of medians (MDMs), mean differences (MDs), or odds ratios (ORs). EXPERT OPINION: Ten studies with 2,281 patients met inclusion criteria (COVID-19: 861 [37.7%], ARDS: 1420 [62.3%]). There were no significant differences between the COVID-19 and ARDS groups for median number of mechanical ventilator-free days (MDM: -7.0 [95% CI: -14.8; 0.7], p = 0.075), ICU LOS (MD: 3.1 [95% CI: -5.9; 12.1], p = 0.501), hospital LOS (MD: 2.5 [95% CI: -5.6; 10.7], p = 0.542), or all-cause mortality (OR: 1.25 [95% CI: 0.78; 1.99], p = 0.361). Compared to the general ARDS population, results did not suggest worse outcomes in COVID-19-related ARDS.

Efficacy of convalescent plasma therapy for COVID-19: A systematic review and meta-analysis.

The purpose of this systematic review and meta-analysis was to examine clinical outcomes associated with convalescent plasma therapy in COVID-19 patients. We performed a literature search on PubMed, medRxiv, Web of Science, and Scopus to identify studies published up to December 10th, 2020 that examined the efficacy of convalescent plasma treatment for COVID-19. The primary endpoints were mortality, clinical improvement, and hospital length of stay. We screened 859 studies that met the search criteria, performed full-text reviews of 56 articles, and identified 15 articles that fulfilled inclusion criteria for meta-analysis. The odds of mortality were significantly lower in the convalescent plasma group compared to the control group (OR = 0.59 [95% CI = 0.44; 0.78], P < .001), although results from two key randomized controlled trials did not support the mortality benefit. The odds of clinical improvement were significantly higher in the convalescent plasma group compared to the control group (OR = 2.02 [95% CI = 1.54; 2.65], P < .001). There was no difference in hospital length of stay between the convalescent plasma group and the control group (MD = -0.49 days [95% CI = -3.11; 2.12], P = .713). In all, these data indicate that a mortality benefit with convalescent plasma is unclear, although there remain benefits with convalescent plasma therapy for COVID-19.

Remdesivir therapy in patients with COVID-19: A systematic review and meta-analysis of randomized controlled trials.

PURPOSE: To perform a systematic review and meta-analysis of randomized controlled trials that examined remdesivir treatment for COVID-19. MATERIALS AND METHODS: A systematic literature search was performed using Pubmed, Embase, and ClinicalTrials.gov to identify studies published up to October 25, 2020 that examined COVID-19 treatment with remdesivir. A total of 3 randomized controlled trials that consisted of 1691 patients were included in the meta-analysis. RESULTS: The odds for mechanical ventilation (MV) or extracorporeal membrane oxygenation (ECMO) following treatment was significantly lower in the remdesivir group compared to the control group (OR = 0.48 [95% CI: 0.34; 0.69], p < 0.001). The odds of early (at day 14/15; OR = 1.42 [95% CI: 1.16; 1.74], p < 0.001) and late (at day 28/29; OR = 1.44 [95% CI: 1.16; 1.79], p = 0.001) hospital discharge were significantly higher in the remdesivir group compared to the control group. There was no difference in the odds for mortality in patients treated with remdesivir (OR = 0.77 [95% CI: 0.56; 1.06], p = 0.108). CONCLUSIONS: Remdesivir attenuates disease progression, leading to lower odds of MV/ECMO and greater odds of hospital discharge for COVID-19 patients. However, remdesivir does not affect odds of mortality.

Efficacy and safety of lopinavir/ritonavir in the treatment of COVID-19: A systematic review.

Objectives: To systematically review the clinical literature reporting the use of Lopinavir/ritonavir (LPV/r) for the treatment of patients with Cornonavirus disease 19 (COVID-19) to assess the efficacy of LPV/r for the treatment of COVID-19.Methods: The authors systematically searched PubMed and MedRxiv databases for studies describing treatment of COVID-19 patients using LPV/r compared to other therapies. Articles were excluded if they were case reports, opinion editorials, preclinical studies, single-armed studies, not written in English, not relevant to the topic, or published before May 2020. The included outcomes were viral clearance as measured by reverse-transcription polymerase chain reaction (RT-PCR) negativity and/or improvement on chest computed tomography (CT), mortality, and adverse events.Results: Among 858 total studies, 16 studies met the inclusion criteria and were included in the qualitative review. These studies consisted of 3 randomized control trials, 3 open-label trials, and 10 observational studies. Most of these studies did not report positive clinical outcomes with LPV/r treatment.Conclusion: The systematic review revealed insufficient evidence of effectiveness and clinical benefit of LPV/r in the treatment of COVID-19 patients. Specifically, LPV/r does not appear to improve clinical outcome, mortality, time to RT-PCR negativity, or chest CT clearance in patients with COVID-19.

A Systematic Review of Intracranial Aneurysms in the Pregnant Patient - A Clinical Conundrum.

Hemodynamic and hormonal changes during pregnancy can increase rates of formation, growth, and rupture of intracranial aneurysms (IA), and the increased incidence of subarachnoid hemorrhage (SA) in pregnant patients represents a risk to both mother and fetus. Despite this, management and treatment guidelines have not been defined for this patient population. In most instances, treatment decisions are made on a case-by-case basis with varying degrees of input from subspecialists. Important considerations, such as aneurysm location, morphology, size, growth pattern, and patient characteristics have not been presented in a management algorithm in the context of the pregnant patient. Given limited and controversial literature describing management of IAs in pregnant patients, we performed a systematic literature review. We then describe our multidisciplinary team approach and provide analysis of existing literature to provide guidelines for the management of the pregnant patient with an IA. A systematic review was undertaken to identify studies describing the management of IAs in the pregnant patient using the PubMed database. Overall maternal and fetal morbidity and mortality rates were determined. Data was analyzed for 1537 patients, including 1115 (73%) pregnant with ruptured intracranial aneurysms. In most cases, these aneurysms were managed conservatively (77%; 781/1013); however, when treatment was provided, surgical clipping was the most common modality (15%; 149/1013). Overall maternal outcomes were reported for 934 cases with morbidity and mortality rates of 5% (42/934) and 21% (194/934), respectively. Overall fetal outcomes were reported for 114 cases with morbidity and mortality rates of 10% (12/119) and 8% (9/119), respectively. Pregnancy-associated physiological changes likely elevate the risk of intracranial aneurysm formation, growth, and rupture. Treatment for aneurysms and SAs is safe and effective during pregnancy when risks are properly mitigated. Due to the complexity of care, such patients should be treated using a collaborative, interdisciplinary approach by a multidisciplinary team.

Sequence selectivity of macrolide-induced translational attenuation.

The prevailing "plug-in-the-bottle" model suggests that macrolide antibiotics inhibit translation by binding inside the ribosome tunnel and indiscriminately arresting the elongation of every nascent polypeptide after the synthesis of six to eight amino acids. To test this model, we performed a genome-wide analysis of translation in azithromycin-treated Staphylococcus aureus. In contrast to earlier predictions, we found that the macrolide does not preferentially induce ribosome stalling near the 5' end of mRNAs, but rather acts at specific stalling sites that are scattered throughout the entire coding region. These sites are highly enriched in prolines and charged residues and are strikingly similar to other ligand-independent ribosome stalling motifs. Interestingly, the addition of structurally related macrolides had dramatically different effects on stalling efficiency. Our data suggest that ribosome stalling can occur at a surprisingly large number of low-complexity motifs in a fashion that depends only on a few arrest-inducing residues and the presence of a small molecule inducer.

RNA CoSSMos: Characterization of Secondary Structure Motifs--a searchable database of secondary structure motifs in RNA three-dimensional structures.

RNA secondary structure is important for designing therapeutics, understanding protein-RNA binding and predicting tertiary structure of RNA. Several databases and downloadable programs exist that specialize in the three-dimensional (3D) structure of RNA, but none focus specifically on secondary structural motifs such as internal, bulge and hairpin loops. The RNA Characterization of Secondary Structure Motifs (RNA CoSSMos) database is a freely accessible and searchable online database and website of 3D characteristics of secondary structure motifs. To create the RNA CoSSMos database, 2156 Protein Data Bank (PDB) files were searched for internal, bulge and hairpin loops, and each loop's structural information, including sugar pucker, glycosidic linkage, hydrogen bonding patterns and stacking interactions, was included in the database. False positives were defined, identified and reclassified or omitted from the database to ensure the most accurate results possible. Users can search via general PDB information, experimental parameters, sequence and specific motif and by specific structural parameters in the subquery page after the initial search. Returned results for each search can be viewed individually or a complete set can be downloaded into a spreadsheet to allow for easy comparison. The RNA CoSSMos database is automatically updated weekly and is available at http://cossmos.slu.edu.

Structural characterization of naturally occurring RNA single mismatches.

RNA is known to be involved in several cellular processes; however, it is only active when it is folded into its correct 3D conformation. The folding, bending and twisting of an RNA molecule is dependent upon the multitude of canonical and non-canonical secondary structure motifs. These motifs contribute to the structural complexity of RNA but also serve important integral biological functions, such as serving as recognition and binding sites for other biomolecules or small ligands. One of the most prevalent types of RNA secondary structure motifs are single mismatches, which occur when two canonical pairs are separated by a single non-canonical pair. To determine sequence-structure relationships and to identify structural patterns, we have systematically located, annotated and compared all available occurrences of the 30 most frequently occurring single mismatch-nearest neighbor sequence combinations found in experimentally determined 3D structures of RNA-containing molecules deposited into the Protein Data Bank. Hydrogen bonding, stacking and interaction of nucleotide edges for the mismatched and nearest neighbor base pairs are described and compared, allowing for the identification of several structural patterns. Such a database and comparison will allow researchers to gain insight into the structural features of unstudied sequences and to quickly look-up studied sequences.

Positional and neighboring base pair effects on the thermodynamic stability of RNA single mismatches.

Many naturally occurring RNA structures contain single mismatches, many of which occur near the ends of helices. However, previous thermodynamic studies have focused their efforts on thermodynamically characterizing centrally placed single mismatches. Additionally, algorithms currently used to predict secondary structure from sequence are based on two assumptions for predicting the stability of RNA duplexes containing this motif. It has been assumed that the thermodynamic contribution of small RNA motifs is independent of both its position in the duplex and the identity of the non-nearest neighbors. Thermodynamically characterizing single mismatches three nucleotides from both the 3' and 5' ends (i.e., off-center) of an RNA duplex and comparing these results to those of the same single mismatch-nearest neighbor combination centrally located have allowed for the investigation of these effects. The thermodynamic contributions of 13 single mismatch-nearest neighbor combinations are reported, but only nine combinations are studied at all three duplex positions and are used to determine trends and patterns. In general, the 5'- and 3'-shifted single mismatches are relatively similar, on average, and more favorable in free energy than centrally placed single mismatches. However, close examination and comparison shows there are several associated idiosyncrasies with these identified general trends. These peculiarities may be due, in part, to the identities of the single mismatch, the nearest neighbors, and the non-nearest neighbors, along with the effects of the single mismatch position in the duplex. The prediction algorithm recently proposed by Davis and Znosko [Davis, A. R., and Znosko, B. M. (2008) Biochemistry 47, 10178-10187] is used to predict the thermodynamic parameters of single mismatch contribution, and those values are compared to the measured values presented here. This comparison suggests the proposed model is a good approximation but could be improved by the addition of parameters that account for positional and/or non-nearest neighbor effects. However, more data are required to improve our understanding of these effects and to accurately account for them.

Thermodynamic characterization of naturally occurring RNA tetraloops.

Although tetraloops are one of the most frequently occurring secondary structure motifs in RNA, less than one-third of the 30 most frequently occurring RNA tetraloops have been thermodynamically characterized. Therefore, 24 stem-loop sequences containing common tetraloops were optically melted, and the thermodynamic parameters DeltaH degrees , DeltaS degrees , DeltaG degrees (37,) and T(M) for each stem-loop were determined. These new experimental values, on average, are 0.7 kcal/mol different from the values predicted for these tetraloops using the model proposed by Vecenie CJ, Morrow CV, Zyra A, Serra MJ. 2006. Biochemistry 45: 1400-1407. The data for the 24 tetraloops reported here were then combined with the data for 28 tetraloops that were published previously. A new model, independent of terminal mismatch data, was derived to predict the free energy contribution of previously unmeasured tetraloops. The average absolute difference between the measured values and the values predicted using this proposed model is 0.4 kcal/mol. This new experimental data and updated predictive model allow for more accurate calculations of the free energy of RNA stem-loops containing tetraloops and, furthermore, should allow for improved prediction of secondary structure from sequence. It was also shown that tetraloops within the sequence 5'-GCCNNNNGGC-3' are, on average, 0.6 kcal/mol more stable than the same tetraloop within the sequence 5'-GGCNNNNGCC-3'. More systemic studies are required to determine the full extent of non-nearest-neighbor effects on tetraloop stability.

Thermodynamic characterization of naturally occurring RNA single mismatches with G-U nearest neighbors.

Due to their prevalence and roles in biological systems, single mismatches adjacent to G-U pairs are important RNA structural elements. Since there are only limited experimental values for the stability of single mismatches adjacent to G-U pairs, current algorithms using free energy minimization to predict RNA secondary structure from sequence assign predicted thermodynamic values to these types of single mismatches. Here, thermodynamic data are reported for frequently occurring single mismatches adjacent to at least one G-U pair. This experimental data can be used in place of predicted thermodynamic values in algorithms that predict secondary structure from sequence using free energy minimization. When predicting the thermodynamic contributions of previously unmeasured single mismatches, most algorithms apply the same thermodynamic penalty for an A-U pair adjacent to a single mismatch and a G-U pair adjacent to a single mismatch. A recent study, however, suggests that the penalty for a G-U pair adjacent to a tandem mismatch should be 1.2 +/- 0.1 kcal/mol, and the penalty for an A-U pair adjacent to a tandem mismatch should be 0.5 +/- 0.2 kcal/mol [Christiansen, M. E. and Znosko, B. M. (2008) Biochemistry 47, 4329-4336]. Therefore, the data reported here are combined with the existing thermodynamic dataset of single mismatches, and nearest neighbor parameters are derived for an A-U pair adjacent to a single mismatch (1.1 +/- 0.1 kcal/mol) and a G-U pair adjacent to a single mismatch (1.4 +/- 0.1 kcal/mol).

Thermodynamic characterization of single mismatches found in naturally occurring RNA.

Many naturally occurring RNA structures contain single mismatches. However, the algorithms currently used to predict RNA structure from sequence rely on a minimal set of data for single mismatches, most of which occur rather infrequently in nature. As a result, several approximations and assumptions are used to predict the stability of RNA duplexes containing the most common single mismatches. Therefore, the relative frequency of single mismatches was determined by compiling and searching a database of 955 RNA secondary structures. Thermodynamic parameters for duplex formation, derived from optical melting experiments, are reported for 28 oligoribonucleotides containing frequently occurring single mismatches. These data were then combined with previous data to construct a dataset of 64 single mismatches, including the 30 most common in the database. Because of this increase in experimental thermodynamic parameters for single mismatches that occur frequently in nature, more accurate free energy calculations have resulted. To improve the prediction of the thermodynamic parameters for duplexes containing single mismatches that have not been experimentally measured, single mismatch-specific nearest neighbor parameters were derived. The free energy of an RNA duplex containing a single mismatch that has not been thermodynamically characterized can be calculated by: DeltaG degrees 37,single mismatch = DeltaG degrees 37,mismatch nt + DeltaG degrees 37,mismatch-NN interaction + DeltaG degrees 37,AU/GU. Here, DeltaG degrees 37,mismatch is -0.4, -2.1, and -0.3 kcal/mol for A.G, G.G, and U.U mismatches, respectively; DeltaG degrees 37,mismatch-NN interaction is 0.7, -0.5, 0.4, -0.4, and -1.0 kcal/mol for 5'YRR3'/3'RRY5', 5'RYY3'/3'YYR5', 5'YYR3'/3'RYY5', 5'YRY3'/3'RYR5', and 5'RRY3'/3'YYR5' mismatch-nearest neighbor combinations, respectively, when A and G are categorized as purines (R) and C and U are categorized as pyrimidines (Y); and DeltaG degrees 37,AU/GU is a penalty of 1.2 kcal/mol for replacing a G-C base pair with either an A-U or G-U base pair. Similar predictive models were also derived for DeltaH degrees single mismatch and DeltaS degrees single mismatch. These new predictive models, in conjunction with the reported thermodynamics for frequently occurring single mismatches, should allow for more accurate calculations of the free energy of RNA duplexes containing single mismatches and, furthermore, allow for improved prediction of secondary structure from sequence.