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Abstract Identification of alloantibodies and achieving a reduction in the rate of red blood cell (RBC) alloimmunization are important issues to prevent transfusion complications. The aim of this study was to identify the antigen and alloantibodies in our patients and to study the association of alloimmunization with previous transfusion. Transfusion records from the blood bank of Kaohsiung Medical University Hospital between 2015 and 2017 were retrospectively enrolled in the study. Antigen and antibody identification was performed using routine blood bank methods. In total, 56,422 transfusion records from 2015 to 2017 were included in the study. Among them, 1858 alloantibody episodes were found in the pre‐transfusion survey, and anti‐Mia, anti‐E, and cold antibodies were the most common alloantibodies, with a prevalence of 3.29% (1858/56,422). Among them, 130 episodes involved newly found alloantibodies with no alloantibodies found in the previous transfusion survey. Tracing back to these newly transfusion‐induced alloantibodies, the antibody was found with a mean of 10.8 ± 7.8 units of packed RBC transfusion, a mean of 66.3 ± 52.8 days, and with a mean of 4.3 ± 2.7 times of transfusion from the first transfusion therapy. An antibody survey revealed that Rh‐ee (62.1%) was the most common phenotype in these newly identified antibodies. In summary, this hospital‐based study revealed that RBC alloantibody rates were present at rates of 3.29%, with anti‐Mia, anti‐E, and cold antibodies being the most common alloantibodies. Among them, anti‐E was the most commonly developed alloantibody. Given that the Rh‐ee group is the most common phenotype in our population, the strategy of using Rh‐ee blood for Rh‐ee recipients is reasonable for transfusion safety.

Abstract Aims Little is known of the impact of systolic pulmonary regurgitation (PR) on acute decompensated heart failure (HF). We assessed the prevalence and prognostic significance of systolic PR in patients with severe HF. Methods and results According to recent 10 year echocardiographic database of E‐Da Hospital, 533 patients admitted for first systolic heart failure (HF) and left ventricular ejection fraction

Abstract Objective This study delineates the clinical and molecular spectrum of ANKLE2‐related microcephaly (MIC), as well as highlights shared pathological mechanisms between ANKLE2 and the Zika virus. Methods We identified 12 individuals with MIC and variants in ANKLE2 with a broad range of features. Probands underwent thorough phenotypic evaluations, developmental assessments, and anthropometric measurements. Brain imaging studies were systematically reviewed for developmental abnormalities. We functionally interrogated a subset of identified ANKLE2 variants in Drosophila melanogaster. Results All individuals had MIC (z‐score ≤ −3), including nine with congenital MIC. We identified a broad range of brain abnormalities including simplified cortical gyral pattern, full or partial callosal agenesis, increased extra‐axial spaces, hypomyelination, cerebellar vermis hypoplasia, and enlarged cisterna magna. All probands had developmental delays in at least one domain, with speech and language delays being the most common. Six probands had skin findings characteristic of ANKLE2 including hyper‐ and hypopigmented macules. Only one individual had scalp rugae. Functional characterization in Drosophila recapitulated the human MIC phenotype. Of the four variants tested, p.Val229Gly, p.Arg236*, and p.Arg536Cys acted as partial‐loss‐of‐function variants, whereas the c.1421‐1G>C splicing variant demonstrated a strong loss‐of‐function effect. Interpretation Deleterious variants in the ANKLE2 gene cause a unique MIC syndrome characterized by congenital or postnatal MIC, a broad range of structural brain abnormalities, and skin pigmentary changes. Thorough functional characterization has identified shared pathogenic mechanisms between ANKLE2‐related MIC and congenital Zika virus infection. This study further highlights the importance of a thorough diagnostic evaluation including molecular diagnostic testing in individuals with MIC.

Abstract RIPK1 is a master regulator of inflammatory signaling and cell death and increased RIPK1 activity is observed in human diseases, including Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS). RIPK1 inhibition has been shown to protect against cell death in a range of preclinical cellular and animal models of diseases. SAR443060 (previously DNL747) is a selective, orally bioavailable, central nervous system (CNS)–penetrant, small‐molecule, reversible inhibitor of RIPK1. In three early‐stage clinical trials in healthy subjects and patients with AD or ALS (NCT03757325 and NCT03757351), SAR443060 distributed into the cerebrospinal fluid (CSF) after oral administration and demonstrated robust peripheral target engagement as measured by a reduction in phosphorylation of RIPK1 at serine 166 (pRIPK1) in human peripheral blood mononuclear cells compared to baseline. RIPK1 inhibition was generally safe and well‐tolerated in healthy volunteers and patients with AD or ALS. Taken together, the distribution into the CSF after oral administration, the peripheral proof‐of‐mechanism, and the safety profile of RIPK1 inhibition to date, suggest that therapeutic modulation of RIPK1 in the CNS is possible, conferring potential therapeutic promise for AD and ALS, as well as other neurodegenerative conditions. However, SAR443060 development was discontinued due to long‐term nonclinical toxicology findings, although these nonclinical toxicology signals were not observed in the short duration dosing in any of the three early‐stage clinical trials. The dose‐limiting toxicities observed for SAR443060 preclinically have not been reported for other RIPK1‐inhibitors, suggesting that these toxicities are compound‐specific (related to SAR443060) rather than RIPK1 pathway‐specific.

Objective Despite proven benefits, less than half of patients with rheumatoid arthritis (RA) are treated using a treat‐to‐target (TTT) strategy. Our objective was to identify critical discrepancies between rheumatologist and patient mental models related to the treatment of RA to inform interventions designed to increase implementation of TTT. Methods We developed rheumatologist and patient mental models using the Mental Models Approach to Risk Communication. We conducted semistructured interviews to elicit views related to RA treatment decisions with 14 rheumatologists and 30 patients with RA. We also included responses (n = 284) to an open‐ended question on a survey fielded to augment qualitative descriptions from the interviews. Interviews were transcribed and coded independently by two members of the research team. Results Rheumatologist and patient mental models for RA treatment are significantly more complex than the TTT model. Both consider domains (system factors and patient readiness) outside of disease activity measurement, target setting, and risk versus benefit assessment in their decision‐making. Furthermore, specific factors were found to be unique to each model. For example, the physician model stresses the importance of evaluating disease activity over time and patient adherence. In contrast, patients discussed the impact of chronic disease weariness, medication‐related fatigue, the importance of feeling adequately informed, and stress associated with changing medications. Conclusion We found several discrepancies primarily related to information gaps and differences in how patients and physicians value trade‐offs that can serve as specific targets to improve patient–physician communication and ultimately inform interventions to improve uptake of TTT.

Abstract Background and Purpose Although cytotoxic platinum‐based adjuvant chemotherapy (pACT) has been recommended for patients with completely resected early‐stage (ES) non–small‐cell lung cancer (ES‐NSCLC), therapeutic regimens for NSCLC have evolved in the past two decades. The study was aimed to examine the effectiveness of postoperative pACT for resected ES‐NSCLC patients with squamous cell carcinoma (SCC) or adenocarcinoma (ADC) according to real‐world data. Methods and Patients Inverse probability treatment weighting (IPTW) was used to adjust baseline characteristics between the group receiving pACT and those not receiving any treatment (observation, OBS) within 3 months after curative surgery. Cox regression models were used to compare overall survival (OS) and treatment failure‐free survival (TFS) between the groups. Results Of 31,208 patients with ES‐NSCLC, 4700 undergoing complete tumor resection were eligible, with a mean follow‐up period of 4.5 years. The pACT (n = 2347) and OBS (n = 2353) groups were well‐balanced after IPTW. The median OS differed between the pACT and OBS groups (77.2 vs. 75.5 months, adjusted hazard ratio [aHR] = 0.87, 95% confidence interval [CI] = 0.79–0.95, p = 0.003), and the 5‐year survival rates were 58.2% and 55.3%, respectively (p

Summary Steroidal oestrogens (C18) are contaminants receiving increasing attention due to their endocrine‐disrupting activities at sub‐nanomolar concentrations. Although oestrogens can be eliminated through photodegradation, microbial function is critical for removing oestrogens from ecosystems devoid of sunlight exposure including activated sludge, soils and aquatic sediments. Actinobacteria were found to be key oestrogen degraders in manure‐contaminated soils and estuarine sediments. Previously, we used the actinobacterium Rhodococcus sp. strain B50 as a model microorganism to identify two oxygenase genes, aedA and aedB, involved in the activation and subsequent cleavage of the estrogenic A‐ring respectively. However, genes responsible for the downstream degradation of oestrogen A/B‐rings remained completely unknown. In this study, we employed tiered comparative transcriptomics, gene disruption experiments and mass spectrometry‐based metabolite profile analysis to identify oestrogen catabolic genes. We observed the up‐regulation of thiolase‐encoding aedF and aedK in the transcriptome of strain B50 grown with oestrone. Consistently, two downstream oestrogenic metabolites, 5‐oxo‐4‐norestrogenic acid (C17) and 2,3,4‐trinorestrogenic acid (C15), were accumulated in aedF‐ and aedK‐disrupted strain B50 cultures. Disruption of fadD3 [3aα‐H‐4α(3'‐propanoate)‐7aβ‐methylhexahydro‐1,5‐indanedione (HIP)‐coenzyme A‐ligase gene] in strain B50 resulted in apparent HIP accumulation in oestrone‐fed cultures, indicating the essential role of fadD3 in actinobacterial oestrogen degradation. In addition, we detected a unique meta‐cleavage product, 4,5‐seco‐estrogenic acid (C18), during actinobacterial oestrogen degradation. Differentiating the oestrogenic metabolite profile and degradation genes of actinobacteria and proteobacteria enables the cost‐effective and time‐saving identification of potential oestrogen degraders in various ecosystems through liquid chromatography–mass spectrometry analysis and polymerase chain reaction‐based functional assays.

Abstract Background Sarcopenic obesity aims to capture the risk of functional decline and cardiometabolic diseases, but its operational definition and associated clinical outcomes remain unclear. Using data from the Longitudinal Aging Study of Taipei, this study explored the roles of the muscle‐to‐fat ratio (MFR) with different definitions and its associations with clinical characteristics, functional performance, cardiometabolic risk and outcomes. Methods (1) Appendicular muscle mass divided by total body fat mass (aMFR), (2) total body muscle mass divided by total body fat mass (tMFR) and (3) relative appendicular skeletal muscle mass (RASM) were measured. Each measurement was categorized by the sex‐specific lowest quintiles for all study participants. Clinical outcomes included all‐cause mortality and fracture. Results Data from 1060 community‐dwelling older adults (mean age: 71.0 ± 4.8 years) were retrieved for the study. Overall, 196 (34.2% male participants) participants had low RASM, but none was sarcopenic. Compared with those with high aMFR, participants with low aMFR were older (72 ± 5.6 vs. 70.7 ± 4.6 years, P = 0.005); used more medications (2.9 ± 3.3 vs. 2.1 ± 2.5, P = 0.002); had a higher body fat percentage (38 ± 4.8% vs. 28 ± 6.4%, P