bluuebunny/crossref_metadata_2025_split huggingface dataset:
Provision and utilization of maternal health services during the COVID-19 pandemic in 16 hospitals in sub-Saharan Africa
Authors: Semaan Aline , Annerstedt Kristi Sidney , Beňová Lenka , Dossou Jean-Paul , Boyi Hounsou Christelle , Agballa Gottfried , Namazzi Gertrude , Kandeya Bianca , Meja Samuel , Ally Mkoka Dickson , Asefa Anteneh , El-halabi Soha , Hanson Claudia 
Published: October 2023

ObjectiveMaintaining provision and utilization of maternal healthcare services is susceptible to external influences. This study describes how maternity care was provided during the COVID-19 pandemic and assesses patterns of service utilization and perinatal health outcomes in 16 referral hospitals (four each) in Benin, Malawi, Tanzania and Uganda.MethodsWe used an embedded case-study design and two data sources. Responses to open-ended questions in a health-facility assessment survey were analyzed with content analysis. We described categories of adaptations and care provision modalities during the pandemic at the hospital and maternity ward levels. Aggregate monthly service statistics on antenatal care, delivery, caesarean section, maternal deaths, and stillbirths covering 24 months (2019 and 2020; pre-COVID-19 and COVID-19) were examined.ResultsDeclines in the number of antenatal care consultations were documented in Tanzania, Malawi, and Uganda in 2020 compared to 2019. Deliveries declined in 2020 compared to 2019 in Tanzania and Uganda. Caesarean section rates decreased in Benin and increased in Tanzania in 2020 compared to 2019. Increases in maternal mortality ratio and stillbirth rate were noted in some months of 2020 in Benin and Uganda, with variability noted between hospitals. At the hospital level, teams were assigned to respond to the COVID-19 pandemic, routine meetings were cancelled, and maternal death reviews and quality improvement initiatives were interrupted. In maternity wards, staff shortages were reported during lockdowns in Uganda. Clinical guidelines and protocols were not updated formally; the number of allowed companions and visitors was reduced.ConclusionVarying approaches within and between countries demonstrate the importance of a contextualized response to the COVID-19 pandemic. Maternal care utilization and the ability to provide quality care fluctuated with lockdowns and travel bans. Women's and maternal health workers' needs should be prioritized to avoid interruptions in the continuum of care and prevent the deterioration of perinatal health outcomes.
Characterization and root cause analysis of immunogenicity to pasotuxizumab (AMG 212), a prostate-specific membrane antigen-targeting bispecific T-cell engager therapy
Authors: Penny Hweixian Leong , Hainline Kelly , Theoharis Nathaniel , Wu Bin , Brandl Christian , Webhofer Christian , McComb Mason , Wittemer-Rump Sabine , Koca Gökben , Stienen Sabine , Bargou Ralf C. , Hummel Horst-Dieter , Loidl Wolfgang , Grüllich Carsten , Eggert Tobias , Tran Ben , Mytych Daniel T. 
Published: October 2023

IntroductionIn oncology, anti-drug antibody (ADA) development that significantly curtails response durability has not historically risen to a level of concern. The relevance and attention ascribed to ADAs in oncology clinical studies have therefore been limited, and the extant literature on this subject scarce. In recent years, T cell engagers have gained preeminence within the prolific field of cancer immunotherapy. These drugs whose mode of action is expected to potently stimulate anti-tumor immunity, may potentially induce ADAs as an unintended corollary due to an overall augmentation of the immune response. ADA formation is therefore emerging as an important determinant in the successful clinical development of such biologics. MethodsHere we describe the immunogenicity and its impact observed to pasotuxizumab (AMG 212), a prostate-specific membrane antigen (PSMA)-targeting bispecific T cell engager (BiTE®) molecule in NCT01723475, a first-in-human (FIH), multicenter, dose-escalation study in patients with metastatic castration-resistant prostate cancer (mCRPC). To explain the disparity in ADA incidence observed between the SC and CIV arms of the study, we interrogated other patient and product-specific factors that may have explained the difference beyond the route of administration. ResultsTreatment-emergent ADAs (TE-ADA) developed in all subjects treated with at least 1 cycle of AMG 212 in the subcutaneous (SC) arm. These ADAs were neutralizing and resulted in profound exposure loss that was associated with contemporaneous reversal of initial Prostate Surface Antigen (PSA) responses, curtailing durability of PSA response in patients. Pivoting from SC to a continuous intravenous (CIV) administration route remarkably yielded no subjects developing ADA to AMG 212. Through a series of stepwise functional assays, our investigation revealed that alongside a more historically immunogenic route of administration, non-tolerant T cell epitopes within the AMG 212 amino acid sequence were likely driving the high-titer, sustained ADA response observed in the SC arm. DiscussionThese mechanistic insights into the AMG 212 ADA response underscore the importance of performing preclinical immunogenicity risk evaluation as well as advocate for continuous iteration to better our biologics.
Case report: A rare case of desmoid-type fibromatosis originating in the small intestine
Authors: Xie Junfeng , Lai Shichang , Wang Yangbiao , Ye Baolong , Huang Zhishun , Xi Kexing 
Published: October 2023

BackgroundDesmoid-type fibromatosis (DF) is characterized by a rare monoclonal fibroblast proliferation that exhibits variable and unpredictable clinical presentation. DF can be classified into sporadic and hereditary types. Despite extensive research efforts, the exact etiology of DF remains elusive.Case descriptionA 31-year-old male patient presented to the hospital with a progressively growing mass in the right lower abdomen, accompanied by abdominal discomfort. Symptoms are discovered 1 week before admission. Enteroscopy revealed no evidence of colonic abnormalities, and blood tests did not indicate any abnormalities. Due to the indeterminate nature of the mass during surgery, a partial resection of the ileum and cecum was performed, followed by ileocolonic end-to-end anastomosis, with no postoperative complications. The final pathological diagnosis confirmed primary desmoid-type fibromatosis of the distal ileum (invasive fibromatosis). To effectively manage DF, we recommend a follow-up schedule for patients. This includes appointments every 3 months in the first year following surgery, followed by appointments every 6 months up to the fifth year, and then once a year thereafter. The follow-up examinations should include collection of the patient’s medical history, physical examination, blood tests, ultrasounds, CT scans, and other relevant assessments. During the first year of the follow-up period, no further treatment was administered, and the patient remained disease-free.ConclusionDesmoid-type fibromatosis (DF) originating from the small intestine is an extremely rare condition that exhibits local invasiveness and can be life-threatening. Despite its benign histology, DF has a high local recurrence rate and lacks metastatic potential. Diagnosis of DF remains challenging, especially in cases where surgical intervention is not feasible due to asymptomatic patients or partial organ impairment. In such cases, a “watchful waiting” approach is recommended as the initial treatment strategy. However, when preoperative diagnosis is difficult, surgery is typically considered the best option. Given the potential for local recurrence and the uncertain long-term prognosis, regular follow-up is necessary.
Genome and transcriptome analysis of Enterococcus faecium from intestinal colonization and Enterococcus faecium from urinary tract infection
Authors: Huang Ge , Zhou Yizheng , Cheng Hai , Lv Tao , Zheng Lisi , Li Chengbin , Chen Yunbo 
Published: October 2023

IntroductionEnterococcus faecium is a common pathogen responsible for urinary tract infections (UTIs) and often establishes extensive colonization within the intestinal tract. Our aim was to assess the genomic and transcriptomic differences between colonized E. faecium without UTI (only-colonization) and colonized E. faecium causing UTI (endogenous infections).MethodWe investigated the correlation between fecal isolates from the same patient and UTI-causing isolates using PFGE and WGS, and classified fecal isolates into two groups: those that solely colonized and those associated with endogenous urinary tract infections. We characterized the genomes of colonization-only and endogenously infected isolates by Scoary GWAS, and the transcriptomes of the isolates at 3 h urine exposure to assess pathogen-related changes.ResultBased on PFGE and WGS, eight isolates of endogenously infected E. faecium and nine isolates of only-colonized E. faecium were characterized and carbon and nitrogen regulated metabolisms such as genes encoding the phosphotransferase (PTS) system were enriched in endogenously infected E. faecium. Transcriptome analysis revealed significant differences in gene expression in the PTS system, lysine synthesis, galactose metabolism and citrate import between endogenously infected and only-colonized E. faecium isolates, highlighting the important role of certain carbon regulatory genes in the colonization and survival of endogenously infected E. faecium.ConclusionIn only-colonized and endogenously infected isolates, we observed differential expression patterns of genes related to carbon metabolism and amino acids, suggesting that metabolic diversity is a strategy for isolates leading to endogenous infection.
Validation of the Body Scan®, a new device to detect small fiber neuropathy by assessment of the sudomotor function: agreement with the Sudoscan®
Authors: Riveline Jean-Pierre , Mallone Roberto , Tiercelin Clarisse , Yaker Fetta , Alexandre-Heymann Laure , Khelifaoui Lysa , Travert Florence , Fertichon Claire , Julla Jean-Baptiste , Vidal-Trecan Tiphaine , Potier Louis , Gautier Jean-Francois , Larger Etienne , Lefaucheur Jean-Pascal 
Published: October 2023

BackgroundSudomotor dysfunction is one of the earliest manifestations of small fiber neuropathy (SFN), reflecting the alteration of sympathetic C fiber innervation of the sweat glands. Among other techniques, such innervation can be assessed by measuring electrochemical skin conductance (ESC) in microsiemens (μS). In this study, ESC was measured at the feet to detect distal SFN. For this objective, the performance of a new device, the Body Scan® (Withings, France), intended for home use, was compared with that of a reference device, the Sudoscan® (Impeto Medical, France), which requires a hospital setting.MethodsIn patients with diabetes with or without neuropathy or non-diabetic patients with lower-limb neuropathy, the diagnostic performance of the Body Scan® measurement was assessed by calculating its sensitivity (Se) and specificity (Sp) to detect at least moderate SFN (Se70 and Sp70), defined by a value of feet ESC ≤ 70 μS and &gt; 50 μS on the Sudoscan® measure, or severe SFN (Se50 and Sp50), defined by a value of feet ESC ≤ 50 μS on the Sudoscan® measure. The agreement between the two devices was assessed with the analysis of Bland–Altman plots, mean absolute error (MAE), and root mean squared error (RMSE) calculations. The repeatability of the measurements was also compared between the two devices.ResultsA total of 147 patients (52% men, mean age 59 years old, 76% diabetic) were included in the analysis. The sensitivity and specificity to detect at least moderate or severe SFN were: Se70 = 0.91 ([0.83, 0.96]), Sp70 = 0.97 ([0.88, 0.99]), Se50 = 0.91 ([0.80, 0.98]), and Sp50 = 0.99 ([0.94, 1]), respectively. The bias and 95% limits of agreement were 1.5 [−5.4, 8.4]. The MAE was 2.9 and the RMSE 3.8. The intra-sample variability was 2.0 for the Body Scan® and 2.3 for the Sudoscan®.ConclusionThe ESC measurements provided by the Body Scan® were in almost perfect agreement with those provided by the reference device, the Sudoscan®, which validates the accuracy of the Body Scan® for the detection of SFN. By enabling simple, rapid, and autonomous use by the patient at home, this new technique will facilitate screening and monitoring of SFN in daily practice.Clinical trial registrationClinicalTrials.gov, identifier NCT05178459.
A nomogram based on ultrasonographic features and clinical indicators for differentiating mass-forming intrahepatic cholangiocarcinoma and liver metastatic colorectal adenocarcinoma
Authors: Bao Wuyongga , Liao Min , Yang Jie , Huang Jiayan , Zeng Keyu , Lu Qiang 
Published: October 2023

ObjectiveThis study aimed to develop and validate a nomogram based on ultrasonographic features and clinical indicators to differentiate mass-forming intrahepatic cholangiocarcinoma (MF-ICC) from hepatic metastatic colorectal adenocarcinoma.Materials and methodsA total of 343 patients with pathologically confirmed MF-ICC or metastatic colorectal adenocarcinoma were enrolled between October 2018 and July 2022. Patients were randomly assigned to training and validation sets at a ratio of 7:3. Preoperative ultrasound features and clinical indicators were retrieved. Univariate logistic regression analysis was employed to select relevant features. Multivariate logistic regression analysis was used to establish a predictive model, which was presented as a nomogram in training sets. The model’s performance was assessed in terms of discrimination, calibration, and clinical usefulness.ResultsThe study included 169 patients with MF-ICC and 174 with liver metastatic colorectal adenocarcinoma, assigned to training (n=238) and validation (n=105) cohorts. The nomogram incorporated ultrasound features (tumor size, lesion number, echogenicity, tumor necrosis, and rim arterial phase hyperenhancement) and clinical information (serum levels of CEA, CA19-9, CA125). The nomogram demonstrated promising performance in differentiating these two entities in both training and validation sets, with an AUC value of 0.937 (95%CI: 0.907,0.969) and 0.916 (95%CI: 0.863,0.968), respectively. The Hosmer–Lemeshow test and calibration curves confirmed good consistency between predictions and observations. Additionally, decision curve analysis confirmed the nomogram’s high clinical practicability.ConclusionThe nomogram based on ultrasound features and clinical indicators demonstrated good discrimination performance in differentiating MF-ICC from metastatic colorectal adenocarcinoma, which may enhance clinical decision-making process in managing these challenging diagnostic scenarios.
Topical ocular application of aggrelyte-2A reduces lens stiffness in mice
Authors: Panja Sudipta , Nam Mi-Hyun , Gaikwad Hanmant , Rankenberg Johanna , Nagaraj Ram H. 
Published: October 2023

Presbyopia is the progressive loss of the ability of the lens to focus on nearby objects due to its increased stiffness. It occurs in the mid-40s and continues to worsen until the mid-60s. The age-associated increase in protein cross-linking in the lens leads to protein aggregation and water insolubility, especially in the nuclear region, contributing to lens stiffness. This study reports the development of aggrelyte-2A (methyl S-acetyl-N-(3,3-dimethylbutanoyl) cysteinate, a derivative of our previously reported aggrelyte-2) for reversing the stiffness of aged lenses. Aggrelyte-2A showed minimal toxicity in cultured mouse lens epithelial cells (up to 2000 µM) and human lens epithelial cells (up to 250 µM). Lenses from aged mice (age: 24-25 months) treated with 1 mM aggrelyte-2A for 24 h, and human lenses (age: 47-67 years) treated with 250 µM aggrelyte-2A for 48 h showed 11-14% reductions in stiffness, accompanied by an increase in acetyllysine in lens proteins, and free-thiols in the lens. Topical application of aggrelyte-2A (40 mM, 5 µl twice daily for 4 weeks) on mouse eyes significantly reduced lens stiffness. The topical application showed no toxicity to the lens, cornea, or retina, as revealed by morphological examination, H&amp;E staining, and optical coherence tomography. These data suggest that aggrelyte-2A could be developed as a presbyopia-reversing therapeutic.
Hematologic and lymphatic system toxicities associated with immune checkpoint inhibitors: a real-world study
Authors: Li Na , Feng Yong , Chen XiaoLing , Li Ye , Zhang Chengmiao , Yin Yin 
Published: October 2023

Introduction: Immune checkpoint inhibitors (ICIs) exert antitumor responses in many types of cancer but may also induce serious or fatal toxicities that affect all organ systems, including the hematologic and lymphatic systems. However, the risk of hematologic and lymphatic system toxicities following different ICI treatments remains unknown. This study aimed to describe the hematologic and lymphatic system toxicities associated with different ICI regimens and the impact of combining ICIs with anti-vascular endothelial growth factor drugs using the United States Food and Drug Administration Adverse Event Reporting System pharmacovigilance database.Methods: The reporting odds ratio (ROR) and information component (IC) indices were used to identify disproportionate reporting of ICI-associated hematologic and lymphatic adverse events (AEs).Results: We extracted 10,971 ICI-associated hematologic and lymphatic AEs from 35,417,155 reports. These AEs were more frequently reported in female patients (ROR: 1.04 95% confidence interval [CI]: 1.01–1.07) and younger patients (ROR: 1.05 95% CI: 1.01–1.09). The disseminated intravascular coagulation fatality rate (63.97%) was the highest among the reported preferred terms, despite its low incidence (3.32%). The time to onset of ICI-related hematologic and lymphatic AEs was relatively short, with 77.44% reported within 3 months. Disproportionate analysis showed that most ICIs were associated with significant overreporting of hematologic and lymphatic AEs (IC025: 0.34 and ROR025: 2.10). Hematologic and lymphatic system AEs were more frequently reported in patients treated with anti-programmed cell death protein 1/programmed cell death ligand 1 monotherapy than in those treated with anti-cytotoxic T-lymphocyte-associated protein 4 monotherapy (ROR: 1.54, 95% CI: 1.38–1.71), with atezolizumab showing the strongest signal (ROR025: 4.19, IC025: 1.00). In patients receiving combined treatment, ICIs plus bevacizumab exerted a higher disproportion signal than monotherapy (ROR: 161, 95% CI: 1.75–1.88).Discussion: The spectrum of hematologic and lymphatic AEs differed according to the ICI regimen. Early recognition and management of ICI-related hematologic and lymphatic AEs are vital in clinical practice.
Adverse events associated with molnupiravir: a real-world disproportionality analysis in food and drug administration adverse event reporting system
Authors: Liang Yankun , Ma Lin , Wang Yuting , Zheng Jingping , Su Ling , Lyu Jun 
Published: October 2023

Molnupiravir, an urgently approved drug during the Coronavirus Disease 2019 (COVID-19) pandemic, serves as the basis for our study, which relies on the Food and Drug Administration Adverse Event Reporting System (FAERS). The objective is to extract adverse event (AE) signals associated with molnupiravir from the FAERS database, thereby providing a reference for post-marketing monitoring of adverse events. Specifically, we extracted individual case safety reports (ICSRs) from the database, focusing on cases with COVID-19 indications and molnupiravir identified as the primary suspect drug. Descriptive analysis of the extracted data was performed, followed by four disproportionality analyses using the reporting odds ratio (ROR) method. These analyses were conducted across four levels, encompassing overall data, reports by health professionals, as well as age and gender differentiations, ensuring the robustness of the analysis results. In total, 116,576 ICSRs with COVID-19 indications and 2,285 ICSRs with molnupiravir as the primary suspect were extracted. Notably, after excluding cases with unknown age or gender, a higher proportion of molnupiravir-related ICSRs were observed among individuals aged 65 years and older (70.07%) and women (54.06%). The most frequently reported adverse events and AE signals were associated with gastrointestinal disorders, as well as skin and subcutaneous tissue disorders. Moreover, individuals aged 65 years and older exhibited a higher risk of cardiac disorders, hepatobiliary disorders, renal and urinary disorders, and vascular disorders. In conclusion, this study found molnupiravir demonstrated a lower risk of serious adverse events compared to other RNA antiviral drugs like remdesivir in patients under 65 years old. However, close monitoring of its safety is still necessary for elderly patients aged 65 years and above. Further studies are warranted to continuously assess the safety profile of molnupiravir as its usage increases, especially in high risk populations.
Simulation and optimization of nutrient uptake and biomass formation using a multi-parameter Monod-type model of tobacco BY-2 cell suspension cultures in a stirred-tank bioreactor
Authors: Nausch Henrik , Baldan Marco , Teichert Katrin , Lutz Jannik , Claussen Carsten , Bortz Michael , Buyel Johannes Felix 
Published: October 2023

IntroductionTobacco (Nicotiana tabacum) cv Bright Yellow-2 (BY-2) cell suspension cultures enable the rapid production of complex protein-based biopharmaceuticals but currently achieve low volumetric productivity due to slow biomass formation. The biomass yield can be improved with tailored media, which can be designed either by laborious trial-and-error experiments or systematic, rational design using mechanistic models, linking nutrient consumption and biomass formation.MethodsHere we developed an iterative experiment-modeling-optimization workflow to gradually refine such a model and its predictions, based on collected data concerning BY-2 cell macronutrient consumption (sucrose, ammonium, nitrate and phosphate) and biomass formation. Results and discussionThe biomass formation was well predicted by an unstructured segregated mechanistic Monod-type model as long as the nutrient concentrations did not approach zero (we omitted phosphate, which was completely depleted). Multi-criteria optimization for sucrose and biomass formation indicated the best tradeoff (in a Paretian sense) between maximum biomass yield and minimum process time by reducing the initial sucrose concentration, whereas the inoculation biomass could be increased to maximize the biomass yield or minimize the process time, which we confirmed in calibration experiments. The model became inaccurate at biomass densities &gt; 8 g L-1 dry mass when sucrose was almost depleted. We compensated for this limitation by including glucose and fructose as sucrose hydrolysis products in the model. The remaining offset between the simulation and experimental data might be resolved by including intracellular pools of sucrose, ammonium, nitrate and phosphate. Overall, we demonstrated that iterative models can be used to systematically optimize conditions for bioreactor-based processes.