Time on previous renal replacement therapy is associated with worse outcomes of COVID-19 in a regional cohort of kidney transplant and dialysis patients

Chronic renal replacement therapy by either a kidney transplant (KTX) or hemodialysis (HD) predisposes patients to an increased risk for adverse outcomes of COVID-19. However, details on this interaction remain incomplete. To provide further characterization, we undertook a retrospective observational cohort analysis of the majority of the hemodialysis and renal transplant population affected by the first regional outbreak of severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) in Germany. In a region of 250,000 inhabitants we identified a total of 21 cases with SARS-CoV-2 among 100 KTX and 260 HD patients, that is, 7 KTX with COVID-19, 14 HD with COVID-19, and 3 HD with asymptomatic carrier status. As a first observation, KTX recipients exhibited trends for a higher mortality (43 vs 18%) and a higher proportion of acute respiratory distress syndrome (ARDS) (57 vs 27%) when compared to their HD counterparts. As a novel finding, development of ARDS was significantly associated with the time spent on previous renal replacement therapy (RRT), defined as the composite of dialysis time and time on the transplant (non-ARDS 4.3 vs ARDS 10.6 years, P = .016). Multivariate logistic regression analysis showed an OR of 1.7 per year of RRT. The association remained robust when analysis was confined to KTX patients (5.1 vs 13.2 years, P = .002) or when correlating the time spent on a renal transplant alone (P = .038). Similarly, longer RRT correlated with death vs survival (P = .0002). In conclusion our data suggest renal replacement vintage as a novel risk factor for COVID-19-associated ARDS and death. The findings should be validated by larger cohorts.     

Comparative functional and pharmacological characterization of Sandoz proposed biosimilar adalimumab (GP2017): rationale for extrapolation across indications

Background: Biosimilars are approved biologics that match reference medicine in quality, safety, and efficacy. The development of Sandoz proposed biosimilar adalimumab (SPBA; GP2017) involved a target-directed, iterative state-of-the-art quality-by-design development program. Here, we describe the functional and pharmacological characterization of SPBA and its proposed mechanism of action in immune-mediated inflammatory diseases.

Methods: Sensitive in vitro binding and functional characterization studies, and nonclinical evaluations (pharmacokinetics, pharmacodynamics, and safety/toxicology) were performed as part of a stepwise approach to confirm the biosimilarity of SPBA with reference adalimumab.

Results: Matching values were reported for SPBA and reference adalimumab in binding assays involving tumor necrosis factor (TNF)-α, complement 1q and human immune effector cell Fcγ receptor subtypes in cell-based bioassays for Fc receptor function (complement- and antibody-dependent cytotoxicity), and in apoptosis inhibition. Furthermore, SPBA and reference adalimumab were equivalent in terms of membrane TNF binding and induction of reverse signaling. Pharmacokinetics of SPBA and reference adalimumab were comparable in rabbits, and the two biologics were equally effective in a human TNF transgenic mouse model of polyarthritis.

Conclusion: SPBA matches reference adalimumab with regards to target binding, functional, pharmacokinetic, and pharmacodynamic properties at the nonclinical level supporting its approval in all indications of the reference adalimumab.     

Multimodal Functional Neuroimaging by Simultaneous BOLD fMRI and Fiber-Optic Calcium Recordings and Optogenetic Control

Recent developments of optogenetic tools and fluorescence-based calcium recording techniques enable the manipulation and monitoring of neural circuits on a cellular level. Non-invasive imaging of brain networks, however, requires the application of methods such as blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI), which is commonly used for functional neuroimaging. While BOLD fMRI provides brain-wide non-invasive reading of the hemodynamic response, it is only an indirect measure of neural activity. Direct observation of neural responses requires electrophysiological or optical methods. The latter can be combined with optogenetic control of neuronal circuits and are MRI compatible. Yet, simultaneous optical recordings are still limited to fiber-optic-based approaches. Here, we review the integration of optical recordings and optogenetic manipulation into fMRI experiments. As a practical example, we describe how BOLD fMRI in a 9.4-T small animal MR scanner can be combined with in vivo fiber-optic calcium recordings and optogenetic control in a multimodal setup. We present simultaneous BOLD fMRI and calcium recordings under optogenetic control in rat. We outline details about MR coil configuration, choice, and usage of opsins and chemically and genetically encoded calcium sensors, fiber implantation, appropriate light power for stimulation, and calcium signal detection, to provide a glimpse into challenges and opportunities of this multimodal molecular neuroimaging approach.     

Mortality and rate of stroke or embolism in atrial fibrillation during long-term follow-up in the embolism in left atrial thrombi (ELAT) study

BACKGROUND: Patients with atrial fibrillation (AF) have a higher mortality and risk of stroke/embolism than patients with sinus rhythm. HYPOTHESIS: The aim of the study was to assess the association of clinical and echocardiographic characteristics with mortality and stroke/embolism and the use of antithrombotic medication in the year 2000 in patients who participated 1990-1995 in the Embolism in Left Atrial Thrombi (ELAT) study. METHODS: The study included 409 outpatients with nonrheumatic AF (62 +/- 12 years, 36% women, 39% intermittent AF). Patients with thrombi received anticoagulation, patients without thrombi aspirin until follow-up in 1995; thereafter, anticoagulation according to clinical risk factors was recommended. Primary events were death and secondary events were stroke/embolism. All patients were contacted during the year 2000. RESULTS: Mean follow-up was 102 months. Mortality was 4%/year; the cause of death was cardiac (n = 84), fatal stroke (n = 26), malignancy (n = 23), sepsis (n = 5), and unknown (n = 24). Multivariate analysis identified age (p < 0.0001), heart failure (p = 0.0013), and reduced left ventricular systolic function (p = 0.0353) as predictors of mortality. Stroke/embolism occurred in 83 patients, with a rate of 3%/year. Multivariate analysis identified age (p = 0.0006) and previous stroke (p = 0.0454) as predictors of stroke/embolism. In the year 2000, 51 (21%) of the 247 surviving patients received no antithrombotic medication, 88 received (36%) oral anticoagulants, 102 (41%) acetylsalicylic acid, and 6 (2%) low-molecular heparin. CONCLUSIONS: Therapy for heart failure and oral anticoagulation in AF should be seriously considered, especially in elderly patients and in those with previous stroke.     

Patterns of Suicidality and Alcohol Use in Alcoholics with Major Depression

The aims of this study were (1) to comprehensively characterize a population of alcoholics with major depression in a psychiatric hospital, (2) to determine the prevalence of suicidal behavior in this sample, and (3) to determine whether quantity of alcohol ingested was associated with level of suicidality. Ratings of drinking, depression, and suicidality were obtained using both self-rated and observer-rated instruments. The prevalence of suicide attempts in the week before hospitalization was remarkably high, approaching 40%, whereas 70% had made a suicide attempt at some point in their lifetime. These suicide attempts were typically impulsive in nature, involving little if any premeditation. Most subjects reported drinking more heavily than usual on the day of their suicide attempt. Recent suicidal behavior was significantly associated with recent very heavy drinking (<70 drinks per week) and with number of drinks per drinking day. Quantity of drinking per drinking day was also significantly higher in those making a recent suicide attempt. However, no association was found between quantity of alcohol consumption and suicidal ideation. These findings suggest that recent heavy alcohol use primarily affects suicidality by increasing the likelihood of acting on suicidal ideation rather than by inducing suicidal ideation.     

Hemodynamic performance following the Ross operation: comparison of two different techniques

BACKGROUND AND AIM OF THE STUDY: The Ross operation as aortic valve replacement has undergone technical evolution. Originally described as a subcoronary implant, the full-root replacement technique is now more common worldwide. It remains unclear which of the two techniques has the better results. Hence, the hemodynamic performances of the two implantation methods, as applied by two experienced centers, were compared as part of the German Ross Registry. METHODS: In total, 132 (Group 1, root replacement, mean age 40 +/- 14 years) and 249 (Group 2, subcoronary implant, mean age 48 +/- 14 years) consecutively operated patients were compared clinically and echocardiographically. Data were analyzed focusing on pulmonary autograft and homograft function at mid-term (2.78 +/- 1.89 versus 2.26 +/- 2.11 years). RESULTS: Echocardiography revealed autograft peak systolic gradients of 5.0 +/- 2.7 mmHg for Group 1 and 6.7 +/- 3.7 mmHg for Group 2 (p < 0.05), and an indexed effective orifice area (EOA) of 1.98 +/- 0.57 cm2/m2 and 1.64 +/- 0.43 cm2/m2 (p < 0.05), respectively. Homograft peak systolic gradients were 15.6 +/- 9.0 mmHg and 11.7 +/- 6.8 mmHg for Groups 1 and 2 (p < 0.05) respectively, and the indexed EOA with regard to the homograft was 1.08 +/- 0.49 cm2/m2 and 1.26 +/- 0.50 cm2/m2 (p < 0.05). Autograft insufficiency grade > I was present in 1.5% (2/132) of Group 1 and 2.8% (7/249) of Group 2 patients. Pulmonary insufficiency grade > I was 17.4% (23/132) for Group 1 and 4.8% (12/249) for Group 2 (p < 0.05). CONCLUSION: Although both groups enjoyed excellent hemodynamics in the mid-term, the root replacement technique had the advantage of larger annulus diameters and greater aortic EOA. Clinically relevant autograft regurgitation in both groups was gratifyingly rare, and seemed to be independent of surgical technique. Long-term durability of the more demanding subcoronary technique versus the problems of larger dimensions of the sinus of Valsalva and sinotubular junction in the free-root technique, remains to be proven. Apparent differences in pulmonary homograft hemodynamics can most likely be explained by surgical differences, younger patients in Group 1, and by homograft variation.