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Das therapeutische Potential von niedrig dosiertem Δ9-Tetrahydrocannabinol bei der Modulation der Alzheimer-Pathologie im 5xFAD-Mausmodell
No full textAn ion-imaging detector for high count rates
No full textThe emergence of high-power ionizing light sources with repetition rates greater than 100 kHz promises vastly improved data acquisition times for electron and ion imaging experiments; however, optimal means to record ion images at high average ion flux are challenging. A popular ion imaging detector uses a double (chevron) microchannel plate (MCP) stack operating at high gain (∼106) and a phosphor screen floated to 4 kV while images are recorded using a CCD or CMOS camera. Such imaging detectors tend to exhibit severe inhomogeneity at high incidence ion flux due to saturation effects in the MCP, even when the amplified current is far below the strip-current limit. This inhomogeneity arises from a local loss of gain in channels experiencing a high frequency of ion-amplification events, even when most channels are behaving normally. Here, we describe an alternative ion imaging scheme using a detector based on a single microchannel plate, a phosphor screen that can be floated to 20 kV, and a Timepix3 based event camera and demonstrate its performance in an ion-imaging experiment performed at a repetition rate of 100 kHz. The reduced gain of the single MCP avoids gain inhomogeneity up to higher count-rates, while the high-voltage phosphor helps maintain high single ion detection efficiency. The detector performs well at an ion flux of 107 ions cm−2 s−1.Horizon Europe European Research Council http://dx.doi.org/10.13039/100019180Deutsche Forschungsgemeinschaft http://dx.doi.org/10.13039/50110000165
Bilateral nephrectomy in autosomal dominant polycystic kidney disease patients before or after renal transplantation: data from a retrospective cohort study
No full textABSTRACT Background The indication and timing of native nephrectomy in autosomal dominant polycystic kidney disease (ADPKD) kidney transplant recipients are a matter of ongoing debate. Data on bilateral nephrectomy in such patients is scarce. This study therefore compares the clinical outcome of ADPKD patients undergoing bilateral nephrectomy before or after transplantation. Methods This retrospective single-center study analyzed all ADPKD patients undergoing kidney transplantation at our department between January 2007 and December 2017. Surgical complications, according to the Clavien-Dindo classification, and long-term graft outcomes were compared between ADPKD kidney transplant recipients undergoing bilateral nephrectomy pre- vs posttransplant. Results A total of 273 kidney transplants were performed in ADPKD patients. Of these, 107 (39.2%) patients required native nephrectomy. Unilateral and bilateral nephrectomy was performed in 36 (33.6%) and 71 (66.4%) patients, respectively. We compared seven patients with bilateral nephrectomy before vs 20 patients after kidney transplantation. Pain and cyst infections were the most common indications in both groups. Operation time (P = .001) and perioperative transfusion requirements (P < .001) were significantly increased in the pretransplant nephrectomy group. The total number of Clavien-Dindo complications grade III (P = .054) and IV (P = .015) was greater in patients with nephrectomy preceding transplantation. However, 1-, 3- and 5-year graft and patient survival (P = .347 and P = .596) were not different between the pre- and posttransplant nephrectomy approaches. Conclusions A posttransplant nephrectomy appears to be a relatively safe procedure. However, bilateral nephrectomies are highly invasive and should be avoided unless absolutely necessary. The timing and surgical outcome after nephrectomy do not significantly affect long-term graft or patient survival
Cardiac transthyretin amyloidosis treatment improves outcomes after aortic valve replacement for severe stenosis
No full textAbstract Background and Aims Concomitant aortic stenosis (AS) and transthyretin-associated cardiac amyloidosis (ATTR-CA) is an increasingly recognized cause of structural heart failure. Aortic valve replacement (AVR) improves prognosis in this population, but the efficacy of ATTR-specific medication remains unclear. This study aimed to investigate the prognostic implications of ATTR-specific medication in patients with dual AS-CA. Methods This is a multicenter, international, transatlantic registry of patients with a concomitant pathology of significant AS (moderate/severe) and ATTR-CA (ClinicalTrials.gov identifier: NCT06129331). AS severity was diagnosed by transthoracic echocardiography and ATTR-CA by myocardial uptake on bone scintigraphy and/or positive endomyocardial biopsy in the absence of monoclonal proteins. Mortality [all-cause and cardiovascular (CV)] and hospitalisation for heart failure (HHF) served as clinical endpoints. Outcomes were compared with a control cohort of confirmed lone AS receiving AVR matched for EuroSCORE II. Results Of 226 patients with dual pathology (85 ± 6 years, 80.4% male) identified in 16 centres across 10 countries, AS was severe in 196 (86.7%), and moderate in 30 (13.3%). Valve treatment strategies were transcatheter/surgical AVR in 71.7%/3.5%, balloon angioplasty in 1.3%, and conservative management in 23.5%. Seventy-three patients (32.3%) were prescribed, and 69 patients (30.5%) eventually received ATTR-specific medication (99% tafamidis) and were younger, with lower EuroSCORE II, a higher portion of moderate AS, but higher interventricular septum thickness and more severely impaired left ventricular function compared with patients without ATTR medication. After 3.6 ± 1.7 years, 112 (49.6%) had died [CV death: 89 (79.5%)] and 58 (25.7%) experienced HHF. ATTR-specific medication was independently associated with lower all-cause [weighted hazard ratio (HR) 0.40, 95% confidence interval (CI) 0.24–0.68] and CV mortality (weighted HR 0.47, 95% CI 0.27–0.83) but not HHF. AVR improved survival in the overall (HR 0.60, 95% CI 0.39–0.93) and severe AS cohort (HR 0.42, 95% CI 0.26–0.70). Patients who received both ATTR-specific medication and AVR had the most favourable prognosis, comparable to a control cohort with lone AS undergoing AVR. Conclusions ATTR-specific treatment and AVR both result in significant survival benefit in dual pathology AS and ATTR-CA. Results should be interpreted in the context of the non-randomized study setting and differences in patient characteristics
FUSCANet: Enhancing Skin Disease Classification Through Feature Fusion and Spatial-Channel Attention Mechanisms
No full textComplete mitochondrial genome of Eupelops contaminatus Choi, 1986 (Acari: Oribatida: Phenopelopidae) from Changbai Mountain in China: characterization and its phylogenetic implications
No full textIn this study, we report the complete mitogenome of Eupelops contaminatus Choi, 1986 (Acari, Oribatida, Phenopelopidae) for the first time. The 14,118 bp mitogenome contains 13 protein- coding genes (PCGs), 22 transfer RNA genes, 2 ribosomal RNA genes, and a non-coding region (AT-rich region). Evolutionary analysis of all PCGs based on the non-synonymous/synonymous substitution rate ratio (ω) indicated that cox1 and atp8 exhibited the lowest and highest evolutionary rates, respectively. Phylogenetic analysis based on the 13 PCGs of mitogenomes indicated that E. contaminatus is sister to Eupelops sp. (LC817331), while they differ in gene arrangement. This study offers insights into the mitogenomic basis of Eupelops species and provides an important data resource for exploring the taxonomy, phylogeny, and evolution of oribatid mites
Gating of hair cell Ca 2+ channels governs the activity of cochlear neurons
No full textOur sense of hearing processes sound intensities spanning six orders of magnitude. In the ear, the receptor potential of presynaptic inner hair cells (IHCs) covers the entire intensity range, while postsynaptic spiral ganglion neurons (SGNs) tile the range with their firing rate codes. IHCs vary the voltage dependence of Ca 2+ channel activation among their active zones (AZs), potentially diversifying SGN firing. Here, we tested this hypothesis in mice modeling the human Ca V 1.3 A749G mutation that causes low-voltage Ca 2+ channel activation. We demonstrate activation of Ca 2+ influx and glutamate release of IHC AZs at lower voltages, increased spontaneous firing in SGNs, and lower sound threshold of Ca V 1.3 A749G/A749G mice. Loss of synaptic ribbons in IHCs at ambient sound levels of mouse husbandry indicates that low-voltage Ca 2+ channel activation poses a risk for noise-induced synaptic damage. We propose that the heterogeneous voltage dependence of Ca V 1.3 activation among presynaptic IHC AZs contributes to the diversity of firing among the postsynaptic SGNs.Voltage dependence of presynaptic Ca 2+ channel activation impacts postsynaptic firing and shapes synaptic vulnerability.Our sense of hearing processes sound intensities spanning six orders of magnitude. In the ear, the receptor potential of presynaptic inner hair cells (IHCs) covers the entire intensity range, while postsynaptic spiral ganglion neurons (SGNs) tile the range with their firing rate codes. IHCs vary the voltage dependence of Ca 2+ channel activation among their active zones (AZs), potentially diversifying SGN firing. Here, we tested this hypothesis in mice modeling the human Ca V 1.3 A749G mutation that causes low-voltage Ca 2+ channel activation. We demonstrate activation of Ca 2+ influx and glutamate release of IHC AZs at lower voltages, increased spontaneous firing in SGNs, and lower sound threshold of Ca V 1.3 A749G/A749G mice. Loss of synaptic ribbons in IHCs at ambient sound levels of mouse husbandry indicates that low-voltage Ca 2+ channel activation poses a risk for noise-induced synaptic damage. We propose that the heterogeneous voltage dependence of Ca V 1.3 activation among presynaptic IHC AZs contributes to the diversity of firing among the postsynaptic SGNs.Voltage dependence of presynaptic Ca 2+ channel activation impacts postsynaptic firing and shapes synaptic vulnerability
Treatment outcomes of successful M1 versus M2 thrombectomy for low-ASPECTS stroke patients
No full textBackground The effectiveness of endovascular thrombectomy (EVT) for low Alberta Stroke Program Early CT score (ASPECTS) stroke patients with occlusion of the second segment of the middle cerebral artery (M2) is unclear. Methods This was a multicenter retrospective study. Patients with M1 or M2 occlusions and low ASPECTS (<6) who underwent successful EVT (modified treatment in cerebral ischemia score of 2b or higher) were included. Primary outcome was futile EVT reperfusion (defined as 90-day modified Rankin scale of 5 or 6). Other outcomes of interest include acceptable outcomes (modified Rankin scale of 3 or less) and intracranial hemorrhage (ICH), and all-cause 90-day mortality. Outcomes for M1 patients were compared to M2 patients with multivariable logistic regression models accounting for potential confounders. Results 173 patients with M1 or M2 occlusions and low ASPECTS (<6) who underwent successful EVT were identified. After multivariable adjustments, M2 patients had significantly higher odds of futile reperfusion (OR 5.48 [95%CI 1.91 to 15.7], p = 0.002), lower odds of acceptable outcomes (OR 0.33 [95%CI 0.12 to 0.89], p = 0.028), and higher odds of all-cause mortality (OR 4.90 [95%CI 1.65 to 14.5], p = 0.004). These findings suggest that EVT's efficacy for low-ASPECTS stroke patients may be diminished for patients with M2 occlusions. M2 occlusion was not significantly associated with ICH. Conclusions Among low-ASEPCTS stroke patients who underwent successful EVT, those with M2 occlusions had significantly higher odds of poor outcome compared to those with M1 occlusions.Stryker https://doi.org/10.13039/100008894MedtronicRapidAIMicroventionBrain Aneurysm Foundation https://doi.org/10.13039/100013490Penumbra https://doi.org/10.13039/10002050
Penalized regression splines in Mixture Density Networks
No full textAbstract Mixture Density Networks (MDN) belong to a class of models that can be applied to data which cannot be sufficiently described by a single distribution since it originates from different components of the main unit and therefore needs to be described by a mixture of densities. In some situations, MDNs may have problems with the proper identification of the latent components. While these identification issues can to some extent be contained by using custom initialization strategies for the network weights, this solution is still less than ideal since it involves subjective opinions. We therefore suggest replacing the hidden layers between the model input and the output parameter vector of MDNs and estimating the respective distributional parameters with penalized cubic regression splines. Results on simulated data from both Gaussian and Gamma mixture distributions motivated by an application to indirect reference interval estimation drastically improved the identification performance with all splines reliably converging to their true parameter values
Biomarkers of Kidney Failure and All-Cause Mortality in CKD
No full textKey Points Established risk factor models demonstrate excellent discrimination for CKD outcomes but do not adequately reflect disease activity or mechanisms. We have developed models solely from novel biomarkers that reflect key disease pathways driving CKD progression with equivalent discrimination. Although biomarkers offer limited incremental gains in risk prediction, they may provide critical insights into disease mechanisms and treatment response. Background CKD carries a variable risk for multiple adverse outcomes, highlighting the need for a personalized approach. This study evaluated several novel biomarkers linked to key disease mechanisms to predict the risk of kidney failure (first event of eGFR <15 ml/min per 1.73 m 2 or KRT), all-cause mortality, and a composite of both. Methods We included 2884 adults with nondialysis CKD from 16 nephrology centers across the United Kingdom. Twenty-one biomarkers associated with kidney damage, fibrosis, inflammation, and cardiovascular disease were analyzed in urine, plasma, or serum. Cox proportional hazards models were used to assess biomarker associations and develop risk prediction models. Results Participants had mean age 63 (15) years; 58% were male and 87% White. Median eGFR was 35 (25–47) ml/min per 1.73 m 2 , and the median urinary albumin-to-creatinine ratio was 197 (32–895) mg/g. During median 48 (33–55) months of follow-up, 680 kidney failure events and 414 all-cause mortality events occurred. For kidney failure, a model combining three biomarkers (soluble TNF receptor 1, soluble cluster of differentiation 40, and urinary collagen type 1 α 1 chain) showed good discrimination (C-index, 0.86; 95% confidence interval [CI], 0.83 to 0.89) but was outperformed by a model using established risk factors (age, sex, ethnicity, eGFR, and urinary albumin-to-creatinine ratio; C-index, 0.90; 95% CI, 0.88 to 0.92). For all-cause mortality, a model using three biomarkers (high-sensitivity cardiac troponin T, N -terminal pro-brain natriuretic peptide, and soluble urokinase plasminogen activator receptor) demonstrated equivalent discrimination (C-index, 0.80; 95% CI, 0.75 to 0.84) to an established risk factor model (C-index, 0.80; 95% CI, 0.76 to 0.84). For the composite outcome, the biomarker model discrimination (C-index, 0.78; 95% CI, 0.76 to 0.81) was numerically higher than for established risk factors (C-index, 0.77; 95% CI, 0.74 to 0.80), and the addition of biomarkers to the established risk factors led to a small but statistically significant improvement in discrimination (C-index, 0.80; 95% CI, 0.77 to 0.82; P value <0.01). Conclusions Risk prediction models incorporating novel biomarkers showed comparable discrimination to established risk factors of kidney failure and all-cause mortality. Clinical Trial registry name and registration number: ClinicalTrials.gov, NCT04084145.Roche Diagnostics http://dx.doi.org/10.13039/100016545UCB BiopharmaEvotec International GmbHAstraZenecaTravere Therapeutics http://dx.doi.org/10.13039/10003153