Significance testing of rank cross-correlations between autocorrelated time series with short-range dependence.

Statistical dependency measures such as Kendall's Tau or Spearman's Rho are frequently used to analyse the coherence between time series in environmental data analyses. Autocorrelation of the data can, however, result in spurious cross correlations if not accounted for. Here, we present the asymptotic distribution of the estimators of Spearman's Rho and Kendall's Tau, which can be used for statistical hypothesis testing of cross-correlations between autocorrelated observations. The results are derived using U-statistics under the assumption of absolutely regular (or ß-mixing) processes. These comprise many short-range dependent processes, such as ARMA-, GARCH- and some copula-based models relevant in the environmental sciences. We show that while the assumption of absolute regularity is required, the specific type of model does not have to be specified for the hypothesis test. Simulations show the improved performance of the modified hypothesis test for some common stochastic models and small to moderate sample sizes under autocorrelation. The methodology is applied to observed climatological time series of flood discharges and temperatures in Europe. While the standard test results in spurious correlations between floods and temperatures, this is not the case for the proposed test, which is more consistent with the literature on flood regime changes in Europe.

Immune response to third SARS-CoV-2 vaccination in seronegative kidney transplant recipients: Possible improvement by mycophenolate mofetil reduction.

Modification of vaccination strategies is necessary to improve the immune response to SARS-CoV-2 vaccination in kidney transplant recipients (KTRs). This multicenter observational study analyzed the effects of the third SARS-CoV-2 vaccination in previously seronegative KTRs with the focus on temporary mycophenolate mofetil (MMF) dose reduction within propensity matched KTRs. 56 out of 174 (32%) previously seronegative KTRs became seropositive after the third vaccination with only three KTRs developing neutralizing antibodies against the omicron variant. Multivariate logistic regression revealed that initial antibody levels, graft function, time after transplantation and MMF trough levels had an influence on seroconversion (P < .05). After controlling for confounders, the effect of MMF dose reduction before the third vaccination was calculated using propensity score matching. KTRs with a dose reduction of ≥33% showed a significant decrease in MMF trough levels to 1.8 (1.2-2.5) µg/ml and were more likely to seroconvert than matched controls (P = .02). Therefore, a MMF dose reduction of 33% or more before vaccination is a promising approach to improve success of SARS-CoV-2 vaccination in KTRs.

Intensity of mycophenolate mofetil treatment is associated with an impaired immune response to SARS-CoV-2 vaccination in kidney transplant recipients.

Kidney transplant recipients (KTRs) are extremely vulnerable to SARS-CoV-2 infection and show an impaired immune response to SARS-CoV-2 vaccination. We analyzed factors related to vaccination efficiency in KTRs. In a multicenter prospective observational study (NCT04743947), IgG antibodies levels against SARS-CoV-2 spike S1 subunit and their neutralization capacity after SARS-CoV-2 vaccination were analyzed in 225 KTRs and compared to 176 controls. After the vaccination, 56 (24.9%) KTRs became seropositive of whom 68% had neutralizing antibodies. This immune response was significantly lower compared to controls (239 [78-519] BAU/ml versus 1826 [560-3180] BAU/ml for KTRs and controls, p < .0001). The strongest predictor for an impaired response was mycophenolate mofetil (MMF) treatment. Multivariate regression analysis revealed that MMF-free regimen was highly associated with seroconversion (OR 13.25, 95% CI 3.22-54.6; p < .001). In contrast, other immunosuppressive drugs had no significant influence. 187 out of 225 KTRs were treated with MMF of whom 26 (13.9%) developed antibodies. 23 of these seropositive KTRs had a daily MMF dose ≤1 g. Furthermore, higher trough MMF concentrations correlated with lower antibody titers (R -0.354, p < .001) supporting a dose-dependent unfavorable effect of MMF. Our data indicate that MMF dose modification could lead to an improved immune response.

Impaired Immune Response to SARS-CoV-2 Vaccination in Dialysis Patients and in Kidney Transplant Recipients.

Background: Patients with kidney failure on dialysis or after renal transplantation have a high risk for severe COVID-19 infection, and vaccination against SARS-CoV-2 is the only expedient prophylaxis. Generally, immune responses are attenuated in patients with kidney failure, however, systematic analyses of immune responses to SARS-CoV-2 vaccination in patients on dialysis and in kidney transplant recipients (KTRs) are still needed. Methods: In this prospective, multicentric cohort study, antibody responses to COVID-19 mRNA vaccines (BNT162b2 [BioNTech/Pfizer] or mRNA-1273 [Moderna]) were measured in 32 patients on dialysis and in 28 KTRs. SARS-CoV-2-specific antibodies and neutralization capacity were evaluated and compared with controls (n=78) of a similar age range. Results: After the first vaccination, SARS-CoV-2-specific antibodies were nearly undetectable in patients with kidney failure. After the second vaccination, 93% of the controls and 88% of patients on dialysis but only 37% of KTRs developed SARS-CoV-2-specific IgG above cutoff. Moreover, mean IgG levels were significantly lower in KTRs (54±93 BAU/ml) compared with patients on dialysis (503±481 BAU/ml; P<0.01). Both KTRs and patients on dialysis had significantly lower IgG levels compared with controls (1992±2485 BAU/ml; P<0.001 and P<0.01, respectively). Importantly, compared with controls, neutralizing antibody titers were significantly lower in KTRs and patients on dialysis. After the second vaccination, 76% of KTRs did not show any neutralization capacity against SARS-CoV-2, suggesting impaired seroprotection. Conclusions: Patients with kidney failure show a significantly weaker antibody response compared with controls. Most strikingly, only one out of four KTRs developed neutralizing antibodies against SARS-CoV-2 after two doses of vaccine. These data suggest that vaccination strategies need modification in KTRs and patients on dialysis.Clinical Trial registry name and registration number: Vaccination Against COVID-19 in Chronic Kidney Disease, NCT04743947.

Detecting Flood-Rich and Flood-Poor Periods in Annual Peak Discharges Across Europe.

This paper proposes a method from Scan statistics for identifying flood-rich and flood-poor periods (i.e., anomalies) in flood discharge records. Exceedances of quantiles with 2-, 5-, and 10-year return periods are used to identify periods with unusually many (or few) threshold exceedances with respect to the reference condition of independent and identically distributed random variables. For the case of flood-rich periods, multiple window lengths are used in the identification process. The method is applied to 2,201 annual flood peak series in Europe between 1960 and 2010. Results indicate evidence for the existence of flood-rich and flood-poor periods, as about 2 to 3 times more anomalies are detected than what would be expected by chance. The frequency of the anomalies tends to decrease with an increasing threshold return period which is consistent with previous studies, but this may be partly related to the method and the record length of about 50 years. In the northwest of Europe, the frequency of stations with flood-rich periods tends to increase over time and the frequency of stations with flood-poor periods tends to decrease. In the east and south of Europe, the opposite is the case. There appears to exist a turning point around 1970 when the frequencies of anomalies start to change most clearly. This turning point occurs at the same time as a turning point of the North Atlantic Oscillation index. The method is also suitable for peak-over-threshold series and can be generalized to higher dimensions, such as space and space-time.

Causative classification of river flood events.

A wide variety of processes controls the time of occurrence, duration, extent, and severity of river floods. Classifying flood events by their causative processes may assist in enhancing the accuracy of local and regional flood frequency estimates and support the detection and interpretation of any changes in flood occurrence and magnitudes. This paper provides a critical review of existing causative classifications of instrumental and preinstrumental series of flood events, discusses their validity and applications, and identifies opportunities for moving toward more comprehensive approaches. So far no unified definition of causative mechanisms of flood events exists. Existing frameworks for classification of instrumental and preinstrumental series of flood events adopt different perspectives: hydroclimatic (large-scale circulation patterns and atmospheric state at the time of the event), hydrological (catchment scale precipitation patterns and antecedent catchment state), and hydrograph-based (indirectly considering generating mechanisms through their effects on hydrograph characteristics). All of these approaches intend to capture the flood generating mechanisms and are useful for characterizing the flood processes at various spatial and temporal scales. However, uncertainty analyses with respect to indicators, classification methods, and data to assess the robustness of the classification are rarely performed which limits the transferability across different geographic regions. It is argued that more rigorous testing is needed. There are opportunities for extending classification methods to include indicators of space-time dynamics of rainfall, antecedent wetness, and routing effects, which will make the classification schemes even more useful for understanding and estimating floods. This article is categorized under:Science of Water > Water ExtremesScience of Water > Hydrological ProcessesScience of Water > Methods.

Amount and direction of temporomandibular joint growth changes in Herbst treatment: a cephalometric long-term investigation.

UNLABELLED: The amount and direction of condylar growth, glenoid fossa displacement, and "effective" temporomandibular joint (TMJ) changes (a summation of condylar growth, glenoid fossa displacement, and condylar position changes within the fossa) were analyzed in 35 Class II, Division 1 malocclusions (23 boys and 12 girls) treated with the Herbst appliance. Lateral head films in habitual occlusion and with the mouth wide open from before (T1) and after 7.5 months of Herbst treatment (T2) as well as 7.5 months (T3) and three years (T4) after treatment were evaluated. As a control group, a sample of 12 untreated male Class II Division I malocclusions was used during a 7.5-month time period corresponding to the treatment period (T2-T1) of the Herbst cases. The results revealed that during the treatment period (T2-T1) condylar growth was directed posteriorly about twice the amount as in the control subjects, and the fossa was displaced in an anterior inferior direction. The effective TMJ changes showed a pattern similar to condylar growth but were more pronounced. During the first posttreatment period (T3-T2), all TMJ changes reverted. The glenoid fossa was displaced backward; the amount of condylar growth and effective TMJ changes was reduced, and the changes were more superiorly directed. During the second posttreatment period (T4-T3), all TMJ changes were considered physiological. CONCLUSION: During Herbst treatment, the amount and direction of TMJ changes (condylar growth, fossa displacement, and effective TMJ changes) were only temporarily affected favorably by Herbst treatment.