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Introduction: Despite representing only 3% of the US population, immunocompromised (IC) individuals account for nearly half of the COVID-19 breakthrough hospitalizations. IC individuals generate a lower immune response after vaccination in general, and the US CDC recommended a third dose of either mRNA-1273 or BNT162b2 COVID-19 vaccines as part of their primary series. Influenza vaccine trials have shown that increasing dosage could improve effectiveness in IC populations. The objective of this systematic literature review and pairwise meta-analysis was to evaluate the clinical effectiveness of mRNA-1273 (50 or 100 mcg/dose) vs BNT162b2 (30 mcg/dose) in IC populations using the GRADE framework. Methods: The systematic literature search was conducted in the World Health Organization COVID-19 Research Database. Studies were included in the pairwise meta-analysis if they reported comparisons of mRNA-1273 and BNT162b2 in IC individuals =18 years of age; outcomes of interest were symptomatic, laboratory-confirmed SARS-CoV-2 infection, SARS-CoV-2 infection, severe SARS-CoV-2 infection, hospitalization due to COVID-19, and mortality due to COVID-19. Risk ratios (RR) were pooled across studies using random-effects meta-analysis models. Outcomes were also analyzed in subgroups of patients with cancer, autoimmune disease, and solid organ transplant. Risk of bias was assessed using the Newcastle-Ottawa Scale for observational studies. Evidence was evaluated using the GRADE framework. Results: Overall, 17 studies were included in the pairwise meta-analysis. Compared with BNT162b2, mRNA-1273 was associated with significantly reduced risk of SARS-CoV-2 infection (RR, 0.85 [95% CI, 0.75-0.97]; P=0.0151; I2 = 67.7%), severe SARS-CoV-2 infection (RR, 0.85 [95% CI, 0.77-0.93]; P=0.0009; I2 = 0%), COVID-19-associated hospitalization (RR, 0.88 [95% CI, 0.79-0.97]; P<0.0001; I2 = 0%), and COVID-19-associated mortality (RR, 0.63 [95% CI, 0.44-0.90]; P=0.0119; I2 = 0%) in IC populations. Results were consistent across subgroups. Because of sample size limitations, relative effectiveness of COVID-19 mRNA vaccines in IC populations cannot be studied in randomized trials. Based on nonrandomized studies, evidence certainty among comparisons was type 3 (low) and 4 (very low), reflecting potential biases in observational studies. Conclusion: This GRADE meta-analysis based on a large number of consistent observational studies showed that the mRNA-1273 COVID-19 vaccine is associated with improved clinical effectiveness in IC populations compared with BNT162b2. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the comparative efficacy and safety of identified first-line therapies for patients with EGFR mutation-positive (EGFRm+) advanced non-small-cell lung cancer (NSCLC), with a focus on ramucirumab + erlotinib. Methods: In the absence of head-to-head studies, a Bayesian network meta-analysis was conducted using randomized clinical trial data to evaluate first-line systemic therapies with erlotinib/gefitinib as the reference treatment. Results: For progression-free survival, ramucirumab + erlotinib was comparable to osimertinib and dacomitinib in the primary analysis. Conclusion: The analysis showed ramucirumab + erlotinib efficacy to be comparable to best-in-class treatment options for previously untreated patients with EGFRm+ advanced NSCLC. Registration information: PROSPERO ID: CRD42020136247 [ABSTRACT FROM AUTHOR]

Aim: To evaluate the comparative efficacy and safety of identified first-line therapies for patients with EGFR mutation-positive (EGFRm+) advanced non-small-cell lung cancer (NSCLC), with a focus on ramucirumab + erlotinib. Methods: In the absence of head-to-head studies, a Bayesian network meta-analysis was conducted using randomized clinical trial data to evaluate first-line systemic therapies with erlotinib/gefitinib as the reference treatment. Results: For progression-free survival, ramucirumab + erlotinib was comparable to osimertinib and dacomitinib in the primary analysis. Conclusion: The analysis showed ramucirumab + erlotinib efficacy to be comparable to best-in-class treatment options for previously untreated patients with EGFRm+ advanced NSCLC. Registration information: PROSPERO ID: CRD42020136247. [ABSTRACT FROM AUTHOR]

Abstract Background New high-throughput sequencing technologies promise a very sensitive and high-resolution analysis of DNA methylation patterns in quantitative terms. However, a detailed and comprehensive comparison with existing validated DNA methylation analysis methods is not yet available. Therefore, a systematic cross-validation of 454 sequencing and conventional pyrosequencing, both of which offer exact quantification of methylation levels with a single CpG dinucleotide resolution, was performed. Results To this end the methylation patterns of 12 loci (GSTπ1, p16INK4a, RASSF1A, SOCS1, MAL, hsa-mir-1-1, hsa-mir-9-3, hsa-mir-34a, hsa-mir-596, hsa-mir-663, MINT31, and LINE-1) were analyzed in ten primary hepatocellular carcinoma specimens. After applying stringent quality control criteria, 35749 sequences entered further analysis. The methylation level of individual CpG dinucleotides obtained by 454 sequencing was systematically compared with the corresponding values obtained by conventional pyrosequencing. Statistical analyses revealed an excellent concordance of methylation levels for all individual CpG dinucleotides under study (r2 = 0.927). Conclusions Our results confirm that 454 sequencing of bisulfite treated genomic DNA provides reliable high quality quantitative methylation data and identify MAL, hsa-mir-9-3, hsa-mir-596, and hsa-mir-663 as new targets of aberrant DNA methylation in human hepatocelluar carcinoma. In addition, the single molecule resolution of 454 sequencing provides unprecedented information about the details of DNA methylation pattern heterogeneity in clinical samples.

Threat sensitivity is a prominent predictor of interpersonal dysfunctions in borderline personality disorder (BPD), leading to intense, aversive feelings of threat and eventually dysfunctional behaviors, such as aggression. In the present study, BPD patients and healthy volunteers classified angry, fearful, neutral, and happy faces presented for 150 ms or 5,000 ms to investigate initial saccades and facial scanning. Patients more often wrongly identified anger, responded slower to all faces, and made faster saccades towards the eyes of briefly presented neutral faces and slower saccades away from fearful eyes compared with healthy volunteers. Latency of initial saccades and fixation duration correlated negatively with the patients' aggressiveness. Supporting previous results, BPD patients did not experience general deficits in facial emotion processing, but a specific hypersensitivity for and deficits in detailed evaluation of threat cues, which was particularly enhanced in aggressive patients. Interventions might benefit from relocating attention towards positive information and detailed evaluation of social cues. [ABSTRACT FROM AUTHOR]

Background: New high-throughput sequencing technologies promise a very sensitive and high-resolution analysis of DNA methylation patterns in quantitative terms. However, a detailed and comprehensive comparison with existing validated DNA methylation analysis methods is not yet available. Therefore, a systematic cross-validation of 454 sequencing and conventional pyrosequencing, both of which offer exact quantification of methylation levels with a single CpG dinucleotide resolution, was performed. Results: To this end the methylation patterns of 12 loci (GSTπ1, p16INK4a, RASSF1A, SOCS1, MAL, hsa-mir-1-1, hsa-mir- 9-3, hsa-mir-34a, hsa-mir-596, hsa-mir-663, MINT31, and LINE-1) were analyzed in ten primary hepatocellular carcinoma specimens. After applying stringent quality control criteria, 35749 sequences entered further analysis. The methylation level of individual CpG dinucleotides obtained by 454 sequencing was systematically compared with the corresponding values obtained by conventional pyrosequencing. Statistical analyses revealed an excellent concordance of methylation levels for all individual CpG dinucleotides under study (r2 = 0.927). Conclusions: Our results confirm that 454 sequencing of bisulfite treated genomic DNA provides reliable high quality quantitative methylation data and identify MAL, hsa-mir-9-3, hsa-mir-596, and hsa-mir-663 as new targets of aberrant DNA methylation in human hepatocelluar carcinoma. In addition, the single molecule resolution of 454 sequencing provides unprecedented information about the details of DNA methylation pattern heterogeneity in clinical samples. [ABSTRACT FROM AUTHOR]

Focus on patient section. • Two vaccines are licensed in the US and Canada to prevent shingles in ≥50-year-olds. • We compare the efficacy, reactogenicity, and safety of these vaccines (ZVL and RZV). • The short term reactogenicity of RZV was higher than that of ZVL. • Both vaccines have comparable safety profiles. • The vaccine efficacy (VE) of RZV was greater than the VE of ZVL in ≥60-year-olds. We estimated the relative efficacy and safety of vaccines for prevention of herpes zoster (HZ) using network meta-analysis (NMA) based on evidence from randomized controlled trials. A systematic literature review evaluated two different HZ vaccines: adjuvanted recombinant zoster vaccine (RZV) and zoster vaccine live (ZVL), with different formulations assessed. Detailed feasibility assessment indicated that a NMA was feasible for efficacy (incidence of HZ and postherpetic neuralgia [PHN]) and safety (serious adverse events [SAE] and reactogenicity [injection-site reactions, systemic reaction]) outcomes. Primary analyses included frequentist NMAs with fixed effects for efficacy outcomes, due to limited data availability, and both fixed and random effects for safety and reactogenicity outcomes. As age is a known effect modifier of vaccine efficacy (VE), VE analyses were stratified by age. RZV demonstrated significantly higher HZ efficacy than ZVL in adults ≥60 years of age (YOA) (VE RZV = 0.92 (95% confidence interval [95%CI]: 0.88, 0.94), VE ZVL = 0.51 (95%CI: 0.44, 0.57)) and adults ≥70 YOA (VE RZV = 0.91 (95%CI: 0.87, 0.94), VE ZVL = 0.37 (95%CI: 0.25, 0.48)). Similarly, RZV demonstrated significantly higher PHN efficacy than ZVL in adults ≥60 YOA (VE RZV = 0.89 (95%CI: 0.70, 0.96), VE ZVL = 0.66 (95%CI: 0.48, 0.78)) and adults ≥70 YOA (VE RZV = 0.89 (95%CI: 0.69, 0.96), VE ZVL = 0.67 (95%CI: 0.44, 0.80)). RZV was associated with significantly more injection-site and systemic reactions compared to most formulations of ZVL and placebo, however definitions and data collection procedures differed across the included studies. There were no statistically significant differences found between RZV and any formulation of ZVL or placebo for SAEs. RZV is significantly more effective in reducing HZ and PHN incidence in adults ≥60 YOA, compared with ZVL. As anticipated with an adjuvanted vaccine, RZV results in more reactogenicity following immunization. No differences in SAEs were found between RZV and ZVL. [ABSTRACT FROM AUTHOR]

Aim: With no head-to-head studies comparing the effectiveness of lanadelumab and berotralstat for prevention of hereditary angioedema (HAE) attacks, this network meta-analysis (NMA) aimed to indirectly compare the effectiveness of these treatments. Materials & methods: The NMA, using the published data from Phase III trials, was performed using a frequentist weighted regression-based approach following Rücker et al. Efficacy outcomes of interest were HAE attack rate per 28 days and ≥90% reduction in monthly HAE attacks. Results & conclusion: In this NMA, lanadelumab 300 mg administered every 2 weeks or every 4 weeks was associated with statistically significantly higher effectiveness versus berotralstat 150 mg once daily (q.d.) or 110 mg q.d. for both efficacy outcomes assessed.