bluuebunny/crossref_metadata_2025_split huggingface dataset:
Anaesthesia of a parturient with uncorrected pentalogy of Fallot undergoing caesarean section and postpartum sterilisation
Authors: Leong Rachel Wei-Li , Chen Jinghui , Mathews Abey Matthew Varughese , Kothandan Harikrishnan 
Published: February 2024

Pentalogy of Fallot is a rare congenital cyanotic heart disease; few patients with uncorrected disease survive to childbearing age. Cardiovascular changes during pregnancy and delivery can lead to haemodynamic instability, while anaesthesia can cause right-to-left shunting and worsen hypoxaemia.We present the learning points from the anaesthetic management of an obstetric patient with uncorrected pentalogy of Fallot. We describe the successful application of general anaesthesia, choice of transoesophageal echocardiography for real-time haemodynamic monitoring and management, and the comprehensive multidisciplinary care of this high cardiovascular risk obstetric patient perioperatively. We also review the literature and discuss the anaesthetic management of patients with pentalogy of Fallot going for caesarean section.
Study protocol of a national multicentre prospective evaluation study assessing the validity and impact of the Dutch Paediatric Early Warning Score (PEWS) in the Netherlands
Authors: Stevens Jikke , de Groot Janke , Luijmes Marie , Bouwens Janneke , Rippen Hester , Hoogervorst-Schilp Janneke , Fuijkschot Joris 
Published: February 2024

IntroductionEarly recognition of clinical deterioration and timely intervention are important to improve morbidity and mortality in paediatric care. The Paediatric Early Warning Score (PEWS) is a scoring system aiming to identify hospitalised children at risk for deterioration. Currently, there is a large heterogeneity of PEWS systems in the Netherlands, with a considerable number remaining unvalidated or self-designed. Therefore, a consensus-based Dutch PEWS has been developed in a national study using the Core Outcome Measures in Effectiveness Trials initiative. The Dutch PEWS is a uniform system that integrates a core set of vital parameters together with pre-existing risk factors and uses risk stratification to proactively follow-up on patients at risk (so-called ‘watcher patients’). This study aims to validate the Dutch PEWS and to determine its impact on improving patient safety in various hospital settings.Methods and analysisThis national study will be a large multicentre evaluation study, in which the Dutch PEWS will be implemented and evaluated in 12 hospitals in the Netherlands. In this study, a mixed methods methodology will be used and evaluated on predefined outcome measures. To examine the validity of the Dutch PEWS, statistical analyses will be undertaken on quantitative data retrieved from electronic health records. Surveys among physicians and nurses; semistructured interviews with healthcare providers and parents; and daily evaluation forms are being conducted to determine the impact of the Dutch PEWS. The study is being conducted from December 2020 to June 2024.
Prevalence and causes of ocular disorders and visual impairment among preterm children in Ethiopia
Authors: Sherief Sadik Taju , Muhe Lulu M , Mekasha Amha , Demtse Asrat , Ali Asim 
Published: February 2024

ObjectiveThe aim of this study was to determine the prevalence, causes of ocular disorders and visual impairment among preterm children previously admitted to neonatal intensive care units in Addis Ababa, Ethiopia.Methods and analysisA prospective screening survey was conducted from February to June 2019 at the paediatric eye clinic of Menelik II Hospital. Children who were preterm at birth and who attended the eye clinic were included in the study. Data on demographic and neonatal characteristics, neonatal and maternal comorbidities and ocular disorders were collected. OR and univariate analysis were used to identify predictors of ocular diseases and visual impairment.ResultsThere were 222 children included in the study with a mean age at presentation of 2.62 years (range 2.08–6.38 years), mean gestational age 34.11 weeks (range 30–36) weeks and mean birth weight 1941.72 g (range 953–3500 g). Nearly two-thirds had ocular disorders with refractive error (51.8%), strabismus (11.3%) and a history of retinopathy of prematurity (ROP) (7.2%) being more common. One-fourth of the children had visual impairment, and the prevalence of amblyopia was 40.1%. Uncorrected refractive errors, strabismus and ROP were causes for visual impairment.ConclusionVisual impairment and amblyopia are common in Ethiopia. There is a need to develop a screening protocol for ocular disorders for preterm children to enhance early detection and prevention of childhood visual impairment.
FDA Approval Summary: Lisocabtagene Maraleucel for Second-Line Treatment of Large B-Cell Lymphoma
Authors: Elmacken Mona , Peredo-Pinto Helkha , Wang Cong , Xu Zhenzhen , Tegenge Million , Jaigirdar Adnan A. , Theoret Marc R. , Purohit-Sheth Tejashri , Kasamon Yvette L. 
Published: February 2024

Abstract
In June 2022, the FDA extended the indication for lisocabtagene maraleucel (liso-cel) to include adults with large B-cell lymphoma (LBCL) who have refractory disease or relapse within 12 months of first-line chemoimmunotherapy (CIT), as well as transplant-ineligible adults with refractory disease or relapse after first-line CIT. Two clinical trials evaluating a single infusion of liso-cel preceded by lymphodepleting chemotherapy supported the second-line indications. TRANSFORM is a randomized, phase 3, open-label trial comparing liso-cel with standard second-line therapy, including planned autologous hematopoietic stem cell transplantation (HSCT), in 184 transplant-eligible patients. On interim analysis, event-free survival (EFS) by independent review committee (IRC) assessment was statistically significantly improved for the liso-cel arm, with a stratified hazard ratio of 0.34 [95% confidence interval (CI), 0.22–0.51; P &lt; 0.0001]; the estimated median EFS was 10.1 months in the liso-cel arm versus 2.3 months in the control arm. PILOT is a single-arm phase 2 trial of second-line liso-cel in patients who were transplant-ineligible due to age or comorbidities but had adequate organ function for chimeric antigen receptor (CAR) T-cell therapy. Among 61 patients who received liso-cel (median age, 74 years), the IRC-assessed complete response rate was 54% (95% CI, 41–67). Among patients achieving complete response, the estimated 1-year rate of continued response was 68% (95% CI, 45–83). Of the 268 patients combined who received liso-cel as second-line therapy for LBCL, cytokine release syndrome occurred in 45% (Grade 3, 1.3%) and CAR T-cell–associated neurologic toxicities occurred in 27% (Grade 3, 7%), warranting a continued risk evaluation and mitigation strategy.
ADCT-602, a Novel PBD Dimer–containing Antibody–Drug Conjugate for Treating CD22-positive Hematologic Malignancies
Authors: Zammarchi Francesca , Havenith Karin E. , Sachini Nikoleta , Janghra Narinder , Chivers Simon , Idusogie Esohe , Gaudio Eugenio , Tarantelli Chiara , Bertelli Francois , Santos Kathleen , Tyrer Peter , Corbett Simon , Spriano Filippo , Golino Gaetanina , Cascione Luciano , Bertoni Francesco , Hartley John A. , van Berkel Patrick H. 
Published: February 2024

Abstract
Relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) and lymphomas have poor patient outcomes; novel therapies are needed. CD22 is an attractive target for antibody–drug conjugates (ADCs), being highly expressed in R/R B-ALL with rapid internalization kinetics. ADCT-602 is a novel CD22-targeting ADC, consisting of humanized mAb hLL2-C220, site specifically conjugated to the pyrrolobenzodiazepine dimer–based payload tesirine. In preclinical studies, ADCT-602 demonstrated potent, specific cytotoxicity in CD22-positive lymphomas and leukemias. ADCT-602 was specifically bound, internalized, and trafficked to lysosomes in CD22-positive tumor cells; after cytotoxin release, DNA interstrand crosslink formation persisted for 48 hours. In the presence of CD22-positive tumor cells, ADCT-602 caused bystander killing of CD22-negative tumor cells. A single ADCT-602 dose led to potent, dose-dependent, in vivo antitumor activity in subcutaneous and disseminated human lymphoma/leukemia models. Pharmacokinetic analyses (rat and cynomolgus monkey) showed excellent stability and tolerability of ADCT-602. Cynomolgus monkey B cells were efficiently depleted from circulation after one dose. Gene signature association analysis revealed IRAK1 as a potential marker for ADCT-602 resistance. Combining ADCT-602 + pacritinib was beneficial in ADCT-602–resistant cells. Chidamide increased CD22 expression on B-cell tumor surfaces, increasing ADCT-602 activity. These data support clinical testing of ADCT-602 in R/R B-ALL (NCT03698552) and CD22-positive hematologic cancers.
Trastuzumab-MMAU Antibody-Auristatin Conjugates: Valine-Glucoserine Linker with Stabilized Maleimide Conjugation Improves In Vivo Efficacy and Tolerability
Authors: Goldberg Shalom D. , Satomaa Tero , Aina Olulanu , Aitio Olli , Burke Krista , Dudkin Vadim , Geist Brian , Irrechukwu Onyi , Hänninen Anna-Liisa , Heiskanen Annamari , Helin Jari , Hiltunen Jukka O. , Kinyamu-Akunda Jacqueline , Klein Donna M. , Kohli Neeraj , Kotiranta Titta , Lähteenmäki Tuula , Niemelä Ritva , Pitkänen Virve , Pynnönen Henna , Rittase William , Wiley Kristen , Zhou Junguo , Saarinen Juhani 
Published: February 2024

Abstract
Antibody–drug conjugates (ADC) have shown impressive clinical activity with approval of many agents in hematologic and solid tumors. However, challenges remain with both efficacy and safety of ADCs. This study describes novel trastuzumab–auristatin conjugates with the hydrophilic monomethylauristatin E (MMAE) prodrug MMAU, and optimization of a glycopeptide linker leading to a wider therapeutic window. Trastuzumab was conjugated with auristatin payloads via a series of linkers using a stabilized maleimide handle. The ADCs were characterized in vitro and their relative in vivo antitumor efficacies were assessed in HER2+ xenograft models. Relative linker stabilities and the mechanism of linker cleavage were studied using in vitro assays. Toxicity and toxicokinetics of the best performing ADC were evaluated in cynomolgus monkey (cyno). The trastuzumab–MMAU ADC with stabilized glycopeptide linker showed maleimide stabilization and higher resistance to cleavage by serum and lysosomal enzymes compared with a valine–citrulline conjugated trastuzumab ADC (trastuzumab–vc-MMAE). A single dose of 1 or 2 mg/kg of trastuzumab–MMAU at drug-to-antibody ratios (DAR) of eight and four respectively resulted in xenograft tumor growth inhibition, with superior efficacy to trastuzumab–vc-MMAE. Trastuzumab–MMAUDAR4 was tolerated at doses up to 12 mg/kg in cyno, which represents 2- to 4-fold higher dose than that observed with vedotin ADCs, and had increased terminal half-life and exposure. The optimized trastuzumab–MMAU ADC showed potent antitumor activity and was well tolerated with excellent pharmacokinetics in nonhuman primates, leading to a superior preclinical therapeutic window. The data support potential utility of trastuzumab–MMAU for treatment of HER2+ tumors.
Coregulation of NDC80 Complex Subunits Determines the Fidelity of the Spindle-Assembly Checkpoint and Mitosis
Authors: Kim Sehong , Lau Thomas T.Y. , Liao Man Kit , Ma Hoi Tang , Poon Randy Y.C. 
Published: February 2024

Abstract

NDC80 complex (NDC80C) is composed of four subunits (SPC24, SPC25, NDC80, and NUF2) and is vital for kinetochore–microtubule (KT–MT) attachment during mitosis. Paradoxically, NDC80C also functions in the activation of the spindle-assembly checkpoint (SAC). This raises an interesting question regarding how mitosis is regulated when NDC80C levels are compromised. Using a degron-mediated depletion system, we found that acute silencing of SPC24 triggered a transient mitotic arrest followed by mitotic slippage. SPC24-deficient cells were unable to sustain SAC activation despite the loss of KT–MT interaction. Intriguingly, our results revealed that other subunits of the NDC80C were co-downregulated with SPC24 at a posttranslational level. Silencing any individual subunit of NDC80C likewise reduced the expression of the entire complex. We found that the SPC24–SPC25 and NDC80–NUF2 subcomplexes could be individually stabilized using ectopically expressed subunits. The synergism of SPC24 downregulation with drugs that promote either mitotic arrest or mitotic slippage further underscored the dual roles of NDC80C in KT–MT interaction and SAC maintenance. The tight coordinated regulation of NDC80C subunits suggests that targeting individual subunits could disrupt mitotic progression and provide new avenues for therapeutic intervention.

Implications:
These results highlight the tight coordinated regulation of NDC80C subunits and their potential as targets for antimitotic therapies.
Targeted Proteomics Reveals Functional Targets for Early Diabetes Susceptibility in Young Adults
Authors: Shah Ravi V. , Zhong Jiawei , Massier Lucas , Tanriverdi Kahraman , Hwang Shih-Jen , Haessler Jeffrey , Nayor Matthew , Zhao Shilin , Perry Andrew S. , Wilkins John T. , Shadyab Aladdin H. , Manson JoAnn E. , Martin Lisa , Levy Daniel , Kooperberg Charles , Freedman Jane E. , Rydén Mikael , Murthy Venkatesh L. 
Published: February 2024

BACKGROUND:
The circulating proteome may encode early pathways of diabetes susceptibility in young adults for surveillance and intervention. Here, we define proteomic correlates of tissue phenotypes and diabetes in young adults.

METHODS:

We used penalized models and principal components analysis to generate parsimonious proteomic signatures of diabetes susceptibility based on phenotypes and on diabetes diagnosis across 184 proteins in >2000 young adults in the CARDIA (Coronary Artery Risk Development in Young Adults study; mean age, 32 years; 44% women; 43% Black; mean body mass index, 25.6±4.9 kg/m
2
), with validation against diabetes in >1800 individuals in the FHS (Framingham Heart Study) and WHI (Women’s Health Initiative).

RESULTS:
In 184 proteins in >2000 young adults in CARDIA, we identified 2 proteotypes of diabetes susceptibility—a proinflammatory fat proteotype (visceral fat, liver fat, inflammatory biomarkers) and a muscularity proteotype (muscle mass), linked to diabetes in CARDIA and WHI/FHS. These proteotypes specified broad mechanisms of early diabetes pathogenesis, including transorgan communication, hepatic and skeletal muscle stress responses, vascular inflammation and hemostasis, fibrosis, and renal injury. Using human adipose tissue single cell/nuclear RNA-seq, we demonstrate expression at transcriptional level for implicated proteins across adipocytes and nonadipocyte cell types (eg, fibroadipogenic precursors, immune and vascular cells). Using functional assays in human adipose tissue, we demonstrate the association of expression of genes encoding these implicated proteins with adipose tissue metabolism, inflammation, and insulin resistance.

CONCLUSIONS:
A multifaceted discovery effort uniting proteomics, underlying clinical susceptibility phenotypes, and tissue expression patterns may uncover potentially novel functional biomarkers of early diabetes susceptibility in young adults for future mechanistic evaluation.
Integrated Stress Response Potentiates Ponatinib-Induced Cardiotoxicity
Authors: Yan Gege , Han Zhenbo , Kwon Youjeong , Jousma Jordan , Nukala Sarath Babu , Prosser Benjamin L. , Du Xiaoping , Pinho Sandra , Ong Sang-Bing , Lee Won Hee , Ong Sang-Ging 
Published: February 2024

BACKGROUND:
Mitochondrial dysfunction is a primary driver of cardiac contractile failure; yet, the cross talk between mitochondrial energetics and signaling regulation remains obscure. Ponatinib, a tyrosine kinase inhibitor used to treat chronic myeloid leukemia, is among the most cardiotoxic tyrosine kinase inhibitors and causes mitochondrial dysfunction. Whether ponatinib-induced mitochondrial dysfunction triggers the integrated stress response (ISR) to induce ponatinib-induced cardiotoxicity remains to be determined.

METHODS:
Using human induced pluripotent stem cells–derived cardiomyocytes and a recently developed mouse model of ponatinib-induced cardiotoxicity, we performed proteomic analysis, molecular and biochemical assays to investigate the relationship between ponatinib-induced mitochondrial stress and ISR and their role in promoting ponatinib-induced cardiotoxicity.

RESULTS:

Proteomic analysis revealed that ponatinib activated the ISR in cardiac cells. We identified GCN2 (general control nonderepressible 2) as the eIF2α (eukaryotic translation initiation factor 2α) kinase responsible for relaying mitochondrial stress signals to trigger the primary ISR effector—ATF4 (activating transcription factor 4), upon ponatinib exposure. Mechanistically, ponatinib treatment exerted inhibitory effects on ATP synthase activity and reduced its expression levels resulting in ATP deficits. Perturbed mitochondrial function resulting in ATP deficits then acts as a trigger of GCN2-mediated ISR activation, effects that were negated by nicotinamide mononucleotide, an NAD
+
precursor, supplementation. Genetic inhibition of ATP synthase also activated GCN2. Interestingly, we showed that the decreased abundance of ATP also facilitated direct binding of ponatinib to GCN2, unexpectedly causing its activation most likely because of a conformational change in its structure. Importantly, administering an ISR inhibitor protected human induced pluripotent stem cell–derived cardiomyocytes against ponatinib. Ponatinib-treated mice also exhibited reduced cardiac function, effects that were attenuated upon systemic ISRIB administration. Importantly, ISRIB does not affect the antitumor effects of ponatinib in vitro.

CONCLUSIONS:
Neutralizing ISR hyperactivation could prevent or reverse ponatinib-induced cardiotoxicity. The findings that compromised ATP production potentiates GCN2-mediated ISR activation have broad implications across various cardiac diseases. Our results also highlight an unanticipated role of ponatinib in causing direct activation of a kinase target despite its role as an ATP-competitive kinase inhibitor.
Neurological Improvement by One-Thirds Is Associated With Early Recanalization in Stroke With Large Vessel Occlusion
Authors: Che Bizhong , Kusuma Yohanna , Bush Steven , Dowling Richard , Williams Cameron , Houlihan Conor , Mitchell Peter J. , Yan Bernard 
Published: February 2024

BACKGROUND:
A proportion of large vessel occlusion strokes demonstrate early recanalization, obviating the initial intention to proceed to endovascular thrombectomy. Neurological improvement is a possible surrogate marker for reperfusion. We aimed to determine the optimal threshold of neurological improvement, as defined by the National Institutes of Health Stroke Scale (NIHSS), which best associates with early recanalization.

METHODS:
We retrospectively analyzed consecutive patients with large vessel occlusion transferred from primary stroke centers to a tertiary comprehensive stroke center in Melbourne, Australia, for possible endovascular thrombectomy from January 2018 to December 2022. Absolute and percentage changes in NIHSS between transfer, as well as other definitions of neurological improvement, were compared using receiver operating characteristic curve analysis for association with recanalization as defined by the absence of occlusion in the internal carotid artery, middle cerebral artery (M1 or M2 segments), or basilar artery on repeat vascular imaging.

RESULTS:

Six hundred and fifty-four transferred patients with large vessel occlusion were included in the analysis: mean age was 68.8±14.0 years, 301 (46.0%) were women, and 338 (52%) received intravenous thrombolytics. The proportion of extracranial internal carotid artery, intracranial internal carotid artery, M1, proximal M2, and basilar artery occlusion was 18.8%, 13.6%, 48.3%, 15.0%, and 4.3%, respectively, on initial computed tomography angiogram. Median NIHSS
primary stroke center
and NIHSS
comprehensive stroke center
scores were 15 (interquartile range, 9–18) and 13 (interquartile range, 8–19), respectively. Early recanalization occurred in 82 (13%) patients. NIHSS reduction of ≥33% was the best tradeoff between sensitivity (64%) and specificity (83%) for identifying recanalization. NIHSS reduction of ≥33% had the highest discriminative ability to predict recanalization (area under the curve, 0.735) in comparison with other definitions of neurological improvement.

CONCLUSIONS:
One-third neurological improvement between the primary hospital and tertiary center was the best predictor of early recanalization.
Pericyte Microvesicles as Plasma Biomarkers Reflecting Brain Microvascular Signaling in Patients With Acute Ischemic Stroke
Authors: Gaceb Abderahim , Roupé Linnea , Enström Andreas , Almasoudi Wejdan , Carlsson Robert , Lindgren Arne G. , Paul Gesine 
Published: February 2024

BACKGROUND:
Blood-based biomarkers have the potential to reflect cerebrovascular signaling after microvascular injury; yet, the detection of cell-specific signaling has proven challenging. Microvesicles retain parental cell surface antigens allowing detection of cell-specific signaling encoded in their cargo. In ischemic stroke, the progression of pathology involves changes in microvascular signaling whereby brain pericytes, perivascular cells wrapping the microcapillaries, are one of the early responders to the ischemic insult. Intercepting the pericyte signaling response peripherally by isolating pericyte-derived microvesicles may provide not only diagnostic information on microvascular injury but also enable monitoring of important pathophysiological mechanisms.

METHODS:
Plasma samples were collected from patients with acute ischemic stroke (n=39) at 3 time points after stroke onset: 0 to 6 hours, 12 to 24 hours, and 2 to 6 days, and compared with controls (n=39). Pericyte-derived microvesicles were isolated based on cluster of differentiation 140b expression and quantified by flow cytometry. The protein content was evaluated using a proximity extension assay, and vascular signaling pathways were examined using molecular signature hallmarks and gene ontology.

RESULTS:

In this case-control study, patients with acute ischemic stroke showed significantly increased numbers of pericyte-derived microvesicles (median, stroke versus controls) at 12 to 24 hours (1554 versus 660 microvesicles/μL;
P
=0.0041) and 2 to 6 days after stroke (1346 versus 660 microvesicles/μL;
P
=0.0237). Their proteome revealed anti-inflammatory properties mediated via downregulation of Kirsten rat sarcoma virus and IL (interleukin)-6/JAK/STAT3 signaling at 0 to 6 hours, but proangiogenic as well as proinflammatory signals at 12 to 24 hours. Between 2 and 6 days, proteins were mainly associated with vascular remodeling as indicated by activation of Hedgehog signaling in addition to proangiogenic signals.

CONCLUSIONS:
We demonstrate that the plasma of patients with acute ischemic stroke reflects (1) an early and time-dependent increase of pericyte-derived microvesicles and (2) changes in the protein cargo of microvesicles over time indicating cell signaling specifically related to inflammation and vascular remodeling.