Risk stratification and response to therapy in patients with pulmonary arterial hypertension and comorbidities: A COMPERA analysis

Background: A diagnosis of idiopathic pulmonary arterial hypertension (IPAH) is frequently made in elderly patients who present with comorbidities, especially hypertension, coronary heart disease, diabetes mellitus, and obesity. It is unknown to what extent the presence of these comorbidities affects the response to PAH therapies and whether risk stratification predicts outcome in patients with comorbidities. Methods: We assessed the database of COMPERA, a European pulmonary hypertension registry, to determine changes after initiation of PAH therapy in WHO functional class (FC), 6-minute walking distance (6MWD), brain natriuretic peptide (BNP) or N-terminal fragment of probrain natriuretic peptide (NT-pro-BNP), and mortality risk assessed by a 4-strata model in patients with IPAH and no comorbidities, 1-2 comorbidities and 3-4 comorbidities. Results: The analysis was based on 1,120 IPAH patients (n = 208 [19%] without comorbidities, n = 641 [57%] with 1-2 comorbidities, and n = 271 [24%] with 3-4 comorbidities). Improvements in FC, 6MWD, BNP/NT-pro-BNP, and mortality risk from baseline to first follow-up were significantly larger in patients with no comorbidities than in patients with comorbidities, while they were not significantly different in patients with 1-2 and 3-4 comorbidities. The 4-strata risk tool predicted survival in patients without comorbidities as well as in patients with 1-2 or 3-4 comorbidities. Conclusions: Our data suggest that patients with IPAH and comorbidities benefit from PAH medication with improvements in FC, 6MWD, BNP/NT-pro-BNP, and mortality risk, albeit to a lesser extent than patients without comorbidities. The 4-strata risk tool predicted outcome in patients with IPAH irrespective of the presence of comorbidities

A randomized controlled trial

Objective We report on the effect of hemoadsorption therapy to reduce cytokines in septic patients with respiratory failure. Methods This was a randomized, controlled, open-label, multicenter trial. Mechanically ventilated patients with severe sepsis or septic shock and acute lung injury or acute respiratory distress syndrome were eligible for study inclusion. Patients were randomly assigned to either therapy with CytoSorb hemoperfusion for 6 hours per day for up to 7 consecutive days (treatment), or no hemoperfusion (control). Primary outcome was change in normalized IL-6-serum concentrations during study day 1 and 7. Results 97 of the 100 randomized patients were analyzed. We were not able to detect differences in systemic plasma IL-6 levels between the two groups (n = 75; p = 0.15). Significant IL-6 elimination, averaging between 5 and 18% per blood pass throughout the entire treatment period was recorded. In the unadjusted analysis, 60-day-mortality was significantly higher in the treatment group (44.7%) compared to the control group (26.0%; p = 0.039). The proportion of patients receiving renal replacement therapy at the time of enrollment was higher in the treatment group (31.9%) when compared to the control group (16.3%). After adjustment for patient morbidity and baseline imbalances, no association of hemoperfusion with mortality was found (p = 0.19). Conclusions In this patient population with predominantly septic shock and multiple organ failure, hemoadsorption removed IL-6 but this did not lead to lower plasma IL-6-levels. We did not detect statistically significant differences in the secondary outcomes multiple organ dysfunction score, ventilation time and time course of oxygenation

Real-World Use, Safety, and Patient Experience of 20% Subcutaneous Immunoglobulin for Primary Immunodeficiency Diseases.

INTRODUCTION The CORE study aimed to provide a detailed understanding of real-world immune globulin subcutaneous (human) 20% solution (Ig20Gly) utilization in patients with primary immunodeficiency diseases (PIDs) in Germany and Switzerland. METHODS Patients with PIDs receiving a stable dose of any subcutaneous immunoglobulin for ≥ 3 months before enrollment were eligible for this multicenter (n = 5), phase 4, non-interventional, prospective, longitudinal cohort study. Besides baseline demographics and clinical characteristics, Ig20Gly utilization and safety data, and patient-reported outcomes (Life Quality Index/Treatment Satisfaction Questionnaire for Medication) were collected at baseline, 6 and 12 months. Statistical analysis was descriptive. RESULTS Overall, 36 patients provided data at baseline [69.4% female; mean age: 41.6 years (7-78 years)]. Totals of 23 and 26 patients attended 6- and 12-month visits, respectively; 16 attended all three visits. One patient withdrew consent before 6-month follow-up. Median maximum infusion rates of Ig20Gly at baseline, 6 months, and 12 months were 26.7, 24.5, and 40.0 mL/h, respectively (10-60 mL/h). Infusion and dosing parameters remained consistent across time points: patients used a median of two infusion sites, primarily the abdomen, and all patients used an infusion pump; all but one infused at home and most self-administered Ig20Gly (80.8-83.3%) at once-weekly intervals (69.2-73.9%). During follow-up, 10 adverse events were reported: none were rated serious, while 2 were considered probably related to Ig20Gly. Total patient-reported outcome scores remained high throughout the study. CONCLUSION The CORE study provides real-world evidence of the flexibility, feasibility, safety, and tolerability of Ig20Gly infusions, at mostly weekly intervals, over 1 year in patients with PIDs. TRIAL REGISTRATION German Clinical Trials Register, DRKS00014562. Registered April 9, 2018, https://drks.de/search/en/trial/DRKS00014562

A Nonsense Mutation in TMEM95 Encoding a Nondescript Transmembrane Protein Causes Idiopathic Male Subfertility in Cattle

Genetic variants underlying reduced male reproductive performance have been identified in humans and model organisms, most of them compromising semen quality. Occasionally, male fertility is severely compromised although semen analysis remains without any apparent pathological findings (i.e.,idiopathic subfertility). Artificial insemination (AI) in most cattle populations requires close examination of all ejaculates before insemination. Although anomalous ejaculates are rejected, insemination success varies considerably among AI bulls. In an attempt to identify genetic causes of such variation, we undertook a genome-wide association study (GWAS). Imputed genotypes of 652, 856 SNPs were available for 7962 AI bulls of the Fleckvieh (FV) population. Male reproductive ability (MRA) was assessed based on 15.3 million artificial inseminations. The GWAS uncovered a strong association signal on bovine chromosome 19 (P = 4.08x10(-59)). Subsequent autozygosity mapping revealed a common 1386 kb segment of extended homozygosity in 40 bulls with exceptionally poor reproductive performance. Only 1.7% of 35, 671 inseminations with semen samples of those bulls were successful. None of the bulls with normal reproductive performance was homozygous, indicating recessive inheritance. Exploiting whole-genome resequencing data of 43 animals revealed a candidate causal nonsense mutation (rs378652941, c. 483C>A, p.Cys161X) in the transmembrane protein 95 encoding gene TMEM95 which was subsequently validated in 1990 AI bulls. Immunohistochemical investigations evidenced that TMEM95 is located at the surface of spermatozoa of fertile animals whereas it is absent in spermatozoa of subfertile animals. These findings imply that integrity of TMEM95 is required for an undisturbed fertilisation. Our results demonstrate that deficiency of TMEM95 severely compromises male reproductive performance in cattle and reveal for the first time a phenotypic effect associated with genomic variation in TMEM95

Trends in COVID-19-associated mortality in patients with pulmonary hypertension: a COMPERA analysis

In patients with pulmonary hypertension, the mortality rate associated with COVID-19 has declined sharply with the emergence of the Omicron variants https://bit.ly/42OMsf

Static and dynamic 68Ga-FAPI PET/CT for the detection of malignant transformation of intraductal papillary mucinous neoplasia of the pancreas.

Purpose: Pancreatic ductal adenocarcinoma (PDAC) may arise from intraductal papillary-mucinous neoplasms (IPMN) with malignant transformation, but a significant portion of IPMN remains to show benign behavior. Therefore, it is important to differentiate between benign IPMN and IPMN lesions undergoing malignant transformation. However, non-operative differentiation by ultrasound, CT, MRI and carbohydrate antigen 19-9 (CA19-9) is still unsatisfactory. Here, we assessed the clinical feasibility of additional assessment of malignancy by positron emission tomography using 68Gallium-labeled Fibroblast Activation Protein Inhibitors (68Ga-FAPI-PET) in 25 patients with magnetic resonance imaging (MRI) - or computed tomography (CT) - proven cystic pancreatic lesions. Methods: 25 patients with cystic pancreatic lesions who were followed up in the European Pancreas Center of Heidelberg University hospital and who were led to surgical resection or fine needle aspiration (FNA) due to suspicious clinical, laboratory chemistry or radiological findings were examined by static (all patients) and dynamic (20 patients) 68Ga-FAPI-PET. Cystic pancreatic lesions were delineated and maximum and mean standardized uptake values (SUVmax / SUVmean) were determined. Time activity curves and dynamic parameters (time to peak, K1, k2, K3, k4) were extracted from dynamic PET data. Receiver operating curves (ROC) of static and dynamic PET parameters were calculated. Results: 11 of the patients suffered from menacing IPMN (high grade IPMN with (6 cases) or without (5 cases) progression into PDAC) and 11 from low grade IPMN, 3 patients from other benign entities. Menacing IMPN showed significantly elevated 68Ga-FAPI uptake compared to low grade IPMN and other benign cystic lesions. In dynamic imaging, menacing IPMN showed increasing time activity curves (TAC) followed by slow decrease afterwards, TAC of low grade IPMN showed an immediate peak followed by rapid decrease for about 10 minutes and slower decrease for the rest of the time. ROC curves showed high sensitivity and specificity (area under the curve (AUC) greater than 80%) of static and dynamic PET parameters for the differentiation of IPMN subtypes. Conclusion: 68Ga-FAPI-PET is a helpful new tool for the differentiation of menacing and low grade IPMN and shows the potential to avoid unnecessary surgery for non-malignant pancreatic IPMN

In frame exon skipping in UBE3B is associated with developmental disorders and increased mortality in cattle

Peer reviewe

A frameshift mutation in ARMC3 is associated with a tail stump sperm defect in Swedish Red (Bos taurus) cattle

Background: Artificial insemination is widely used in many cattle breeding programs. Semen samples of breeding bulls are collected and closely examined immediately after collection at artificial insemination centers. Only ejaculates without anomalous findings are retained for artificial insemination. Although morphological aberrations of the spermatozoa are a frequent reason for discarding ejaculates, the genetic determinants underlying poor semen quality are scarcely understood. Results: A tail stump sperm defect was observed in three bulls of the Swedish Red cattle breed. The spermatozoa of affected bulls were immotile because of severely disorganized tails indicating disturbed spermatogenesis. We genotyped three affected bulls and 18 unaffected male half-sibs at 46,035 SNPs and performed homozygosity mapping to map the fertility disorder to an 8.42 Mb interval on bovine chromosome 13. The analysis of whole-genome re-sequencing data of an affected bull and 300 unaffected animals from eleven cattle breeds other than Swedish Red revealed a 1 bp deletion (Chr13: 24,301,425 bp, ss1815612719) in the eleventh exon of the armadillo repeat containing 3-encoding gene (ARMC3) that was compatible with the supposed recessive mode of inheritance. The deletion is expected to alter the reading frame and to induce premature translation termination (p.A451fs26). The mutated protein is shortened by 401 amino acids (46 %) and lacks domains that are likely essential for normal protein function. Conclusions: We report the phenotypic and genetic characterization of a sterilizing tail stump sperm defect in the Swedish Red cattle breed. Exploiting high-density genotypes and massive re-sequencing data enabled us to identify the most likely causal mutation for the fertility disorder in bovine ARMC3. Our results provide the basis for monitoring the mutated variant in the Swedish Red cattle population and for the early identification of infertile animals.Peer reviewe

Maternal placenta modulates a deleterious fetal mutation

Intrauterine growth restriction (IUGR) is caused by dysregulation of placental metabolism. Paternally inherited IUGR mutations in the fetus influence maternal physiology via the placenta. However, it is not known whether the maternal placenta also affects the extent of IUGR in such fetuses. In cattle and other ruminants, maternal-fetal communication occurs primarily at the placentomes. We previously identified a 3 deletion in the noncoding MER1 repeat containing imprinted transcript 1 (MIMT1) gene that, when inherited from the sire, causes IUGR and late abortion in Ayshire cattle with variable levels of severity. Here, we compared the transcriptome and genomic imprinting in fetal and maternal placentome components of wild-type and MIMT1(Del/WT) fetuses before IUGR became apparent, to identify key early events. Transcriptome analysis revealed fewer differentially expressed genes in maternal than fetal MIMT1(Del/WT) placentome. AST1, within the PEG3 domain, was the only gene consistently reduced in IUGR in both fetal and maternal samples. Several genes showed an imprinting pattern associated with IUGR, of which only secernin 3 (SCRN3) and paternally expressed 3 (PEG3) were differentially imprinted in both placentome components. Loss of strictly monoallelic, allele-specific expression (similar to 80:20) of PEG3 in the maternal MIMT1(Del/WT) placenta could be associated with incomplete penetrance of MIMT1(Del). Our data show that dysregulation of the PEG3 domain is involved in IUGR, but also reveal that maternal placental tissues may affect the penetrance of the paternally inherited IUGR mutation.Peer reviewe