On the relevance of prognostic information for clinical trials: A theoretical quantification.

The question of how individual patient data from cohort studies or historical clinical trials can be leveraged for designing more powerful, or smaller yet equally powerful, clinical trials becomes increasingly important in the era of digitalization. Today, the traditional statistical analyses approaches may seem questionable to practitioners in light of ubiquitous historical prognostic information. Several methodological developments aim at incorporating historical information in the design and analysis of future clinical trials, most importantly Bayesian information borrowing, propensity score methods, stratification, and covariate adjustment. Adjusting the analysis with respect to a prognostic score, which was obtained from some model applied to historical data, received renewed interest from a machine learning perspective, and we study the potential of this approach for randomized clinical trials. In an idealized situation of a normal outcome in a two-arm trial with 1:1 allocation, we derive a simple sample size reduction formula as a function of two criteria characterizing the prognostic score: (1) the coefficient of determination R2 on historical data and (2) the correlation ρ between the estimated and the true unknown prognostic scores. While maintaining the same power, the original total sample size n planned for the unadjusted analysis reduces to ( 1 - R 2 ρ 2 ) × n $(1 - R^2 \rho ^2) \times n$ in an adjusted analysis. Robustness in less ideal situations was assessed empirically. We conclude that there is potential for substantially more powerful or smaller trials, but only when prognostic scores can be accurately estimated.

Assessing relative COVID-19 mortality during the second wave: a prospective Swiss population-based study.

OBJECTIVE: During the first COVID-19 wave in Switzerland, relative mortality was at least eight times higher compared with the uninfected general population. We aimed to assess sex-specific and age-specific relative mortality associated with a SARS-CoV-2 diagnosis during the second wave. DESIGN: Prospective population-based study. SETTING: Individuals testing positive for SARS-CoV-2 after the start of the second wave on 1 October 2020 were followed up until death or administrative censoring on 31 December 2020. PARTICIPANTS: 5 179 740 inhabitants of Switzerland in fall 2018 aged 35-95 years (without COVID-19) and 257 288 persons tested positive for SARS-CoV-2 by PCR or antigen testing during the second wave. PRIMARY AND SECONDARY OUTCOME MEASURES: The planned outcome measure was time to death from any cause, measured from the date of a SARS-CoV-2 diagnosis or 1 October in the general population. Information on confirmed SARS-CoV-2 diagnoses and deaths was matched by calendar time with the all-cause mortality of the general Swiss population of 2018. Proportional hazards models were used to estimate sex-specific and age-specific mortality rates and probabilities of death within 60 days. RESULTS: The risk of death for individuals tested positive for SARS-CoV-2 in the second wave in Switzerland increased at least sixfold compared with the general population. HRs, reflecting the risk attributable to a SARS-CoV-2 infection, were higher for men (1.40, 95% CI 1.29 to 1.52) and increased for each additional year of age (1.01, 95% CI 1.01 to 1.02). COVID-19 mortality was reduced by at least 20% compared with the first wave in spring 2020. CONCLUSION: General mortality patterns, increased for men and older persons, were similar in spring and in fall. Absolute and relative COVID-19 mortality was smaller in fall. TRIAL REGISTRATION: The protocol for this study was registered on 3 December 2020 at https://osf.io/gbd6r.

The Accuracy of Repeated Sleep Studies in OSA: A Longitudinal Observational Study With 14 Nights of Oxygen Saturation Monitoring.

BACKGROUND: Strong evidence exists for clinically relevant night-to-night variability of respiratory events in patients with suspected OSA. RESEARCH QUESTION: How many sleep study nights are required to diagnose OSA accurately? STUDY DESIGN AND METHODS: Patients with suspected OSA underwent up to 14 nights of pulse oximetry (PO) at home and one night of in-hospital respiratory polygraphy (RP). The accuracy of each of the 13 sleep study nights was analyzed using the mean oxygen desaturation index 3% (ODI3%) of all 14 nights as a reference. Multiple regression analyses assessed possible predictors for night-to-night variability. RESULTS: One hundred three patients underwent in-hospital RP. Using only the results of the RP, 19.7% were misdiagnosed using an ODI3% cutoff of 15/h. One hundred eight patients underwent properly performed PO studies at home with a coefficient of variation (CV) of 31.5% (SD, 14.7%) across all nights. The first PO night demonstrated a sensitivity of 71.4% (95% CI, 55.4%-84.3%) and a specificity of 89.4% (95% CI, 79.4%-95.6%) to diagnose moderate OSA. Using only the first PO night, the negative predictive value was 83.1%. Adding a second recording night increased sensitivity up to 88.1% (95% CI, 74.4%-96.0%) with a slightly lower specificity of 85.9% (95% CI, 74.9%-93.4%). The ODI3% of the in-hospital RP showed an independent negative association to the log-transformed CV (exponentiated coefficient, 0.989; 95% CI, 0.984-0.995). INTERPRETATION: One single night of in-hospital RP may miss relevant OSA. Multiple study nights, for example, using ambulatory oxygen saturation monitoring, increase accuracy for diagnosing moderate OSA. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT03819361; URL: www.clinicaltrials.gov.

Obstructive sleep apnoea and the progression of thoracic aortic aneurysm: a prospective cohort study.

BACKGROUND: Obstructive sleep apnoea (OSA) is associated with an increased prevalence of aortic aneurysms and it has also been suggested that severe OSA furthers aneurysm expansion in the abdomen. We evaluated whether OSA is a risk factor for the progression of ascending thoracic aortic aneurysm (TAA). METHODS: Patients with TAA underwent yearly standardised echocardiographic measurements of the ascending aorta over 3 years and two level III sleep studies. The primary outcome was the expansion rate of TAA in relation to the apnoea-hypopnoea index (AHI). Secondary outcomes included surveillance for aortic events (composite end-points of rupture/dissection, elective surgery or death). RESULTS: Between July 2014 and March 2020, 230 patients (median age 70 years, 83.5% male) participated in the cohort. At baseline, 34.8% of patients had AHI ≥15 events·h-1. There was no association between TAA diameter and AHI at baseline. After 3 years, mean±sd expansion rates were 0.55±1.25 mm at the aortic sinus and 0.60±1.12 mm at the ascending aorta. In the regression analysis, after controlling for baseline diameter and cardiovascular risk factors, there was strong evidence for a positive association of TAA expansion with AHI (aortic sinus estimate 0.025 mm, 95% CI 0.009-0.040 mm; p<0.001 and ascending aorta estimate 0.026 mm, 95% CI 0.011-0.041 mm; p=0.001). 20 participants (8%) experienced an aortic event; however, there was no association with OSA severity. CONCLUSION: OSA may be a modest but independent risk factor for faster TAA expansion and thus potentially contributes to life-threatening complications in aortic disease.

Efficacy and safety of tafenoquine for malaria chemoprophylaxis (1998-2020): A systematic review and meta-analysis.

BACKGROUND: In 2018, tafenoquine was approved for malaria chemoprophylaxis. We evaluated all available data on the safety and efficacy of tafenoquine chemoprophylaxis. METHODS: This systematic review followed the PRISMA guidelines and was registered on PROSPERO (CRD42019123839). We searched PubMed, Embase, Scopus, CINAHL and Cochrane databases. Two authors (JDM, PS) screened all papers. RESULTS: We included 44 papers in the qualitative and 9 in the quantitative analyses. These 9 randomized, controlled trials included 2495 participants, aged 12-60 years with 27.3% women. Six studies were conducted in Plasmodium spp.-endemic regions; two were human infection studies. 200 mg weekly tafenoquine and higher dosages lead to a significant reduction of Plasmodium spp. infection compared to placebo and were comparable to 250 mg mefloquine weekly with a protective efficacy between 77.9 and 100% or a total risk ratio of 0.22 (95%-CI: 0.07-0.73; p = 0.013) in favour of tafenoquine. Adverse events (AE) were comparable in frequency and severity between tafenoquine and comparator arms. One study reported significantly more gastrointestinal events in tafenoquine users (p ≤ 0.001). Evidence of increased, reversible, asymptomatic vortex keratopathy in subjects with prolonged tafenoquine exposures was found. A single, serious event of decreased macular sensitivity occurred. CONCLUSION: This systematic review and meta-analysis of trials of G6PD-normal adults show that weekly tafenoquine 200 mg is well tolerated and effective as malaria chemoprophylaxis focusing primarily on Plasmodium falciparum but also on Plasmodium vivax. Our safety analysis is limited by heterogenous methods of adverse events reporting. Further research is indicated on the use of tafenoquine in diverse traveller populations.

Antimicrobial and Insecticidal: Cyclic Lipopeptides and Hydrogen Cyanide Produced by Plant-Beneficial Pseudomonas Strains CHA0, CMR12a, and PCL1391 Contribute to Insect Killing.

Particular groups of plant-beneficial fluorescent pseudomonads are not only root colonizers that provide plant disease suppression, but in addition are able to infect and kill insect larvae. The mechanisms by which the bacteria manage to infest this alternative host, to overcome its immune system, and to ultimately kill the insect are still largely unknown. However, the investigation of the few virulence factors discovered so far, points to a highly multifactorial nature of insecticidal activity. Antimicrobial compounds produced by fluorescent pseudomonads are effective weapons against a vast diversity of organisms such as fungi, oomycetes, nematodes, and protozoa. Here, we investigated whether these compounds also contribute to insecticidal activity. We tested mutants of the highly insecticidal strains Pseudomonas protegens CHA0, Pseudomonas chlororaphis PCL1391, and Pseudomonas sp. CMR12a, defective for individual or multiple antimicrobial compounds, for injectable and oral activity against lepidopteran insect larvae. Moreover, we studied expression of biosynthesis genes for these antimicrobial compounds for the first time in insects. Our survey revealed that hydrogen cyanide and different types of cyclic lipopeptides contribute to insecticidal activity. Hydrogen cyanide was essential to full virulence of CHA0 and PCL1391 directly injected into the hemolymph. The cyclic lipopeptide orfamide produced by CHA0 and CMR12a was mainly important in oral infections. Mutants of CMR12a and PCL1391 impaired in the production of the cyclic lipopeptides sessilin and clp1391, respectively, showed reduced virulence in injection and feeding experiments. Although virulence of mutants lacking one or several of the other antimicrobial compounds, i.e., 2,4-diacetylphloroglucinol, phenazines, pyrrolnitrin, or pyoluteorin, was not reduced, these metabolites might still play a role in an insect background since all investigated biosynthetic genes for antimicrobial compounds of strain CHA0 were expressed at some point during insect infection. In summary, our study identified new factors contributing to insecticidal activity and extends the diverse functions of antimicrobial compounds produced by fluorescent pseudomonads from the plant environment to the insect host.