bluuebunny/crossref_metadata_2025 huggingface dataset:
Insight into antiphospholipid syndrome: the role and clinical utility of neutrophils extracellular traps formation
Authors: Zaiema Shams ElDoha Galal ElDin , Elwafa Menna Allah Zakaria Mohammad Ali Ab , Hassan Shaymaa Gamal Arafa , El Adwey Radwa Hassan Abou El Fotoh , Ghorab Raghda Mohammed Mostafa , Galal Raghda El Sayed Abdel Monem
Published: March 2024

Antiphospholipid syndrome (APLS) is a systemic immune dysregulation distinguished by repetitive complications and pregnancy loss in the absence of definite etiology. Most research focuses on the laboratory detection and clinical features of APLS, but its precise etiology remains to be deeply explored. NETosis is a newly developed theory in the pathophysiology of APLS which may serve as the missing bridge between coagulation and inflammation reaching the disease progression and severity. We aimed in this study to navigate the prognostic role of NETosis in thrombotic APLS. Our study included 49 newly diagnosed APLS patients (both 1ry and 2ry) who met clinical and laboratory criteria as perthe international consensus statement on the update of the classification criteria for definite APLSand were sub-classified according to the occurrence of thrombotic events in thrombotic and non-thrombotic types. In addition, 20 sex and age-matched reactive subjects and 20 sex and age-matched healthy volunteer controls were enrolled. NETosis formation was assessed by measuring serum Myeloperoxidase (MPO) and Histones level using the enzyme-linked immunosorbent assay (ELISA) technique. Both MPO and Histones levels were able to discriminate among APLS cases from normal controls, showing significant cutoffs of > 2.09 ng/ml for MPO and > 1.45 ng/ml for Histones (AUC values were 0.987and 1.000, respectively). These values can be used as predictors for NETosis pathophysiology in APLS patients. Additionally, these markers demonstrated a significant association with several prognostic indicators, including thrombosis, higher PT and INR, and lower hemoglobin (Hb) levels which are supposed to be ameliorated by using NETs inhibitors.In conclusion, we suggest that measuring NETosis markers, MPO, and Histones, in the early course of APLS using proposed cutoff values will facilitate the timely initiation of anti-NETosis therapy and improve the overall prognosis, particularly for patients with thrombotic APLS.
Propofol improves survival in a murine model of sepsis via inhibiting Rab5a-mediated intracellular trafficking of TLR4
Authors: Zhou Bo-Wei , Zhang Wen-Juan , Zhang Fang-Ling , Yang Xiao , Ding Yu-Qi , Yao Zhi-Wen , Yan Zheng-Zheng , Zhao Bing-Cheng , Chen Xiao-Dong , Li Cai , Liu Ke-Xuan
Published: March 2024

Background

Propofol is a widely used anesthetic and sedative, which has been reported to exert an anti-inflammatory effect. TLR4 plays a critical role in coordinating the immuno-inflammatory response during sepsis. Whether propofol can act as an immunomodulator through regulating TLR4 is still unclear. Given its potential as a sepsis therapy, we investigated the mechanisms underlying the immunomodulatory activity of propofol.

Methods

The effects of propofol on TLR4 and Rab5a (a master regulator involved in intracellular trafficking of immune factors) were investigated in macrophage (from Rab5a−/− and WT mice) following treatment with lipopolysaccharide (LPS) or cecal ligation and puncture (CLP) in vitro and in vivo, and peripheral blood monocyte from sepsis patients and healthy volunteers.

Results

We showed that propofol reduced membrane TLR4 expression on macrophages in vitro and in vivo. Rab5a participated in TLR4 intracellular trafficking and both Rab5a expression and the interaction between Rab5a and TLR4 were inhibited by propofol. We also showed Rab5a upregulation in peripheral blood monocytes of septic patients, accompanied by increased TLR4 expression on the cell surface. Propofol downregulated the expression of Rab5a and TLR4 in these cells.

Conclusions

We demonstrated that Rab5a regulates intracellular trafficking of TLR4 and that propofol reduces membrane TLR4 expression on macrophages by targeting Rab5a. Our study not only reveals a novel mechanism for the immunomodulatory effect of propofol but also indicates that Rab5a may be a potential therapeutic target against sepsis.
Women’s preference for a vaginal birth in Brazilian private hospitals: effects of a quality improvement project
Authors: Domingues Rosa Maria Soares Madeira , Dias Marcos Augusto Bastos , do Carmo Leal Maria
Published: March 2024

Background

In 2015, a quality improvement project called “Adequate Childbirth Project” (PPA) was implemented in Brazilian private hospitals in order to reduce cesarean sections without clinical indication. The PPA is structured in four components, one of which is directed at women and families. The objective of this study is to evaluate the effects of PPA on women’s preference for vaginal birth (VB) at the end of pregnancy.

Methods

Evaluative research conducted in 12 private hospitals participating in the PPA. Interviews were carried out in the immediate postpartum period and medical record data were collected at hospital discharge. The implementation of PPA activities and women’s preference for type of birth at the beginning and end of pregnancy were compared in women assisted in the PPA model of care and in the standard of care model, using a chi-square statistical test. To estimate the effect of PPA on women’s preference for VB at the end of pregnancy, multiple logistic regression was performed with selection of variables using a causal diagram.

Results

Four thousand seven hundred ninety-eight women were interviewed. The implementation of the planned activities of PPA was less than 50%, but were significantly more frequent among women assisted in the PPA model of care. Women in this group also showed a greater preference for VB at the beginning and end of pregnancy. The PPA showed an association with greater preference for VB at the end of pregnancy in primiparous (OR 2.54 95% CI 1.99–3.24) and multiparous women (OR 1.44 95% CI 0.97–2.12), although in multiparous this association was not significant. The main factor associated with the preference for VB at the end of pregnancy was the preference for this type of birth at the beginning of pregnancy, both in primiparous (OR 18.67 95% CI 14.22–24.50) and in multiparous women (OR 53.11 95% CI 37.31–75.60).

Conclusions

The PPA had a positive effect on women’s preference for VB at the end of pregnancy. It is plausible that more intense effects are observed with the expansion of the implementation of the planned activities. Special attention should be given to information on the benefits of VB in early pregnancy.
Improving measurement-based care implementation in youth mental health through organizational leadership and climate: a mechanistic analysis within a randomized trial
Authors: Williams Nathaniel J. , Ehrhart Mark G. , Aarons Gregory A. , Esp Susan , Sklar Marisa , Carandang Kristine , Vega Nallely R. , Brookman-Frazee Lauren , Marcus Steven C.
Published: March 2024

Background

Theory and correlational research indicate organizational leadership and climate are important for successful implementation of evidence-based practices (EBPs) in healthcare settings; however, experimental evidence is lacking. We addressed this gap using data from the WISDOM (Working to Implement and Sustain Digital Outcome Measures) hybrid type III effectiveness-implementation trial. Primary outcomes from WISDOM indicated the Leadership and Organizational Change for Implementation (LOCI) strategy improved fidelity to measurement-based care (MBC) in youth mental health services. In this study, we tested LOCI’s hypothesized mechanisms of change, namely: (1) LOCI will improve implementation and transformational leadership, which in turn will (2) mediate LOCI’s effect on implementation climate, which in turn will (3) mediate LOCI’s effect on MBC fidelity.

Methods

Twenty-one outpatient mental health clinics serving youth were randomly assigned to LOCI plus MBC training and technical assistance or MBC training and technical assistance only. Clinicians rated their leaders’ implementation leadership, transformational leadership, and clinic implementation climate for MBC at five time points (baseline, 4-, 8-, 12-, and 18-months post-baseline). MBC fidelity was assessed using electronic metadata for youth outpatients who initiated treatment in the 12 months following MBC training. Hypotheses were tested using longitudinal mixed-effects models and multilevel mediation analyses.

Results

LOCI significantly improved implementation leadership and implementation climate from baseline to follow-up at 4-, 8-, 12-, and 18-month post-baseline (all ps < .01), producing large effects (range of ds = 0.76 to 1.34). LOCI’s effects on transformational leadership were small at 4 months (d = 0.31, p = .019) and nonsignificant thereafter (ps > .05). LOCI’s improvement of clinic implementation climate from baseline to 12 months was mediated by improvement in implementation leadership from baseline to 4 months (proportion mediated [pm] = 0.82, p = .004). Transformational leadership did not mediate LOCI’s effect on implementation climate (p = 0.136). Improvement in clinic implementation climate from baseline to 12 months mediated LOCI’s effect on MBC fidelity during the same period (pm = 0.71, p = .045).

Conclusions

LOCI improved MBC fidelity in youth mental health services by improving clinic implementation climate, which was itself improved by increased implementation leadership. Fidelity to EBPs in healthcare settings can be improved by developing organizational leaders and strong implementation climates.

Trial registration

ClinicalTrials.gov identifier: NCT04096274. Registered September 18, 2019.
Impact of delayed removal of pectus bar on outcomes following Nuss repair: a retrospective analysis
Authors: Keong Der-En , Tzeng I-Shiang , Htut Nay , Fan Yu-Jiun , Hsieh Min-Shiau , Cheng Yeung-Leung
Published: March 2024

Background

Usually, pectus bars are removed 3 years after the Nuss procedure in patients with pectus excavatum. However, the optimal timing for postoperative pectus bar removal remains undefined. Our study investigated the effects of delayed pectus bar removal after Nuss repairs.

Methods

Retrospective data were collected on patients who underwent Nuss procedures for pectus excavatum and had their bars removed from August 2014 to December 2020. Patients with correction periods > 3 years were divided into group A (< 6 years) and group B (≥ 6 years). Propensity score matching was used to compare complications and radiological outcomes associated with bar removal.

Results

Of the 542 patients who underwent bar removal, 451 (Group A: 419 patients, Group B: 32) had correction duration > 3 years. The average correction duration was 4.5 ± 1.4 years. After propensity score matching analysis, group B [median duration: 8.0 (6.0–16.2) years] exhibited significantly longer median operative times (85 vs. 55 min; P = 0.026), higher callus formation rates (68.8% vs. 46.9%; P = 0.029), and greater median intraoperative blood loss (35 vs. 10 mL; P = 0.017) than group A [median duration: 4.2 (3.0–5.9) years]. However, following bar removal, the groups showed no statistical differences in the surgical complication rates (group A: 6.3% vs. group B: 9.4%; P = 0.648) or median ratio of radiological improvement (an improvement on the Haller index on chest radiography; 21.0% vs. 22.2%; P = 0.308).

Conclusions

Delaying pectus bar removal after Nuss repair presents certain challenges but does not compromise overall outcomes. These findings suggest that a longer correction period may be unnecessary. However, further multicenter studies with long-term follow-up are warranted to assess long-term outcomes.
An occupational mechanical job exposure index based on five Norwegian nationwide surveys of living conditions on work environment
Authors: Hermansen Åsmund
Published: March 2024

Objectives

Nordic register data are not collected for research purposes, and various dimensions of working conditions are typically missing in register-based research. One way to address the issue of missing information on the work environment in register data is to utilize a job exposure matrix (JEM). The purpose of this paper is to document and provide access to a Mechanical Job Exposure Matrix (JEM) and a validated Occupational Mechanical Job Exposure Index based on the constructed JEM, allowing researchers to utilize the index in register-based research. The JEM and the Occupational Mechanical Job Exposure Index were created using data from five nationwide Surveys of Living Conditions on work environment conducted in Norway in 2006, 2009, 2013, 2016, and 2019, encompassing a total of 43,977 respondents. The index can be merged to register data using occupational codes (STYRK-98) and gender, which is information collected by the registries. The ultimate aim of constructing the index was to create a comprehensive measure of mechanical job exposures for use in future analyses of Norwegian register data.

Data description

This paper provides the scripts documenting the construction of the Mechanical Job Exposure Matrix (JEM) and the Occupational Mechanical Job Exposure Index, as well as a data file including the matrix and the index. A script for merging the matrix and index to register data is also provided.
Tetralogy of Fallot complicated by multiple cerebral abscesses in a child: a case report
Authors: Kamabu Larrey Kasereka , Sikakulya Franck Katembo , Kataka Louange Maha , Vivalya Bives Nzanzu Mutume , Lekuya Hervé Monka , Obiga Doomwin Oscar Deogratius , Sekabunga Juliet Nalwanga , Bbosa Godfrey S.
Published: March 2024

Introduction

Brain abscesses are rare but potentially fatal condition and can be associated with cyanotic congenital heart disease of which 5–18.7% of these patients that develop cerebral abscess commonly have tetralogy of Fallot (TOF).

Case presentation

We report a case of 3-year-old Muganda male that presented with convulsions, cyanosis and difficulty in breathing. The patient had a combination intervention of medical treatment and surgical drainage of the abscess. Post-operative Computerized tomography scan images and pre-operative brain Computerized tomography scans were compared. The multiple rings enhancing lesions were reduced in number and sizes. The largest measured ring was 44 × 22.5×16mm compared to the previous; 42 × 41×36mm. The mass effect had reduced from 16 mm to 7.5 mm. The periventricular hypodensities persisted. Findings showed radiological improvement with residual abscesses, subacute subdural hematoma and pneumocranium. The patient was treated with intravenous ceftriaxone 1 g OD for six weeks and he showed marked improvement and was discharged home after 3 months.

Conclusion

A comprehensive strategy involving medications, surgical drainage, and early neurosurgical consultation is vital in treating brain abscesses in uncorrected TOF. Early identification of the pathogen, appropriate antibiotic therapy, and vigilant follow-up through clinical assessments and imaging are crucial, potentially spanning a 4–8-week treatment.
Glucose phosphate isomerase deficiency demasked by whole-genome sequencing: a case report
Authors: Holme Sissel , van Wijk Richard , Rasmussen Andreas Ørslev , Petersen Jesper , Glenthøj Andreas
Published: March 2024

Background

Glucose-6-phosphate isomerase deficiency is a rare genetic disorder causing hereditary nonspherocytic hemolytic anemia. It is the second most common glycolytic enzymopathy in red blood cells. About 90 cases are reported worldwide, with symptoms including chronic hemolytic anemia, jaundice, splenomegaly, gallstones, cholecystitis, and in severe cases, neurological impairments, hydrops fetalis, and neonatal death.

Case presentation

This paper details the case of the first Danish patient diagnosed with glucose-6-phosphate isomerase deficiency. The patient, a 27-year-old white female, suffered from lifelong anemia of unknown origin for decades. Diagnosis was established through whole-genome sequencing, which identified two GPI missense variants: the previously documented variant p.(Thr224Met) and a newly discovered variant p.(Tyr341Cys). The pathogenicity of these variants was verified enzymatically.

Conclusions

Whole-genome sequencing stands as a potent tool for identifying hereditary anemias, ensuring optimal management strategies.
Synthesis of soundfields through irregular loudspeaker arrays based on convolutional neural networks
Authors: Comanducci Luca , Antonacci Fabio , Sarti Augusto
Published: March 2024

Most soundfield synthesis approaches deal with extensive and regular loudspeaker arrays, which are often not suitable for home audio systems, due to physical space constraints. In this article, we propose a technique for soundfield synthesis through more easily deployable irregular loudspeaker arrays, i.e., where the spacing between loudspeakers is not constant, based on deep learning. The input are the driving signals obtained through a plane wave decomposition-based technique. While the considered driving signals are able to correctly reproduce the soundfield with a regular array, they show degraded performances when using irregular setups. Through a complex-valued convolutional neural network (CNN), we modify the driving signals in order to compensate the errors in the reproduction of the desired soundfield. Since no ground truth driving signals are available for the compensated ones, we train the model by calculating the loss between the desired soundfield at a number of control points and the one obtained through the driving signals estimated by the network. The proposed model must be retrained for each irregular loudspeaker array configuration. Numerical results show better reproduction accuracy with respect to the plane wave decomposition-based technique, pressure-matching approach, and linear optimizers for driving signal compensation.
Process and outcome evaluation of a social norms approach intervention on alcohol use among Flemish university students: a quasi-experimental study
Authors: van Roozendaal Hanna , Derickx Katleen , Ponnet Koen , Deforche Benedicte , Thienpondt Annelies , Glazemakers Inge , Verhulst Stijn , De Dooy Jozef , van der Lely Nico , Van Hal Guido
Published: March 2024

Background

Alcohol consumption is prevalent among students, with a common tendency to overestimate peers' alcohol use, contributing to increased consumption. This misperception is evident among Flemish students. This study aimed to develop and assess a Social Norms Approach (SNA) intervention targeting Flemish students to correct misperceptions and subsequently reduce alcohol use.

Methods

The 'Alcoholfacts' social media campaign was implemented using a quasi-experimental design from November 2022 to March 2023. A process evaluation followed Medical Research Council guidance, and intervention effects were evaluated using baseline and post-intervention surveys. Multiple linear regression with a Difference-in-Difference approach was performed for outcome assessment, using an intention-to-treat approach.

Results

The process evaluation showed that 36.3% of the intervention group had seen the campaign and that most of the exposed students found the campaign credible (73.3%). However, 54.8% of the exposed students did not find the campaign appealing. Results of the outcome assessment indicated that students of the intervention group at endline estimated students’ alcohol consumption significantly lower (bootstrapped p = 0.013; B = -1.93, bootstrapped CI = -3.620 to -0.565) compared to students of the control group. However, no significant intervention effect on student’s alcohol consumption was found (bootstrapped p = 0.741; B = -0.32, bootstrapped CI = -2.101 to 1.534).

Conclusions

The study supports the efficacy of an SNA campaign in correcting misperceptions but did not yield an immediate reduction in alcohol consumption. Future research should involve the target group in campaign material development to enhance attractiveness and impact.
Multi-omics cluster defines the subtypes of CRC with distinct prognosis and tumor microenvironment
Authors: Ma Yuan , Li Jing , Zhao Xu , Ji Chao , Hu Weibin , Ma YanFang , Qu Fengyi , Sun Yuchen , Zhang Xiaozhi
Published: March 2024

Background

Colorectal cancer (CRC) is a complex malignancy characterized by diverse molecular profiles, clinical outcomes, and limited precision in prognostic markers. Addressing these challenges, this study utilized multi-omics data to define consensus molecular subtypes in CRC and elucidate their association with clinical outcomes and underlying biological processes.

Methods

Consensus molecular subtypes were obtained by applying ten integrated multi-omics clustering algorithms to analyze TCGA-CRC multi-omics data, including mRNA, lncRNA, miRNA, DNA methylation CpG sites, and somatic mutation data. The association of subtypes with prognoses, enrichment functions, immune status, and genomic alterations were further analyzed. Next, we conducted univariate Cox and Lasso regression analyses to investigate the potential prognostic application of biomarkers associated with multi-omics subtypes derived from weighted gene co-expression network analysis (WGCNA). The function of one of the biomarkers MID2 was validated in CRC cell lines.

Results

Two CRC subtypes linked to distinct clinical outcomes were identified in TCGA-CRC cohort and validated with three external datasets. The CS1 subtype exhibited a poor prognosis and was characterized by higher tumor-related Hallmark pathway activity and lower metabolism pathway activity. In addition, the CS1 was predicted to have less immunotherapy responder and exhibited more genomic alteration compared to CS2. Then a prognostic model comprising five genes was established, with patients in the high-risk group showing substantial concordance with the CS1 subtype, and those in the low-risk group with the CS2 subtype. The gene MID2, included in the prognostic model, was found to be correlated with epithelial–mesenchymal transition (EMT) pathway and distinct DNA methylation patterns. Knockdown of MID2 in CRC cells resulted in reduced colony formation, migration, and invasion capacities.

Conclusion

The integrative multi-omics subtypes proposed potential biomarkers for CRC and provided valuable knowledge for precision oncology.
Effects of nicotine on microRNA-124 expression in bile duct ligation-induced liver fibrosis in rats
Authors: Hajiasgharzadeh Khalil , Shahabi Parviz , Karimi-Sales Elham , Alipour Mohammad Reza
Published: March 2024

Background

Nicotine, the main compound of smoking may exert its effects by changing the expression of microRNAs (miRNAs). This study was conducted to further investigate the molecular mechanisms of miRNA-dependent effects of nicotine in an animal model of liver fibrosis.

Methods

The bile duct ligation (BDL) approach was used to create a model of liver fibrosis. Twenty-four male Wistar rats were used in the study. The effects of nicotine administration on miRNA-124 expression, as well as alpha-smooth muscle actin (liver fibrosis marker) and chemokine ligand 2 (an inflammatory chemokine), were investigated using RT-qPCR. In addition, the mRNA and protein expression of signal transducer and activator of transcription 3 (STAT-3; as a potential target for miRNA-124) were investigated by RT-qPCR and immunofluorescence, respectively. Liver enzyme activity levels were measured using a colorimetric assay. In addition, the effects of nicotine on the process of liver fibrosis were investigated with histological studies.

Results

The development of liver fibrosis in BDL rats and nicotine administration led to a decrease in miRNA-124 expression. The decrease in the expression is accompanied by the increase in the expression of fibrotic and proinflammatory genes. Also, an increase in STAT-3 mRNA and protein expression was observed in the fibrotic rats that received nicotine. In addition, the significant increase in bilirubin and liver enzymes in fibrotic rats worsens with nicotine administration. The results of histological studies also confirm these results.

Conclusion

Considering that miRNA-124 is an anti-inflammatory miRNA, it can be concluded that the decrease in its expression due to nicotine exposure leads to an increase in inflammatory processes and subsequently to an increase in liver fibrosis.
A three-dimensional model of terrain-induced updrafts for movement ecology studies
Authors: Thedin Regis , Brandes David , Quon Eliot , Sandhu Rimple , Tripp Charles
Published: March 2024

Background

Spatially explicit simulation models of animal movements through the atmosphere necessarily require a representation of the spatial and temporal variation of atmospheric conditions. In particular, for movements of soaring birds that rely extensively on vertical updrafts to avoid flapping flight, accurate and reliable estimation of the vertical component of wind is critical. The interaction between wind and complex terrain shapes both the horizontal and vertical wind fields, highlighting the need to model the coupling between local terrain features and atmospheric conditions at scales relevant to animal movement.

Methods

In this work, we propose a new empirical model for estimating the orographic updraft field. The model is developed using computational fluid dynamics simulations of canonical atmospheric conditions over moderately complex terrain. To isolate buoyancy and thermal effects, and focus on terrain-induced effects, we use only simulations of a neutrally stratified atmosphere to develop the model. The model, which we name Engineering Vertical Velocity Estimator (EVVE), is simple to implement and is a function of the underlying terrain elevation map, the desired height above ground level (AGL), and wind conditions at a reference height (80 m). We validate the model with data from the Alaiz mountain (Spain) field campaign.

Results

Compared to observations, the proposed improved model estimates the updrafts at 120 m AGL with a mean error of 0.11 m/s ($$\sigma =0.28$$

σ
=
0.28

m/s), compared to 0.85 m/s ($$\sigma =0.58$$

σ
=
0.58

m/s) for its baseline. For typical land-based wind turbine hub heights of 80 m AGL, the proposed model has a mean error of 0.04 m/s ($$\sigma =0.25$$

σ
=
0.25

m/s), compared to baseline 0.54 m/s ($$\sigma =0.45$$

σ
=
0.45

m/s) estimations. We illustrate an application of the model in movement ecology by comparing simulated tracks and presence maps of golden eagles (Aquila chrysaetos) moving across two distinct landscapes. The tracks and presence maps are obtained using a simple heuristic-based movement model, with the updraft field given by the proposed model and a wind vector-based estimation approach that is currently in wide use in movement ecology studies of raptors and other soaring birds.

Conclusions

We highlight that movement model results can be sensitive to the underlying orographic updraft model, especially in studies of fine-scale movements in regions of complex topography. We suggest adopting the proposed model rather than the wind vector estimation method for studies of soaring bird movements.
A rare clinical case of systemic AA amyloidosis with cardiac involvement complicating ankylosing spondylitis: a case report
Authors: Barakat Leïla , Echchilali Khadija , Moudatir Mina , El Kabli Hassan , Ettagmouti Yassine , Haboub Mériem , Arous Salim , Benouna Mohamed Ghali , Drighil Abdenasser , Habbal Rachida , Azim Meryame , Mazti Asmae , Regragui Meriem , Bennani Guebessi Nissrine , Karkouri Mehdi
Published: March 2024

Background

Ankylosing spondylitis (AS) is a type of chronic inflammation that is most prevalent in young adults and is characterized by an inflammatory enthesiopathy that gradually develops toward ossification and ankylosis. If inflammation is left unchecked, it can potentially lead to complications such as secondary amyloidosis, also known as AA amyloidosis, involving the deposition of amyloid serum A protein. Our case presents with a thyroid localization of AA amyloidosis which is secondary to this AS. Such a case has been described in only four cases in the literature. Cardiac localization of AA amyloidosis has been exceptionally described in the literature.

Case presentation

We report the case of a young patient with severe AS complicated by secondary amyloidosis with thyroid, cardiac, and probably renal localization. He was treated with anti-TNF therapy, and his condition improved significantly.

Conclusions

Our case presents several localizations of AA amyloidosis secondary to this AS. Although cardiac involvement is rare in secondary AA amyloidosis, it should always be screened for, even in a cardiacly asymptomatic patient.
Human Epidermal Growth Factor Receptor 2–Low Breast Cancer Brain Metastases: An Opportunity for Targeted Systemic Therapies in a High-Need Patient Population
Authors: Chehade Rania , Nofech-Mozes Sharon , Plotkin Anna , Fan Kevin Yijun , Das Sunit , Sahgal Arjun , Moravan Veronika , Jerzak Katarzyna Joanna
Published: March 2024

PURPOSE

Trastuzumab deruxtecan is a new treatment option for patients with advanced human epidermal growth factor receptor 2 (HER2)–low breast cancer (BC). Although HER2-low status has been characterized in early and advanced BC, it has yet to be fully characterized in brain metastases (BrM).

METHODS

Patients who underwent surgery for BC BrM at Sunnybrook Health Sciences Centre and for whom HER2 status was available on resected BrM were studied. Estrogen receptor, progesterone receptor, and HER2 status were assessed on the basis of ASCO/College of American Pathologists (CAP) guidelines. HER2-zero was defined as immunohistochemistry (IHC) 0; HER2-low was defined as IHC 1+ or IHC 2+ with fluorescence in situ hybridization (FISH)–negative status. HER2-positive (HER2+) was defined as IHC 3+ or IHC 2+ with positive FISH. Clinicopathologic features were recorded. We also assessed the prognostic association between extent of HER2 expression and (1) brain-specific progression-free survival (bsPFS), as well as (2) overall survival (OS).

RESULTS

In this retrospective cohort of 102 patients with resected BC BrM, 53% (n = 54) were HER2+, 29.4% (n = 30) were HER2-low, and 17.6% (n = 18) had HER2-zero status. Among BrM that were triple-negative on the basis of ASCO/CAP guidelines, 63.6% (n = 14/22) were reclassified as being HER2-low. Sixty percent (n = 15/25) of BrM that were hormone receptor–positive/HER2-negative (HR+/HER2–) were reclassified as being HER2-low. In total, 51 patients had matched primary breast and BrM tissue available; results of HER2 status when categorized as HER2-zero, HER2-low, and HER2+ were concordant in 82.3% (n = 42/51) of cases (Cohen's kappa, 0.58; P = .07). There was no significant association between HER2-zero, HER2-low, and HER2+ status in BrM and either bsPFS or OS.

CONCLUSION

Among patients with surgically resected BrM, a high proportion of those with metastatic triple-negative BC and HR+/HER2– disease have HER2-low BrM with potential to benefit from HER2-targeted therapy.
Comprehensive Immunogenomic Profiling of IDH1-/2-Altered Cholangiocarcinoma
Authors: Makawita Shalini , Lee Sunyoung , Kong Elisabeth , Kwong Lawrence N. , Abouelfetouh Zeyad , Danner De Armas Anaemy , Xiao Lianchun , Murugesan Karthikeyan , Danziger Natalie , Pavlick Dean , Korkut Anil , Ross Jeffrey S. , Javle Milind
Published: March 2024

PURPOSE

Isocitrate dehydrogenase ( IDH) 1/ 2 genomic alterations (GA) occur in 20% of intrahepatic cholangiocarcinoma (iCCA); however, the immunogenomic landscape of IDH1-/2-mutated iCCA is largely unknown.

METHODS

Comprehensive genomic profiling (CGP) was performed on 3,067 cases of advanced iCCA. Tumor mutational burden (TMB), PD-L1 expression (Dako 22C3), microsatellite instability (MSI), and genomic loss of heterozygosity (gLOH) as a surrogate marker for homologous recombination deficiency were examined. RNA sequencing of 73 patient samples was analyzed for differences in stromal/immune cell infiltration, immune marker expression, and T-cell inflammation. Tissue microarray arrays were subjected to multiplex immunohistochemistry and colocalization analysis in 100 surgical samples. Retrospective clinical data were collected for 501 patients with cholangiocarcinoma to examine median overall survival (mOS) in IDH1/2+ versus IDHwt.

RESULTS

Of 3,067 iCCA cases subjected to CGP, 426 (14%) were IDH1+ and 125 (4%) were IDH2+. IDH1 GA included R132C (69%) and R132L/G/S/H/F (16%/7%/4%/3%/<1%). IDH2 GA occurred at R172 (94.4%) and R140 (6.6%). No significant difference was seen in median gLOH between IDH1+ versus IDHwt iCCA ( P = .37), although patterns of comutations differed. MSI-High ( P = .009), TMB ≥10 mut/Mb ( P < .0001), and PD-L1 positivity were lower in IDH1/2+ versus IDHwt iCCA. Resting natural killer cell population, CD70, and programmed cell death 1 expression were significantly higher in non– IDH1-mutated cases, whereas V-set domain containing T-cell activation inhibitor 1 (B7-H4) expression was significantly higher in IDH1+. No significant difference in mOS was observed between IDH1/2+ versus IDHwt patients.

CONCLUSION

Significant differences in GA and immune biomarkers are noted between IDH1/ 2+ and IDHwt iCCA. IDH1-/2-mutated tumors appear immunologically cold without gLOH. These immunogenomic data provide insight for precision targeting of iCCA with IDH alterations.
Efficient genome editing using modified Cas9 proteins in zebrafish
Authors: Dorner Laura , Stratmann Benedikt , Bader Laura , Podobnik Marco , Irion Uwe
Published: March 2024

The zebrafish (Danio rerio) is an important model organism for basic as well as applied bio-medical research. One main advantage is its genetic tractability, which was greatly enhanced by the introduction of the CRISPR/Cas method a decade ago. The generation of loss-of-function alleles via the production of small insertions or deletions in the coding sequences of genes with CRISPR/Cas systems is now routinely achieved with high efficiency. The method is based on the error prone repair of precisely targeted DNA double strand breaks by non-homologous end joining (NHEJ) in the cell nucleus. However, editing the genome with base pair precision, by homology-directed repair (HDR), is by far less efficient and therefore often requires large-scale screening of potential carriers by labour intensive genotyping. Here we confirm that the Cas9 protein variant SpRY, with relaxed PAM requirement, can be used to target some sites in the zebrafish genome. In addition, we demonstrate that the incorporation of an artificial nuclear localisation signal (aNLS) into the Cas9 protein variants not only enhances the efficiency of gene knockout but also the frequency of HDR, thereby facilitating the efficient modification of single base pairs in the genome. Our protocols provide a guide for a cost-effective generation of versatile and potent Cas9 protein variants and efficient gene editing in zebrafish.
Loss of UBE2S causes meiosis I arrest with normal spindle assembly checkpoint dynamics in mouse oocytes
Authors: Sun Si-Min , Zhao Bing-Wang , Li Yuan-Yuan , Liu Hong-Yang , Xu Yuan-Hong , Yang Xue-Mei , Guo Jia-Ni , Ouyang Ying-Chun , Weng Chang-Jiang , Guan Yi-Chun , Sun Qing-Yuan , Wang Zhen-Bo
Published: March 2024

The timely degradation of proteins that regulate the cell cycle is essential for oocyte maturation. Oocytes are equipped to degrade proteins via the ubiquitin-proteasome system. In meiosis, anaphase promoting complex/cyclosome (APC/C), an E3 ubiquitin-ligase, is responsible for the degradation of proteins. Ubiquitin-conjugating enzyme E2 S (UBE2S), an E2 ubiquitin-conjugating enzyme, delivers ubiquitin to APC/C. APC/C has been extensively studied, but the functions of UBE2S in oocyte maturation and mouse fertility are not clear. In this study, we used Ube2s knockout mice to explore the role of UBE2S in mouse oocytes. Ube2s-deleted oocytes were characterized by meiosis I arrest with normal spindle assembly and spindle assembly checkpoint dynamics. However, the absence of UBE2S affected the activity of APC/C. Cyclin B1 and securin are two substrates of APC/C, and their levels were consistently high, resulting in the failure of homologous chromosome separation. Unexpectedly, the oocytes arrested in meiosis I could be fertilized and the embryos could become implanted normally, but died before embryonic day 10.5. In conclusion, our findings reveal an indispensable regulatory role of UBE2S in mouse oocyte meiosis and female fertility.
Anticipatory Anxiety and Wishful Thinking
Authors: Engelmann Jan B. , Lebreton Maël , Salem-Garcia Nahuel A. , Schwardmann Peter , van der Weele Joël J.
Published: March 2024

Across five experiments (N = 1,714), we test whether people engage in wishful thinking to alleviate anxiety about adverse future outcomes. Participants perform pattern recognition tasks in which some patterns may result in an electric shock or a monetary loss. Diagnostic of wishful thinking, participants are less likely to correctly identify patterns that are associated with a shock or loss. Wishful thinking is more pronounced under more ambiguous signals and only reduced by higher accuracy incentives when participants’ cognitive effort reduces ambiguity. Wishful thinking disappears in the domain of monetary gains, indicating that negative emotions are important drivers of the phenomenon. (JEL C91, D12, D83, D91)
The Political Development Cycle: The Right and the Left in People’s Republic of China from 1953
Authors: Cheremukhin Anton , Golosov Mikhail , Guriev Sergei , Tsyvinski Aleh
Published: March 2024

We quantify the effects of the political development cycle—the fluctuations between the Left (Maoist) and the Right (pragmatist) development policies—on growth and structural transformation of China in 1953–1978. The left policies prioritized structural transformation toward nonagricultural production and consumption at the expense of agricultural development. The right policies prioritized agricultural consumption through slower structural transformation. The imperfect implementation of these policies led to large welfare costs of the political development cycle in a distorted economy undergoing a structural change. (JEL D72, N15, N45, N55, O21, P21, P24)
Elevation-dependent growth trends of Picea orientalis (L.) Peterm forests in the Fırtına Creek Basin (Rize/Turkey)
Authors: Işık Fatih , Bahadır Muhammet , Zeybek Halil İbrahim , Hatipoğlu İlter Kutlu
Published: March 2024

Changes in climatic conditions have ecological and economic consequences or impact for trees and forest stands. In this respect, it is crucial to understand the radial growth trends of trees, their ecological response across elevation gradients, and the possible impacts of climate change on the species. In this study, Picea orientalis (L.) Peterm, located in the Fırtına Creek Basin in the northern part of the Eastern Black Sea Mountains in northeastern Turkey, was investigated along different elevation gradients in the context of climate-growth response. In the study, six site chronologies along an elevation gradient from 900 m to 2050 m were developed. Dendroclimatological methods were applied to assess the elevation-dependent radial growth characteristics of trees. In total, 200 increment cores were collected from 98 living trees. The relationships between climate and tree ring growth along the elevation gradient showed a positive relationship between growth and temperature at upper elevations (1700–1900 m) and a positive relationship between growth and precipitation at middle elevations (1400–1600 m). In particular, January–April mean temperatures and May rainfall were positively correlated with tree-ring growth. At lower elevations (900–1100 m), the correlation coefficients between climate and growth are insignificant because, at these altitudes, the species have optimum ecological conditions. It was also found that mean temperatures between 0 °C and 2 °C in January–April and total precipitation between 60 and 100 mm in January–February positively affect tree growth. However, if these thresholds are exceeded, it is possible that growth may be adversely affected. This research underscores the complex interplay between climate variables and tree growth along elevation gradients, highlighting the need for adaptive management strategies in the face of changing climatic conditions.
Path-Based Formulations for the Design of On-demand Multimodal Transit Systems with Adoption Awareness
Authors: Guan Hongzhao , Basciftci Beste , Van Hentenryck Pascal
Published: March 2024

This paper reconsiders the On-Demand Multimodal Transit Systems (ODMTS) Design with Adoptions problem (ODMTS-DA) to capture the latent demand in on-demand multimodal transit systems. The ODMTS-DA is a bilevel optimization problem, for which Basciftci and Van Hentenryck proposed an exact combinatorial Benders decomposition. Unfortunately, their proposed algorithm only finds high-quality solutions for medium-sized cities and is not practical for large metropolitan areas. The main contribution of this paper is to propose a new path-based optimization model, called P-Path, to address these computational difficulties. The key idea underlying P-Path is to enumerate two specific sets of paths which capture the essence of the choice model associated with the adoption behavior of riders. With the help of these path sets, the ODMTS-DA can be formulated as a single-level mixed-integer programming model. In addition, the paper presents preprocessing techniques that can reduce the size of the model significantly. P-Path is evaluated on two comprehensive case studies: the midsize transit system of the Ann Arbor – Ypsilanti region in Michigan (which was studied by Basciftci and Van Hentenryck) and the large-scale transit system for the city of Atlanta. The experimental results show that P-Path solves the Michigan ODMTS-DA instances in a few minutes, bringing more than two orders of magnitude improvements compared with the existing approach. For Atlanta, the results show that P-Path can solve large-scale ODMTS-DA instances (about 17 millions variables and 37 millions constraints) optimally in a few hours or in a few days. These results show the tremendous computational benefits of P-Path which provides a scalable approach to the design of on-demand multimodal transit systems with latent demand.

History: Accepted by Andrea Lodi, Area Editor for Design & Analysis of Algorithms—Discrete.

Funding: This work was partially supported by National Science Foundation Leap-HI [Grant 1854684] and the Tier 1 University Transportation Center (UTC): Transit - Serving Communities Optimally, Responsively, and Efficiently (T-SCORE) from the U.S. Department of Transportation [69A3552047141].

Supplemental Material: The software that supports the findings of this study is available within the paper and its Supplemental Information ( https://pubsonline.informs.org/doi/suppl/10.1287/ijoc.2023.0014 ) as well as from the IJOC GitHub software repository ( https://github.com/INFORMSJoC/2023.0014 ). The complete IJOC Software and Data Repository is available at https://informsjoc.github.io/ .
Optimal Auction Design with Deferred Inspection and Reward
Authors: Alaei Saeed , Belloni Alexandre , Makhdoumi Ali , Malekian Azarakhsh
Published: March 2024

In a variety of auction contexts, particularly those facilitated by digital marketplaces, auctioneers are now empowered to review the valuations submitted by purchasers and modify the final payments accordingly. Alaei et al. formulate and study the optimal design of such auctions, demonstrating that both the analysis and implementation vastly depart from classical settings. In particular, the analysis requires tools from convex analysis and the calculus of variations, which could be of independent interest in other mechanism design questions.
Mental capacity: legal considerations
Authors: Ellis Peter
Published: March 2024

In this paper, Peter Ellis discusses the topic of mental capacity. What is legal capacity, and why is it so important?
Effect of Biodeterioration on Modeling Parameters of Code-Compliant Cross-Laminated Timber Lateral Connections
Authors: Morrell Ian , Udele Kenneth E. , Morrell Jeffrey J. , Sinha Arijit
Published: March 2024

The effect of biodeterioration on the structural connection performance of timber for conventional framing and mass timber has been investigated recently, but there is a need for additional data as well as for the development of analytical models to utilize these data. An empirical material model (seismic analysis of wood frame shear walls) was fitted to cyclic connection test data of four species of cross-laminated timber at different levels of biodeterioration by two brown-rot fungi. These model inputs were then analyzed to account for trends between wood species and fungal species. Weak trends were most prominent for initial stiffness, intercept load, and displacement at peak force. Correlations were poor with postyield and postpeak stiffness modifiers. These relationships were consistent both as a function of time and as a function of mass loss, but additional data are needed to more accurately predict the effects. The limited relationships likely reflect the variations in fungal decay across the test members.
Mediprintic sp. z o.o.'s 3D printed forearm orthosis project stakeholder analysis.
Authors: Zakręcki Andrzej , Zawada Piotr
Published: March 2024

Cel: Celem badań było wykonanie analizy interesariuszy dla projektu badawczo-rozwojowego firmy Mediprintic sp. z o.o. w celu potwierdzenia poprawnie zidentyfikowanych podmiotów do współpracy w ramach projektu 1.1.2 PARP Platformy Startowe. Metody: Do oceny wybranych interesariuszy wykorzystano: narzędzie do identyfikacji interesariuszy i ich interesów, narzędzie do identyfikacji znaczenia i wpływu interesariuszy, analiza ryzyka dla podjętych działań podmiotu realizującego projektu z interesariuszami wraz z ustaleniem niezbędnych wskaźników oceny osiągnięcia kamienia milowego. Wyniki: Na podstawie przeprowadzonych badań wyselekcjonowano 14 kluczowych interesariuszy dla pomyślności realizacji projektu, które mają istotne znaczenie aby firma Mediprintic sp. z o.o. mogła wprowadzić swój produkt na rynek medyczny. Omówienie: Przeprowadzenie analizy interesariuszy ułatwia proces decyzyjny dla kadry zarządczej w celu priorytetyzacji podejmowanych działań uwzględniając ryzyka współpracy z poszczególnym partnerami biznesowymi.
Inclusion in an Interdisciplinary Leadership Training Program: Perspectives From Self-Advocates
Authors: Wayne Allison P. , Roach Andrew T. , LaMotte Krysta , Crenshaw Mark , Graybill Emily
Published: March 2024

Leadership Education in Neurodevelopmental and Related Disabilities (LEND) programs are interdisciplinary, graduate-level training programs that seek to promote improved outcomes for individuals with disabilities and their families. Many of these programs include individuals with disabilities as members of the self-advocacy discipline. In this study, 10 self-advocate trainees were interviewed to provide insight into the value of including self-advocates in training and the kinds of accommodations and supports that facilitated their success and inclusion. Interviewees endorsed the importance of including self-advocates in LEND programs. Although several accommodations were discussed as helpful, interpersonal supports from faculty and peers were equally important in ensuring their success and inclusion in LEND. The findings from this study provide support for the expansion of self-advocacy as a formal discipline in LEND programs.