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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.

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, Highlights • Remdesivir reduces the odds for mechanical ventilation or extracorporeal membrane oxygenation in COVID-19 patients. • Remdesivir improves the odds for hospital discharge. • Remdesivir does not lower the odds for mortality. • Remdesivir can attenuate COVID-19 progression, but it is less effective in treating critically-ill patients.

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.

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

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.

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.

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.

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.

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.

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 ΔH°, ΔS°, ΔG°37, and TM 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.

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.

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.

The known functions and roles of RNA in nature are vast. Similarly, the types of secondary structure motifs present in RNA are also diverse. These include canonical helices and non-canonical regions, such as internal, bulge, hairpin, and multi-branch loops. Single mismatches, or 1×1 internal loops, are the most frequently occurring secondary structure motif in ribosomal RNA (1) and often times serve integral structural and/or functional roles (2–12). Consequently, single mismatches have been utilized in therapeutic techniques as a target (13–16), an aptamer drug (17, 18), and a probe (19–22). One example of a therapeutic technique utilizing this secondary structure motif is demonstrated by recent studies examining the positional effect of single mismatches on the efficacy of RNA interference (RNAi) activity by placing mismatches at the center and the 5′ and 3′ ends of the sense stranded-small interfering RNA (ss-siRNA) component (19–22). siRNA duplexes with single mismatches placed at the 3′ terminus of the sense strand showed increased RNAi activity when compared to perfectly matched siRNA duplexes or those containing mismatches at the center or 5′ end. These enhanced siRNAs are known as ‘fork-siRNA duplexes’ (19, 22). Furthermore, the activity of short hairpin RNAs (shRNAs) has also been shown to be increased by the incorporation of 3′ terminal single mismatches and a decreased overall thermodynamic stability (ΔG). Westerhout and Berkhout further demonstrated shRNAs were most effective if they possessed a free energy value within a defined window, while also containing 3′ terminal mismatches (21). Synthetic fork-siRNAs and shRNAs are effective therapeutics to suppress gene expression by interacting with the RNA-induced silencing complexes (RISCs) and thereby invoking sequence-specific RNAi activity. 3′ terminal mismatches allow for recognition and duplex unwinding by the RISC helicase activity (23–27). It has been proposed they also minimize off-target gene silencing by resulting in direction specific disassociation of the siRNA and act as sequence specific RNAi mediators in RISC (19). The algorithms most commonly used to predict secondary structure from sequence are based on free energy minimization (28–34) using nearest neighbor parameters and have been incorporated into user-friendly, computer programs. In this method, a given sequence is folded into possible conformations. The total free energy values for each conformation are calculated by summing together the free energy parameters of all secondary structure motifs (experimental or predicted). This results in an optimal structure and a series of suboptimal structures. The optimal structure has the lowest free energy and is predicted to be the predominate structure in solution. These prediction algorithms utilize two methods when assigning free energy parameters to non-canonical regions. If thermodynamic parameters for a given motif are available, the experimentally determined free energy value is assigned. If such parameters have not been experimentally determined, a predicted free energy value is assigned. Much work has been done to thermodynamically characterize single mismatches placed in the center of a duplex (1, 35–37). These studies have shown the contribution of single mismatches to duplex thermodynamics to be dependent on the identity of the nearest neighbors and the identity of the mismatched nucleotides (1, 35–37). For example, we (36) recently proposed a single mismatch specific algorithm which utilizes three parameters consisting of a total of nine variables. The free energy of an RNA duplex containing a single mismatch which has not been thermodynamically characterized can be calculated by: ΔG°37,singlemismatch=ΔG°37,mismatchnt+ΔG°37,mismatch−NNinteraction+ΔG°37,AU+ΔG°37,GU (1) Here, ΔG°37,mismatch nt is −0.3, −2.1, and −0.6 kcal/mol for A·G, G·G, and U·U mismatches, respectively; ΔG°37,mismatch-NN interaction is 0.6, 0.0, 0.6, −0.5, and −0.9 kcal/mol for [Y5′R_R3′R3′R_Y5′],[R5′Y_Y3′Y3′Y_R5′],[Y5′Y_R3′R3′Y_Y5′],[Y5′R_Y3′R3′Y_R5′], and [R5′R_Y3′Y3′Y_R5′] mismatch and nearest neighbor combinations, respectively, when A and G are categorized as purines (R) and C and U are categorized as pyrimidines (Y); ΔG°37,AU is a penalty of 1.1 kcal/mol for replacing a G-C closing base pair with an A-U base pair; and ΔG°37,GU is a penalty of 1.4 kcal/mol for replacing a G-C closing base pair with a G-U base pair. All other combinations of single mismatch nucleotides and nearest neighbors are assumed to contribute no favorable or unfavorable contributions to duplex stability and are assigned a free energy value of zero (36). In addition to the identity of the nearest neighbors and mismatched nucleotides, it is important to note studies have reported the dependence of the thermodynamic stability of small RNA motifs on the duplex position and the identity of non-nearest neighbors (37–42). An example of the thermodynamic dependence on the motif’s duplex position was demonstrated by Kierzek and coworkers investigating the thermodynamics of single mismatches (37). A·A and U·U single mismatches had increased stability the closer they were placed towards the end of the duplex, while G·G single mismatches were unaffected by position in the duplex (37). An investigation of bulges of one nucleotide (38) demonstrated thermodynamic dependence on the identity of non-nearest neighbors and further showed a clear and direct relationship between the thermodynamic stability of the parental duplex and the thermodynamic contribution of the bulge. For example, the bulge [G5′C_U3′C3′A5′] was placed in the center of two different duplex sequences and a 3.0 kcal/mol difference in free energy contribution between the two duplexes was obtained (38). Similarly, a recent thermodynamic study on 1×2 loops (43) showed a strong dependence on the identity of non-nearest neighbors. Placing the 1 × 2 loop [C5′C_C3′G3′AU_G5′] in the center of two different duplex sequences resulted in a difference in free energy contribution of 2.8 kcal/mol (43, 44). Additionally, for tetraloops, or hairpins of four, non-nearest neighbor effects were observed when comparing the thermodynamics of tetraloop contribution to duplex stability when placed in the sequences 5′GCCNNNNGGC3′ and 5′GGCNNNNGCC3′. When tetraloops are placed in the latter stem sequence, they were, on average, 0.6 kcal/mol more stable than in the former sequence (44). Because current secondary structure prediction algorithms assume the thermodynamic contribution of small RNA motifs is independent of both its position in the duplex and identity of the non-nearest neighbors, these results suggest a better understanding of positional and non-nearest neighbor effects may lead to improved algorithms to predict secondary structure from sequence. This work investigates the positional and non-nearest neighbor effects on the thermodynamic contribution of single mismatches by thermodynamically characterizing the same single mismatch-nearest neighbor combinations at three duplex positions within the same stem. Results show positional and/or non-nearest neighbor effects play a role in defining the thermodynamic contribution of single mismatches to duplex stability.