Long-term renal outcome of Cryopyrin-associated periodic syndrome (CAPS) under anti-Interleukin-1 therapy.

Cryopyrin-associated periodic syndromes (CAPS) are orphan hereditary auto-inflammatory diseases with various phenotypes, including chronic kidney disease (CKD). Current therapies inhibit interleukin-1 (IL-1) to achieve clinical and serological remission; however, the effect on kidney involvement remains unclear. The objective of this study was to investigate the long-term efficacy of anti-IL-1 treatment with special emphasis on renal outcome. We retrospectively analysed clinical, genetic and laboratory data of patients with CAPS under anti-IL-1 therapy from a single-centre university outpatient clinic. Patients with CAPS (n = 28) were followed for a median of 11 (IQR 8.5-13) years. Four patients at various ages (19%), bearing the most common CAPS mutation R260W, had significant CKD at presentation. All affected patients were related; however, other family members with the same genetic variant did not develop CKD. While anti-IL-1 therapy was effective in lowering symptom burden and inflammatory parameters in all CAPS patients, two of the four individuals with significant CKD had persistent proteinuria and worsening kidney function. None of the patients without renal affection at therapy initiation developed relevant CKD in the follow-up period. We showed that in patients with CAPS: (1) CKD is a common complication; (2) renal involvement shows familial predisposition beyond the mutational status and is independent of age; (3) anti-IL-1 therapy results in sustained improvement of inflammatory parameters and symptom load and (4) may prevent development of CAPS-associated CKD but not affect kidney involvement when already present. Overall, early therapy initiation might sufficiently prevent renal disease manifestation and attenuate progression.

Clinical presentation and genetic variants in patients with autoinflammatory diseases: results from the German GARROD registry.

To investigate clinical symptoms and genetic variants in patients from the German anti-IL-1 registry for autoinflammatory orphan diseases (GARROD) between 2013 and 2022. Multicentre, retrospective analysis of demographic, clinical and genetic data of patients with autoinflammatory diseases (AID) who received anti-IL-1 targeted therapy. The cohort comprised 152 patients with familial Mediterranean fever (FMF; n = 71), cryopyrin-associated periodic syndromes (CAPS; n = 43), TNF-receptor associated periodic syndrome (TRAPS; n = 19), mevalonate kinase deficiency (MKD; n = 3) and unclassified AID (uAID; n = 16). Inflammatory attacks started in 61.2% of the patients before the age of 18 years. The delay between the first AID attack and anti-IL-1 therapy was 17.8 years. Monogenetic AIDs were diagnosed by clinical symptoms. Genetic analyses confirmed the diagnosis in 87.3% of patients with FMF, 65.2% with CAPS and 94.8% with TRAPS. Among this group, heterozygous MEFV variants and variants of unknown significance (VUS) were detected in 22.5% of patients with FMF, 51.2% with CAPS and 47.4% with TRAPS. Patients with VUS were older at disease onset which is consistent with a milder phenotype. Twenty-four patients had secondary AA amyloidosis (AA) at initiation of anti-IL-1 therapy. The mean age of these patients was 16.4 years at their first attack and 44.9 years at the time of AA diagnosis. Turkish-Armenian ancestry correlated with MEFV variants and higher FMF disease activity compared to German ancestry. Molecular genetic analyses should substantiate the clinical diagnosis of a monogenetic AID. Our data support the concept of variable penetrance of VUS which can be associated with late-onset AID.

Pre-existing chronic kidney disease, aetiology of acute kidney injury and infection do not affect renal outcome and mortality.

BACKGROUND: We aimed to study the role of aetiology, pre-existing chronic kidney disease (CKD) and infections in acute kidney injury (AKI) on renal outcome and mortality. METHODS: This retrospective study analysed patients with AKI admitted to a university nephrology department from January 1st, 2020 through December 31st, 2020. Aetiology of AKI, underlying renal disease in case of pre-existing CKD and presence of infections were assessed. Development of renal function and risk of death were studied with follow-up until January 31st, 2023. RESULTS: Of 1402 patients screened, 432 patients (30.8%, 67.9 ± 15.4 years) fulfilled the inclusion criteria, half of the population presented with advanced CKD. Even though CKD patients were more often in need of chronic dialysis at time of discharge (6.9% vs 4.5%, p < .001), duration of hospital stay was shorter and in-hospital mortality tended to be lower when compared to AKI without prior renal disease. Neither aetiology of AKI nor pre-existing CKD had an impact on the combined endpoint of end-stage kidney disease and mortality (log rank 0.433 and 0.909). Overall, septic patients showed the highest in-hospital mortality (23.5%) and longest hospital stay (30.0 ± 22.8 days, p < .001), while patients with urosepsis had the shortest hospitalisation time (9.7 days) with lowest risk for dialysis (4.4%). Of note, outcome did not differ in patients with AKI when considering the infectious status. CONCLUSIONS: Overall renal outcome and mortality in AKI patients were not affected by the cause of AKI, pre-existent CKD or infectious status. Only severity of AKI had a negative impact on outcome.

Digital elevation models of the sea-ice surface from airborne laser scanning during MOSAiC.

Airborne laser scanners (ALS) are used to map the sea-ice surface at sub-meter resolution. We conducted 64 flights over the Arctic sea ice between September 2019 and September 2020 during the Multidisciplinary drifting Observatory for the Study of Arctic Climate (MOSAiC) expedition to measure sea-ice surface elevation. The flights ranged from repeated, local-scale 5 × 5 km2 floe grid surveys to regional-scale transects more than 100 km long. We provide data at different processing levels: geolocated elevation point clouds and gridded segments of elevation and freeboard with a spatial resolution of 0.5 m. The latter product is corrected for atmospheric backscatter, sea-ice drift, and offset in elevation due to degraded INS/GNSS solutions > 85° N. For floe grid surveys, all data are combined to merged two-dimensional elevation maps. Other provided parameters include laser reflectance and echo width. The presented data offer a unique possibility to study the temporal evolution, spatial distribution, and variability of the snow and sea-ice surface and their properties in addition to validating satellite products.

Evaluation of simple diagnostic parameters in acute kidney injury in hospitalized patients-diagnostic recommendations for non-nephrologists.

Acute kidney injury (AKI) is very common in hospitalized patients, affecting patient's mortality and morbidity. Major causes are prerenal AKI and acute tubular necrosis (ATN). Even though a variety of parameters/indices exist, their reliability and practicability are controversial: in fact, there is a need for a simple diagnostic approach for AKI in in-patients with parameters easily obtained in any hospital. The objective of the study was: (1) to assess reliability of simple laboratory parameters/indices to differentiate pre-/intrarenal AKI; (2) to evaluate the most reliable and feasible parameters/indices; and (3) to identify the possible impact of confounding factors. Retrospectively, in-patients with AKI hospitalized in 2020 in a university nephrology department were included. Spot urine and 24-h collection urine was analyzed with urine sodium (UNa), urine specific gravity (USG), fractional excretion of sodium (FENa), fractional excretion of urea (FEUrea), urine osmolality (UOsm), urine to plasma creatinine ratio (UCr/PCr) and renal failure index (RFI). Overall, 431 patients were included. UNa, UOsm, USG and RFI showed high specificity > 85% for prerenal AKI, UNa and RFI provided good specificity for ATN. Loop diuretics, ACE inhibitors/AT1 blockers or pre-existing chronic kidney disease had no impact. In patients with AKI, UNa, USG and RFI: (1) proved to be very specific for prerenal AKI and showed high sensitivity for ATN; (2) can be easily determined using serum and spot urine; and (3) are not confounded by medication or comorbidities. These parameters/indices are helpful to identify the aetiology of AKI and to guide therapy, thereby improving patients' safety and outcome.

Helicopter-borne RGB orthomosaics and photogrammetric digital elevation models from the MOSAiC Expedition.

The Multidisciplinary Drifting Observatory for the Study of Arctic Climate (MOSAiC) expedition took place between October 2019 and September 2020 giving the rare opportunity to monitor sea-ice properties over a full annual cycle. Here we present 24 high-resolution orthomosaics and 14 photogrammetric digital elevation models of the sea-ice surface around the icebreaker RV Polarstern between March and September 2020. The dataset is based on >34.000 images acquired by a helicopter-borne optical camera system with survey flights covering areas between 1.8 and 96.5 km2 around the vessel. Depending on the flight pattern and altitude of the helicopter, ground resolutions of the orthomosaics range between 0.03 and 0.5 m. By combining the photogrammetric products with contemporaneously acquired airborne laser scanner reflectance measurements selected orthomosaics could be corrected for cloud shadows which facilitates their usage for sea-ice and melt pond classification algorithms. The presented dataset is a valuable data source for the interdisciplinary MOSAiC community building a temporal and spatially resolved baseline to accompany various remote sensing and in situ research projects.

[Why is the histomorphological diagnosis of small salivary gland tumours so much more difficult?] / Warum ist die histomorphologische Diagnostik von Tumoren kleiner Speicheldrüsen so viel schwieriger?

There is a widespread impression among clinicians and pathologists that the histomorphological diagnosis of minor salivary gland tumours is more difficult and more frequently misdiagnosed than that of major glands. This is based on subjective clinical impression; scientific proof of and potential reasons for this difference are lacking. We identified 14 putative clinical, histopathological and combined clinical-histological reasons and four consequences, which together could explain the perceived greater difficulty of diagnosing minor gland tumours. We performed a thorough literature search and a statistical comparison of data from a personal large consultation series (biased for "difficult" cases) with cumulated data from a routine, unselected (non-consultation) series from the literature. Through this comparison, we could prove with statistical significance a series of reasons and consequences for this greater diagnostic difficulty in minor glands. Frequent incisional biopsies, almost obligatory low-grade bland cytology in malignant tumours and insufficient clinical-pathological communication emerged as the most important reasons. The special anatomic location of the hard palate contributes to further diagnostic difficulties, such as tumour necrosis, mucosal ulceration, pseudoinvasion and the "tumoural-mucosal fusion" phenomenon. Knowledge of these pitfalls in clinic and pathology can help overcome these difficulties and reduce the misdiagnosis rate in minor gland tumours. Our findings result in a series of recommendations both for the clinic and pathology.

[New information about tumours of the salivary glands : WHO classification 2022]. / Neues zu Tumoren der Speicheldrüsen : WHO-Klassifikation 2022.

The WHO 2022 classification of head and neck tumours contains another slight increase in the number of listed benign and malignant tumour entities of the salivary glands. This includes conceptual changes and alterations in the terminology of some entities. While some new features are regarded as preliminary or provisional, others are strongly disputed (for example the terminology of intraductal carcinoma). The impact of molecular findings, mainly recurrent gene fusions, continues to increase rapidly and some have been included in the definition of certain tumour entities. The significance of molecular findings is, however, still largely restricted to diagnostic aspects. Newly included entities include microsecretory carcinoma (defined by an SS18::MEF2C fusion), sclerosing microcystic adenocarcinoma (similar to skin adnexal tumours of the same name) and mucinous adenocarcinoma (characterized by AKT1 mutations with heterogeneous morphology).

Tunneled central venous catheters for hemodialysis-unfairly condemned? Catheter-related complications in a university hospital setting.

BACKGROUND: Central venous catheters (CVCs) provide an immediate hemodialysis access but are considered to be of elevated risk for complications. It remains unclear, if CVCs per se have relevant impact on clinical outcome. We provide an assessment of CVC-associated complications and their impact on mortality. METHODS: In a single center retrospective study, CVC patients between JAN2015-JUN2021 were included. Data on duration of CVC use, complications and comorbidities was collected. Estimated 6-month mortality was compared to actual death rate. RESULTS: About 478 CVCs were analyzed. Initiation of dialysis was the main reason for CVC implantation. Death was predominant for termination of CVC use. Infections were rare (0.6/1000 catheter days), complications were associated with certain comorbidities. Actual 6-month mortality was lower than predicted (14.3% vs 19.6%). CONCLUSION: (1) CVCs are predominantly implanted for initiation of hemodialysis; (2) serious complications are rare; (3) complications are associated with certain comorbidities; and (4) CVC patients survive longer than predicted.

Open-Source Chromatographic Data Analysis for Reaction Optimization and Screening.

Automation and digitalization solutions in the field of small molecule synthesis face new challenges for chemical reaction analysis, especially in the field of high-performance liquid chromatography (HPLC). Chromatographic data remains locked in vendors' hardware and software components, limiting their potential in automated workflows and data science applications. In this work, we present an open-source Python project called MOCCA for the analysis of HPLC-DAD (photodiode array detector) raw data. MOCCA provides a comprehensive set of data analysis features, including an automated peak deconvolution routine of known signals, even if overlapped with signals of unexpected impurities or side products. We highlight the broad applicability of MOCCA in four studies: (i) a simulation study to validate MOCCA's data analysis features; (ii) a reaction kinetics study on a Knoevenagel condensation reaction demonstrating MOCCA's peak deconvolution feature; (iii) a closed-loop optimization study for the alkylation of 2-pyridone without human control during data analysis; (iv) a well plate screening of categorical reaction parameters for a novel palladium-catalyzed cyanation of aryl halides employing O-protected cyanohydrins. By publishing MOCCA as a Python package with this work, we envision an open-source community project for chromatographic data analysis with the potential of further advancing its scope and capabilities.

Identification of Multimorbidity Patterns in Rheumatoid Arthritis Through Machine Learning.

OBJECTIVE: Recognizing that the interrelationships between chronic conditions that complicate rheumatoid arthritis (RA) are poorly understood, we aimed to identify patterns of multimorbidity and to define their prevalence in RA through machine learning. METHODS: We constructed RA and age- and sex-matched (1:1) non-RA cohorts within a large commercial insurance database (MarketScan) and the Veterans Health Administration (VHA). Chronic conditions (n = 44) were identified from diagnosis codes from outpatient and inpatient encounters. Exploratory factor analysis was performed separately in both databases, stratified by RA diagnosis and sex, to identify multimorbidity patterns. The association of RA with different multimorbidity patterns was determined using conditional logistic regression. RESULTS: We studied 226,850 patients in MarketScan (76% female) and 120,780 patients in the VHA (89% male). The primary multimorbidity patterns identified were characterized by the presence of cardiopulmonary, cardiometabolic, and mental health and chronic pain disorders. Multimorbidity patterns were similar between RA and non-RA patients, female and male patients, and patients in MarketScan and the VHA. RA patients had higher odds of each multimorbidity pattern (odds ratios [ORs] 1.17-2.96), with mental health and chronic pain disorders being the multimorbidity pattern most strongly associated with RA (ORs 2.07-2.96). CONCLUSION: Cardiopulmonary, cardiometabolic, and mental health and chronic pain disorders represent predominant multimorbidity patterns, each of which is overrepresented in RA. The identification of multimorbidity patterns occurring more frequently in RA is an important first step in progressing toward a holistic approach to RA management and warrants assessment of their clinical and predictive utility.

New entity of microsecretory adenocarcinoma of salivary glands: first case with recurrence and metastases - proof of malignancy.

Microsecretory adenocarcinoma (MSA) of the salivary glands is a recently described entity. Due to lack of reported metastases, in 30 cases described until now, the designation as low-grade cancer was so far solely based on demonstration of local tumor invasion and in a single case with perineural invasion. We herein describe the first documented case with local recurrence and hematogenous metastases.

Erythrocyte Sedimentation Rate in Patients with Renal Insufficiency and Renal Replacement Therapy.

BACKGROUND: Determination of the erythrocyte sedimentation rate (ESR) is a simple diagnostic tool for estimating systemic inflammation. It remains unclear whether ESR is influenced by renal disease or renal replacement therapy (RRT). OBJECTIVE: To report the incidence and extent of ESR elevations in patients with chronic kidney disease (CKD) and the possible impact of RRT. METHODS: We performed a single-center, retrospective study in inpatients with or without renal disease and in those with RRT, comparing ESR levels and other laboratory and clinical information. RESULTS: A total of 203 patients were included. On average, ESR was elevated (mean [SD], 51.7 [34.6] mm/h), with no statistically significant difference between the patient groups. Only those receiving PD showed significantly higher ESR (78.3 [33.1] mm/h; P < .001). CONCLUSIONS: ESR testing can be used without restriction in patients with CKD and in patients undergoing hemodialysis and who have received kidney transplantation; however, this measurement should be monitored carefully in patients with PD.

Monitoring a changing Arctic: Recent advancements in the study of sea ice microbial communities.

Sea ice continues to decline across many regions of the Arctic, with remaining ice becoming increasingly younger and more dynamic. These changes alter the habitats of microbial life that live within the sea ice, which support healthy functioning of the marine ecosystem and provision of resources for human-consumption, in addition to influencing biogeochemical cycles (e.g. air-sea CO2 exchange). With the susceptibility of sea ice ecosystems to climate change, there is a pressing need to fill knowledge gaps surrounding sea ice habitats and their microbial communities. Of fundamental importance to this goal is the development of new methodologies that permit effective study of them. Based on outcomes from the DiatomARCTIC project, this paper integrates existing knowledge with case studies to provide insight on how to best document sea ice microbial communities, which contributes to the sustainable use and protection of Arctic marine and coastal ecosystems in a time of environmental change.

Results from a national survey on COVID-19-associated mucormycosis in Germany: 13 patients from six tertiary hospitals.

BACKGROUND: Most COVID-19-associated mucormycosis (CAM) cases are reported from India and neighbouring countries. Anecdotally cases from Europe have been presented. OBJECTIVE: To estimate the disease burden and describe the clinical presentation of CAM in Germany. METHODS: We identified cases through German mycology networks and scientific societies, and collected anonymised clinical information via FungiScope®. RESULTS: We identified 13 CAM cases from six tertiary referral hospitals diagnosed between March 2020 and June 2021. Twelve patients had severe or critical COVID-19, eleven were mechanically ventilated for a median of 8 days (range 1-27 days) before diagnosis of CAM. Eleven patients received systemic corticosteroids. Additional underlying medical conditions were reported for all but one patient, five were immunocompromised because of malignancy or organ transplantation, three were diabetic. Eleven patients developed pneumonia. Mortality was 53.8% with a median time from diagnosis of mucormycosis to death of 9 days (range 0-214 days) despite treatment with liposomal amphotericin B and/or isavuconazole in 10 of 13 cases. CAM prevalence amongst hospitalised COVID-19 patients overall (0.67% and 0.58% in two centres) and those admitted to the intensive care unit (ICU) (1.47%, 1.78% and 0.15% in three centres) was significantly higher compared to non-COVID-19 patients (P < .001 for respective comparisons). CONCLUSION: COVID-19-associated mucormycosis is rare in Germany, mostly reported in patients with comorbidities and impaired immune system and severe COVID-19 treated in the ICU with high mortality compared to mainly rhino-orbito-cerebral CAM in patients with mild COVID-19 in India. Risk for CAM is higher in hospitalised COVID-19 patients than in other patients.

Oxidative formation of bis-N-methylquinolinone from anti-head-to-head N-methylquinolinone cyclodimer.

The light-driven formation and cleavage of cyclobutane structural motifs resulting from [2 + 2]-pericyclic reactions, as found in thymine and coumarin-type systems, is an important and intensively studied photochemical reaction. Various applications are reported utilizing these systems, among others, in cross-linked polymers, light-triggered drug release, or other technical applications. Herein coumarin is most frequently used as the photoactive group. Quite often, a poor quantum yield for dimerization and cyclobutane-cleavage and a lack of reversibility are described. In this work, we present the identification of a heterogeneous pathway of dimer cleavage found in a rarely studied coumarin analog molecule, the N-methyl-quinolinone (NMQ). The monomer was irradiated in a tube flow-reactor and the reaction process was monitored using online HPLC measurements. We found the formation of a pseudo-equilibrium between monomeric and dimeric NMQ and a continuous rise of a side product via oxidative dimer splitting and proton elimination which was identified as 3,3'-bis-NMQ. Oxidative conversion by singlet oxygen was identified to be the cause of this non-conventional cyclobutane cleavage. The addition of antioxidants suppressing singlet oxygen enables achieving a 100% photochemical conversion from NMQ to the anti-head-to-head-NMQ-dimer. Using dissolved oxygen upon light activation to singlet oxygen limits the reversibility of the photochemical [2 + 2]-cycloaddition and cycloreversion of NMQ and most likely comparable systems. Based on these findings, the development of highly efficient cycloaddition-cycloreversion systems should be enabled.

Why is the histomorphological diagnosis of tumours of minor salivary glands much more difficult?

AIMS: There is a widespread perception among clinicians and pathologists that the histomorphological assessment of minor salivary gland (MinSG) tumours is more difficult and hampered by more misdiagnoses than that of major salivary gland tumours. This is based on a vague, subjective clinical impression, lacking scientific proof. The aim of the present study was to identify and statistically verify potential reasons that could explain this difference. METHODS AND RESULTS: We identified 14 putative clinical, pathological and combined clinicopathological reasons that, altogether, could explain the phenomenon of the perceived greater diagnostic difficulty associated with MinSG tumours. We performed a comprehensive literature search and a statistical comparison of data from a large personal consultation series (biased for difficult cases) with cumulated data from straightforward, unselected (non-consultation) series from the literature. By performing this comparison, we identified, with statistical significance, a comprehensive series of reasons, as well as of consequences, of the greater difficulty in diagnosing MinSG tumours. CONCLUSIONS: Among the 14 criteria, high frequencies of initial incisional biopsies and of a low-grade category in malignant tumours emerged as the two most important reasons for enhanced diagnostic difficulty. Very rare entities, unusual locations, shortcomings in clinicopathological communication, and pecularities of the special anatomical location of the hard palate, such as tumour necrosis, mucosal ulceration, pseudoinvasion, and the peculiar phenomenon of 'tumoral-mucosal fusion', contribute to further diagnostic difficulties. The awareness of these shortcomings and pitfalls enables us to provide a series of recommendations for clinicians and pathologists that might aid in assessment and reduce the rate of misdiagnosis of MinSG tumours.

Identifying Glycemic Variability in Diabetes Patient Cohorts and Evaluating Disease Outcomes.

Glycemic variability (GV) is an obstacle to effective blood glucose control and an autonomous risk factor for diabetes complications. We, therefore, explored sample data of patients with diabetes mellitus who maintained better amplitude of glycemic fluctuations and compared their disease outcomes with groups having poor control. A retrospective study was conducted using electronic data of patients having hemoglobin A1C (HbA1c) values with five recent time points from Think Whole Person Healthcare (TWPH). The control variability grid analysis (CVGA) plot and coefficient of variability (CV) were used to identify and cluster glycemic fluctuation. We selected important variables using LASSO. Chi-Square, Fisher's exact test, Bonferroni chi-Square adjusted residual analysis, and multivariate Kruskal-Wallis tests were used to evaluate eventual disease outcomes. Patients with very high CV were strongly associated (p < 0.05) with disorders of lipoprotein (p = 0.0014), fluid, electrolyte, and acid-base balance (p = 0.0032), while those with low CV were statistically significant for factors influencing health status such as screening for other disorders (p = 0.0137), long-term (current) drug therapy (p = 0.0019), and screening for malignant neoplasms (p = 0.0072). Reducing glycemic variability may balance alterations in electrolytes and reduce differences in lipid profiles, which may assist in strategies for managing patients with diabetes mellitus.

Improved cognitive function after kidney transplantation compared to hemodialysis.

End-stage renal disease is associated with chronic stress that in turn may result in endocrine changes, affect cognitive, and physical capacities and increase the risk for cardiovascular events. The objective of this study was to evaluate and characterize possible stress parameters and compare cognitive function in those patients. Physiological and biochemical stress parameters as well as cognitive function were assessed in 17 hemodialysis and 18 renal transplant patients and both groups were compared. Serum cortisol and interleukin-6 levels were elevated in both groups but showed no significant difference. Cholesterol and low-density lipoprotein levels were significantly higher in patients following renal transplantation. While heart rate variability was comparable in both groups, most cognitive tests showed better results in renal transplant patients. We showed that: (1) cognitive function may improve following renal transplantation; (2) standard biochemical stress parameters are not useful to discriminate stress in patients with chronic kidney disease; and (3) heart rate variability is unaltered in this setting.