bluuebunny/crossref_metadata_2025 huggingface dataset:
Optimization design of stamping die for large-size three-dimensional curved thick plate
Authors: Yan Lei , Qi Chang
Published: December 2024

Stamping is a highly efficient and precise way to fabricate metal plates with complex shapes, commonly used in practical engineering. Lowering the weight of die components is essential to reduce manufacturing and operational costs. Despite using a single topology optimization process, the previous study experienced difficulty in gaining the optimal structural configurations and their specific dimensions while considering structural performance and die weight. Therefore, a three-phase optimization procedure is proposed, namely model preparation, conceptual design, and detailed design. Firstly, using the proposed node-to-node load mapping strategy, the history of the load distribution across the die face is transferred to multiple loading cases in static analysis models. Then, the solid isotropic microstructure with penalization (SIMP) method based topology optimization is employed to achieve better structural configurations. Finally, a multiple-surrogate-models-based size optimization approach is implemented to obtain the specific dimensions. Applications on stamping die for large-size three-dimensional curved thick plate were conducted. The results showed that topology optimization could deliver more efficient structural configurations, which reduced the weight of the upper die, restrike punch, and lower die by 22.6%, 48.7%, and 39.9%, respectively, while still meeting most of the performance requirements. Furthermore, after size optimization, an increase of the restrike punch weight by 22% was obtained to meet the performance constraints, while the upper and lower dies had a further reduction in weight of 19.1% and 8% without violating the performance constraints. Therefore, the proposed optimization procedure is verified to be effective in reducing the die weights while meeting all performance requirements.
“You aren’t one of us”: The costs of validation of our criticism on an in-group by out-group members
Authors: Feng Chun , Guo Tieyuan
Published: December 2024

Although the intergroup sensitivity effect has indicated that people are more defensive to out-group members’ criticism compared to in-group members’ criticism, it is still unclear how people react when they criticize their in-group and others validate their criticism. In two studies, we applied the tripartite model of self and social identity theory to investigate how people respond to such validation when the validation was from an out-group member compared to when it was from an in-group member. We found that even though participants initiated the criticism of their in-group, they perceived the out-group validation more as a criticism of their selves than the in-group validation. Consequently, their relationship with the person who validated was negatively influenced when the person was an out-group member compared to an in-group member. Furthermore, the effect was moderated by their psychological closeness to the in-group. Specifically, when participants felt closer to the in-group, they perceived the out-group (vs. in-group) validation more as a criticism of their selves, and thus their relationship with the person who validated was more negatively influenced. However, these effects disappeared (Study 1) or became smaller (Study 2) when participants felt less close to the in-group.
Epilepsia partialis continua in a child with disseminated tuberculosis: a case report and review of literature
Authors: Mahesan Aakash , Wander Arvinder , Singh Ramandeep , Gaddigoudar Madhu S. , Meena Ankit Kumar
Published: December 2024

Tuberculosis can present myriad manifestations, affecting multiple organ systems. Common central nervous system (CNS) manifestations include vomiting, headache, blurred vision, neck stiffness, altered sensorium, seizures, and focal neurological deficits. Epilepsia partialis continua (EPC) is a rare manifestation of CNS tuberculosis. An 11-year-old female patient presented with abnormal twitching movements on the left side, specifically involving the upper limbs, while maintaining full awareness, which is suggestive of EPC. This was preceded by symptoms such as headache, poor appetite, and abdominal pain for 3 months, along with a transient episode of weakness in the left upper limb. An electroencephalogram revealed abundant spike-wave discharges from F8 T4 and C4 P4 in the right hemisphere. The EPC was refractory to anti-seizure medications. Brain MRI revealed multiple contrast-enhancing lesions and magnetic resonance spectroscopy showed a lipid peak that suggested tuberculomas. Further investigations confirmed multisystem involvement, including the gastrointestinal and genitourinary tracts. The treatment of EPC involves addressing the underlying etiology alongside the use of anti-seizure medications. In our patient, the EPC responded well to antitubercular therapy combined with corticosteroids. Given the prevalence of tuberculosis in developing countries, it should be considered early in the differential diagnosis, as it is a treatable cause of EPC.
Afropolitan Influence: Gender, Comedy, and Social Media in Global Africa
Authors: Crigler Robin K.
Published: December 2024

Gender and humor have always been intimately related. In many societies, comedy is traditionally understood as a masculine pursuit, and women’s existence in comedic spaces has been subject to intense scrutiny by male commentators. Africa’s burgeoning stand-up comedy scene is an important site of contestation in this regard, but in recent years social media has afforded opportunities for African women to bypass traditional industry gatekeepers. In online spaces like Instagram, TikTok, and X (Twitter), African women creators have built massive audiences that cross national and continental boundaries. In this project, I draw on interviews with three prominent female comedy creators—Stella Dlangalala, Thenjiwe Mosely, and Beverly Adaeze—and use their work to shed light on how female comedians negotiate their position(s) in digital spaces rooted in Nigeria, South Africa, the United States, the United Kingdom, and beyond. While social media affords autonomy to performers, success as a comedian-influencer demands more from women than jokes. Feminism, Afropolitanism, and commodification intertwine in the stories of these performers. The gendered body, viewed through the lens of parasocial intimacy that short-form video facilitates, emerges as a site of great significance. In addition, I argue for greater critical attention to what I call “algorithmic mystery”—the influence of opaque social media algorithms in promoting, maintaining, and severing digital connections.
From setbacks to success: lessons from the journey of RSV vaccine development
Authors: Cnossen Victor M. , van Leeuwen Rogier P. , Mazur Natalie I. , Vernhes Charlotte , ten Voorde Wouter , Burggraaf Jacobus , de Visser Saco J. , Roestenberg Meta , Kamerling Ingrid M. C.
Published: December 2024

Respiratory syncytial virus (RSV) causes high worldwide infant mortality, as well as a high disease burden in the elderly. Efforts in vaccine development over the past 60 years have recently delivered three approved vaccines and two monoclonal antibodies (mAbs). Looking back at the eventful history of RSV vaccine development, several factors can be identified that have hampered the developmental pathway, including the occurrence of enhanced RSV disease (ERD) in the first vaccine attempt and the difficulty in characterizing and stabilizing the pre-fusion F protein as a vaccine target. Moreover, the need for large trials to test vaccine efficacy, usually done late in development, and the lack of a correlate of protection (CoP) result in significant uncertainties in RSV vaccine development. The use of controlled human infection models (CHIMs) may provide a solution for some of these problems: through swift, cost-efficient and closely monitored assessment of vaccine safety and efficacy in early clinical phases, vaccines can either ‘fail fast’ or show results supporting further investments. Moreover, CHIMs facilitate the assessment of disease and could assist in the identification of a CoP supporting late-stage development. Although some factors may affect translatability to real-world vaccine efficacy, CHIMs can support the clinical development pathway in various ways. We advocate for, and demonstrate, a conceptual and rational design of RSV vaccine development. Assessing protective efficacy early on would result in the most cost-efficient pathway and identification of target populations should be done as early as possible. For RSV, elderly individuals and people in low- and middle-income countries are high-impact populations for RSV prevention. While RSV immunization is now available in certain regions, global access is not accomplished yet, and worldwide prevention does not seem within reach. Quick and cost-effective assessments of candidates currently in the pipeline could contribute to future successes in the battle against RSV.
Long-term efficacy and safety of danicopan as add-on therapy to ravulizumab or eculizumab in PNH with significant EVH
Authors: Kulasekararaj Austin , Griffin Morag , Piatek Caroline , Shammo Jamile , Nishimura Jun-ichi , Patriquin Christopher , Schrezenmeier Hubert , Barcellini Wilma , Panse Jens , Gaya Anna , Patel Yogesh , Liu Peng , Filippov Gleb , Sicre de Fontbrune Flore , Risitano Antonio , Lee Jong Wook
Published: December 2024

Complement C5 inhibitor treatment with ravulizumab or eculizumab for paroxysmal nocturnal hemoglobinuria (PNH) improves outcomes and survival. Some patients remain anemic due to clinically significant extravascular hemolysis (cs-EVH; hemoglobin [Hb] ≤9.5 g/dL and absolute reticulocyte count [ARC] ≥120 × 109/L). In the phase 3 ALPHA trial, participants received oral factor D inhibitor danicopan (150 mg 3 times daily) or placebo plus ravulizumab or eculizumab during the 12-week, double-blind treatment period 1 (TP1); those receiving placebo switched to danicopan during the subsequent 12-week, open-label TP2 and continued during the 2-year long-term extension (LTE). There were 86 participants randomized in the study, of whom 82 entered TP2, and 80 entered LTE. The primary end point was met, with Hb improvements from baseline at week 12 (least squares mean change, 2.8 g/dL) with danicopan. For participants switching from placebo to danicopan at week 12, improvements in mean Hb were observed at week 24. Similar trends were observed for the proportion of participants with ≥2 g/dL Hb increase, ARC, proportion of participants achieving transfusion avoidance, and Functional Assessment of Chronic Illness Therapy–Fatigue scale scores. Improvements were maintained up to week 72. No new safety signals were observed. The breakthrough hemolysis rate was 6 events per 100 patient-years. These long-term data demonstrate sustained efficacy and safety of danicopan plus ravulizumab/eculizumab for continued control of terminal complement activity, intravascular hemolysis, and cs-EVH in PNH. This trial was registered at www.clinicaltrials.gov as #NCT04469465.
Prediction of miRNA-disease associations based on PCA and cascade forest
Authors: Zhang Chuanlei , Li Yubo , Dong Yinglun , Chen Wei , Yu Changqing
Published: December 2024

Background

As a key non-coding RNA molecule, miRNA profoundly affects gene expression regulation and connects to the pathological processes of several kinds of human diseases. However, conventional experimental methods for validating miRNA-disease associations are laborious. Consequently, the development of efficient and reliable computational prediction models is crucial for the identification and validation of these associations.

Results

In this research, we developed the PCACFMDA method to predict the potential associations between miRNAs and diseases. To construct a multidimensional feature matrix, we consider the fusion similarities of miRNA and disease and miRNA-disease pairs. We then use principal component analysis(PCA) to reduce data complexity and extract low-dimensional features. Subsequently, a tuned cascade forest is used to mine the features and output prediction scores deeply. The results of the 5-fold cross-validation using the HMDD v2.0 database indicate that the PCACFMDA algorithm achieved an AUC of 98.56%. Additionally, we perform case studies on breast, esophageal and lung neoplasms. The findings revealed that the top 50 miRNAs most strongly linked to each disease have been validated.

Conclusions

Based on PCA and optimized cascade forests, we propose the PCACFMDA model for predicting undiscovered miRNA-disease associations. The experimental results demonstrate superior prediction performance and commendable stability. Consequently, the PCACFMDA is a potent instrument for in-depth exploration of miRNA-disease associations.
The median effective dose of ciprofol combined with sufentanil in suppressing the laryngeal mask airway insertion response in both young and older adult patients
Authors: Zhou Xuelei , Zhao Li , Mao Wei , Chen Linlin , Liu Xianchun , Li Linji
Published: December 2024

Background

Ciprofol, a novel intravenous anesthetic, exhibits similar sedation mechanisms and pharmacokinetic properties to propofol. However, ciprofol demonstrates greater potency and is associated with reduced injection pain compared to propofol. Given the varying sensitivities to anesthetic agents across different age groups, this study aims to determine the median effective dose (ED50) of ciprofol required to suppress the laryngeal mask airway (LMA) insertion response in both young and older adult patients, as well as to assess its potential adverse reactions.

Methods

In this study, 46 patients scheduled for surgery under general anesthesia with LMA insertion were recruited. Upon entering the operating room, patients were intravenously administered ciprofol (0.4 mg·kg− 1) and sufentanil (0.3 µg·kg− 1), followed by LMA insertion after three minutes. To derive robust confidence intervals for both ED50 and ED95, we performed an analysis using a logistic regression model combined with bootstrap resampling.

Results

In the young adult group, the ED50 and ED95 of ciprofol for suppressing the LMA insertion response were 0.38 mg·kg− 1 (95% CI, 0.35–0.41) and 0.46 mg·kg− 1 (95%CI, 0.40–0.56), respectively. In the older adult group, the respective ED50 and ED95 were 0.29 mg·kg− 1 (95% CI, 0.26–0.32) and 0.37 mg·kg− 1 (95% CI, 0.30–0.78). Regarding adverse reactions, although there were differences in the incidence of injection pain, hypotension, and bradycardia between the young and older groups, no statistically significant differences were observed between the two groups.

Conclusion

In this study, significant differences were observed in the ED50 of ciprofol for suppressing the LMA insertion response between young and older adult patients. The ED50 of ciprofol for young adult patients was 0.38 mg·kg− 1 (95% CI, 0.35–0.41), while for older adult patients it was0.29 mg·kg− 1 (95% CI, 0.26–0.32).

Trial registration

This study was registered on February 17, 2024, with the China Clinical Trial Registration Center (www.chictr.org.cn; Registration Number: ChiCTR2400080891).
Acute kidney injury and in-hospital outcomes after transcatheter aortic valve replacement in patients without chronic kidney disease: insights from the national inpatient sample
Authors: Ye Congyan , Ma Xueping , Shi Bo , Yan Rui , Fu Shizhe , Wang Kairu , Yan Ru , Jia Shaobin , Yang Shengping , Cong Guangzhi
Published: December 2024

Background

Acute kidney injury (AKI) complicates transcatheter aortic valve replacement (TAVR), leading to higher mortality. The incidence and effects of AKI on clinical outcomes in patients undergoing TAVR without chronic kidney disease (CKD) are unclear. We aimed to determine the association between AKI and in-hospital outcomes in patients with TAVR using propensity score matching (PSM).

Methods

Using International Classification of Diseases-10th Revision codes, we queried the National Inpatient Sample for TAVR performed between 2016 and 2021. Patients were divided into two groups according to perioperative AKI development. Patients with CKD or on permanent hemodialysis at baseline were excluded. We conducted 1:1 PSM to assemble a cohort of patients with similar baseline characteristics. Multivariate logistic regression was used to assess the association between AKI and in-hospital outcomes. Sensitivity analysis was conducted to evaluate the robustness of our inferences.

Results

Of 47,372 unweighted patient admissions for TAVR, 1617 (3.41%) had a concomitant diagnosis of AKI. The incidence of AKI decreased from 4.82 to 3.18% from 2016 to 2021 (P-trend < 0.01). Before PSM, patients with AKI had a significantly higher rate of in-hospital mortality compared with those without AKI (6.12% vs. 0.48%, respectively; odds ratio [OR] 8.59, 95% confidence interval [CI] 6.32–11.68). Using the PSM algorithm, 1579 well-matched patients were included in each group. After PSM, an association was observed between patients with TAVR and concomitant AKI and a higher risk of in-hospital mortality (6.21% vs. 1.08%, respectively; OR 5.96; 95% CI 3.54–10.04). In subgroup analyses stratified according to age (≤ 80 and > 80 years), sex (male/female), and hypertension status, consistent associations were observed between AKI and the risk of in-hospital mortality. AKI patients were at higher risk for acute myocardial infarction (OR 1.78, 95% CI 1.35–2.34), major bleeding (OR 1.62, 95% CI 1.13–2.33), blood transfusion (OR 1.65, 95% CI 1.28–2.11), and cardiogenic shock (OR 3.73, 95% CI 2.77–5.01). No significant betweengroup differences were observed in stroke (P = 0.12).

Conclusion

AKI was a strong predictor of in-hospital mortality in patients undergoing TAVR without CKD and was associated with higher post-procedure complication rates.
Effect of the Norwegian agreement on a more inclusive working life on use of sick leave and pregnancy benefits among pregnant women: a cohort study
Authors: Hasting Rachel Louise , Hoff Rune , Merkus Suzanne L , Gran Jon Michael , Mehlum Ingrid S
Published: December 2024

Background

We aimed to estimate the effect of the voluntary Norwegian Agreement on a More Inclusive Working Life (IA Agreement) on use of sickness absence (SA) and pregnancy benefits among pregnant women.

Methods

Pregnant women (n = 112,486) with a birth during 1.12.2003–31.12.2010 were followed from 6 to 37 gestational weeks in a continuous time multistate model with the following states: work, full SA, graded SA, pregnancy benefits, maternity leave, and other. Women working in IA companies were compared to those in non-IA companies regarding incidence and duration of SA and pregnancy benefits. Differences between groups with respect to calendar year, age, civil status, education, industry, and number of employees in the company were adjusted for using inverse probability of treatment weighting. Absolute differences in probabilities over time, expected length of stay (ELOS) in each state and differences in ELOS between IA and non-IA were calculated. 95% confidence intervals (CI) were generated using bootstrapping (1,000 repetitions).

Results

Adjusted analyses suggest that women working in IA companies were more likely to be in full SA in the first and last trimesters, but less likely between 14 and 28 weeks, than those in non-IA companies. The probability of being in work mirrored this, with women in IA companies tending to spend half a day more in work (ELOS difference 0.55, 95% CI -1.79, 3.02). Differences were not statistically significant. The use of graded SA was slightly higher (ELOS difference 0.46, 95% CI -0.87, 1.72) and the use of pregnancy benefits slightly lower (ELOS difference − 0.43, 95% CI -1.32, 0.42) among those in IA companies compared to non-IA companies.

Conclusions

Women in IA companies tended to spend more time in work and graded SA, but less time on pregnancy benefits. Differences in full SA varied during pregnancy and were most positive mid-pregnancy. This indicates that IA measures could be more effective for conditions experienced at this point. However, effects were small and not statistically significant, which may indicate the IA Agreement has not focused much on pregnant women.

Key terms

IA Agreement, MBRN, MoBa, multistate models, pregnancy, pregnancy benefits, sickness absence, work participation.
Inactivation of the conserved protease LonA increases production of xylanase and amylase in Bacillus subtilis
Authors: Wang Biwen , Kes Mariah B. M. J. , van Saparoea Anna C. H. van den Berg , Dugar Gaurav , Luirink Joen , Hamoen Leendert W.
Published: December 2024

Background

Bacillus subtilis is widely used for industrial enzyme production due to its capacity to efficiently secrete proteins. However, secretion efficiency of enzymes varies widely, and optimizing secretion is crucial to make production commercially viable. Previously, we have shown that overexpression of the xylanase XynA lowers expression of Clp protein chaperones, and that inactivation of CtsR, which regulates and represses clp transcription, increases the production of XynA. In the current study, we examined whether the same is the case for overexpression of the α-amylase AmyM from Geobacillus stearothermophilus by B. subtilis, and why XynA shows a different timing of secretion compared to AmyM.

Results

Transcriptome analyses revealed that B. subtilis cells overexpressing AmyM exhibited a distinct profile compared to XynA overexpressing cells, however there were also similarities and in both cases expression of CtsR controlled genes was downregulated. In contrast to XynA, inactivation of CtsR did not improve AmyM production. Upregulation of other protein chaperones, including GroEL/ES and DnaJ/K, by inactivating their transcriptional repressor HrcA, had almost no effect on XynA yields and in fact considerably lowered that of AmyM. Despite using the same promoter, the production of XynA peaks well before AmyM reaches its optimal secretion rate. Transcriptome and ribosome profiling indicated that this is neither related to transcription nor to translation regulation. We show that the reduced secretion in the stationary phase is partially due to the activity of secreted proteases, but also due to the activity of the intracellular protease LonA. The absence of this protein resulted in a 140% and 20% increased production for XynA and AmyM, respectively.

Conclusion

The combination of transcriptome and ribosome profiling offered important information to determine at which cellular level production bottlenecks occurred. This helped us to identify LonA protease as an important factor influencing enzyme production yields in B. subtilis.
Evaluation of effectiveness of bacteriophage purification methods
Authors: Binte Mohamed Yakob Adil Siti Saleha , Tucci Joseph , Irving Helen , Cianciarulo Cassandra , Kabwe Mwila
Published: December 2024

The use of bacteriophages for therapy has increased over the last decade. While there is need for clear regulatory pathways for bacteriophage approval for mainstream use in clinical practice, practitioners and patients have been able to access bacteriophage therapy under compassionate grounds and through magistral preparations. However, there is currently no standard for purifying these bacteriophages to ensure safety, and good manufacturing practice certification may not be achieved in these emergency uses. In this study, we employed an Interleukin Receptor Associated Kinase (IRAK) 3 knockout monocyte-based assay to evaluate the endotoxin removal efficacy of three common bacteriophage purification methods: Triton X-100 exposure, CsCl density gradient ultracentrifugation, and Pierce™ High-Capacity Endotoxin Removal Resin spin columns. In our experiments we tested these purification methods on three different bacteriophage morphotypes: siphovirus, podovirus and myovirus. We showed that the lowest endotoxin levels and immune responses were achieved when purifying bacteriophages with Triton-X treatment. The results from purifying with CsCl density gradient ultracentrifugation were comparable, and these were both significantly better than purification with Pierce™ High-Capacity Endotoxin Removal Resin spin columns. We also showed that Triton X-100 purification resulted in the lowest loss of bacteriophage titres. Finally, of the bacteriophages tested here, it did not appear that virus morphology affected efficacy of endotoxin removal.
Pulsatilla chinensis functions as a novel antihyperlipidemic agent by upregulating LDLR in an ERK-dependent manner
Authors: Song Wei-fang , Wang Rui-jun , Yao Rui-xin , Jiang Qiu-yan , Feng Juan , Luo Kun , Di Zheng-han , Ma Cheng-mei , Xie Lan
Published: December 2024

Background

Pulsatilla chinensis (PC) is a traditional Chinese medicine (TCM) known for its beneficial activities. It has been historically used to treat dysentery, vaginal trichomoniasis, bacterial infections, and malignant tumors. The therapeutic potential of PC in the management of hypercholesterolemia remains largely unexplored.

Methods

A high-throughput screening based on high-throughput sequencing was conducted in HepG2 cells to construct gene expression profiles for several hundred TCMs. In vivo evaluation of the efficacy of PC was performed using rats with hypercholesterolemia. Transcriptome analysis was carried out on PC-treated rat livers and HepG2 cells to investigate the mechanism of action of PC in vitro. The findings were further validated using RT-qPCR and western blot techniques.

Results

PC was identified as similar to Rhizoma Coptidis based on signature genes related to metabolism. Administration of PC via gavage in rats with hypercholesterolemia for 11 weeks resulted in substantially reduced serum total cholesterol and low-density lipoprotein (LDL) cholesterol and ameliorated fatty liver. Transcriptome analysis revealed that PC regulated various pathways associated with lipid metabolism. The LDL receptor (LDLR), a key player in cholesterol metabolism, was upregulated by PC both in vivo and in vitro. It was discovered that PC achieved this upregulation by activating extracellular regulated protein kinase (ERK) signaling in HepG2 cells. To uncover the major bioactive components responsible for the anti- hypercholesterolemia effect of PC, two major saponins, named Pulsatilla saponin D (PCD) and PC anemoside B4 (PCB4), were assessed. PCD, but not PCB4, was identified as the active ingredient responsible for the upregulation of LDLR by PC.

Conclusion

These findings demonstrated that PC acts as an antihypercholesterolemic agent by upregulating LDLR in an ERK-dependent manner and holds potential in the treatment of hypercholesterolemia.
Quality of life after idiopathic multicentric Castleman disease in China: a cross-sectional, multi-center survey of patient reported outcome and caregiver reported outcome
Authors: Chen Jia , Zhang Miao-yan , Gao Yu-han , Zhang Lu , Li Jian
Published: December 2024

The majority of multicentric Castleman disease (MCD) patients in China are of the idiopathic subtype (iMCD) with systemic manifestations. However, the impact of iMCD on life quality, mental and psychological status, social function, and caregiving burden is poorly understood. To address this gap, a cross-sectional web-based survey was conducted with 178 iMCD patients and 82 caregivers, including 42 patient-caregiver dyads. Patient-reported outcome measurements were performed using four self-administered questionnaires (MCD-SS, SF-36, PHQ-9, and WPAI:GH). Caregiver-reported outcome measurements were performed using three questionnaires (SF-36, Zarit-22, CRA) to assess the caregiving burden. Correlation analysis was performed in patient-caregiver dyads. Patients reported a median of nine symptoms by MCD-SS, with a high mean score of 4.34 for the Fatigue domain. Their SF-36 scores indicated significant declines in physical and mental health compared to the Chinese general population (p < 0.001). Based on PHQ-9, around 65% of patients exhibited depressive symptoms, with 28.6% of them experiencing mild to severe major depression. Only 47.2% (84/178) of the patients were employed, and 28.5% experienced impaired work time. Caregivers also reported lower SF-36 scores than the general population (p < 0.05) and expressed feeling of self-criticism, lack of family support and financial problems. Correlations were observed between patients’ symptom burden, mental health impairment and caregiving burden (correlation coefficient: 0.31 ~ 0.55). Our study concluded that fatigue and depressive symptoms significantly impact the life quality and social well-being of iMCD patients. The disease also affect the physical and mental health of caregivers, leading to feelings of guilt and a lack of family support.
Multi-stakeholder sessions on major innovation topics in rare disease clinical trials
Authors: Bodden Daniel , Schoenen Stefanie , Wied Stephanie , Verbeeck Johan , Dirani Maya , Abou Daya Hiba , Heussen Nicole , Molenberghs Geert , Hilgers Ralf-Dieter , Nabbout Rima
Published: December 2024

Background

The European Joint Programme on Rare Diseases aims to enhance the rare diseases research ecosystem by bringing together stakeholders such as research funders, institutions and patient organizations. Work Package 20 focuses on the validation, use and development of innovative methodologies for rare disease clinical trials. This paper reports on the outcomes of a retreat held in April 2023, where areas for innovation and educational needs in rare disease clinical trials were discussed in multi-stakeholder sessions.

Methods

Multi-stakeholder sessions covered the topics: Future Educational System, Randomization in Rare Disease Clinical Trials, Endpoints in Rare Disease Clinical Trials and Using History Course Data. The sessions began with expert presentations to set the scene, followed by guided discussions facilitated by questions on a collaborative digital whiteboard. Participants wrote responses, which were then discussed live with the experts.

Results

Training is needed for diverse stakeholders in rare disease clinical trials to enhance understanding and drive innovation. Challenges include a lack of standardized terminology for multiple endpoints, inadequate understanding of randomization in small sample studies and various obstacles in effectively using natural history data.

Conclusion

Creating a comprehensive and sustainable educational program for rare diseases clinical trial methodology requires strategic collaboration and adherence to FAIR principles. The workshop highlighted the need for innovations for topics in areas such as handling missing data, optimizing the extraction of information from small samples, remote endpoint measurement and new randomized inference techniques. Additionally, integrating innovations into tailored training programs is crucial for advancing the field.
Diagnosis of Diamond-Blackfan anemia in adulthood: case series and review of the literature
Authors: Versino Francesco , Bianchi Paola , Fermo Elisa , Barcellini Wilma , Fattizzo Bruno
Published: December 2024

Diamond–Blackfan anemia (DBA) is a rare constitutional inherited bone marrow failure syndrome (iBMF) characterized by progressive severe non-regenerative anemia and congenital abnormalities. Diagnosis is made by identification of a DBA-causing variant, typically in a ribosomal protein gene. More than 99% of patients are diagnosed in the pediatric age, but clinical manifestation may be mild and severe anemia can occur later in the patient’s life. Moreover, the expanding availability of molecular testing is increasing the ability to identify DBA variants also in adults with a non-canonical DBA phenotype. Therefore, adult hematologists must maintain a high clinical suspicion and awareness towards possible DBA diagnosis in adulthood. In this context, the most common differential diagnoses are acquired BMFs such as pure red cell aplasia (PRCA) or hypoplastic myelodysplastic syndrome (MDS). Here, we present three adult patients diagnosed with DBA, where the identification of the causative mutation occurred several years from PRCA misdiagnosis or was made after screening for an affected relative. We also provide a review of 16 cases available in the literature and give hints on possible treatment strategies.
Dementia with lewy bodies patients with high tau levels display unique proteome profiles
Authors: Greally Sinead , Kumar Mukesh , Schlaffner Christoph , van der Heijden Hanne , Lawton Elisabeth S. , Biswas Deeptarup , Berretta Sabina , Steen Hanno , Steen Judith A.
Published: December 2024

Background

Clinical studies have long observed that neurodegenerative disorders display a range of symptoms and pathological features and, in some cases, overlap, suggesting that these diseases exist on a spectrum. Dementia with Lewy Bodies (DLB), a synucleinopathy, is a prominent example, where symptomatic similarities with tauopathy, Alzheimer’s disease, are observed. Although tau pathology has been observed in DLB, the interplay between tau and α-synuclein is poorly understood at a molecular level.

Methods

Quantitative mass spectrometry analysis was used to measure protein abundance in the insoluble fraction from cortical brain tissue from pathologically diagnosed DLB subjects (n = 30) and age-matched controls (n = 29). Using tau abundance, we stratified the DLB subjects into two subgroups termed DLBTau+ (higher abundance) and DLBTau− (lower abundance). We conducted proteomic analysis to characterize and compare the cortical proteome of DLB subjects exhibiting elevated tau, as well as the molecular modifications of tau and α-synuclein to explore the dynamic between tau and α-synuclein pathology in these patients.

Results

Proteomic analyses revealed distinct global protein dysregulations in DLBTau+ and DLBTau− subjects when compared to controls. Notably, DLBTau+ patients exhibited increased levels of tau, along with ubiquitin, and APOE, indicative of cortical proteome alterations associated with elevated tau. Comparing DLBTau+ and DLBTau− groups, we observed significant upregulation of cytokine signaling and metabolic pathways in DLBTau− patients, while DLBTau+ subjects showed increases in protein ubiquitination processes and regulation of vesicle-mediated transport. Additionally, we examined the post-translational modification patterns of tau and α-synuclein. Our analysis revealed distinct phosphorylation and ubiquitination sites on α-synuclein between groups. Moreover, we observed increased modifications on tau specifically within the DLBTau+ subgroup.

Conclusion

This molecular-level data supports the idea of neurodegenerative disease as a continuum of diseases with distinct PTM profiles DLBTau+ and DLBTau− patients in comparison to AD. These findings further emphasize the importance of identifying specific and tailored therapeutic approaches targeting the involved proteopathies in the neurodegenerative disease spectrum.
BRCA2 germline mutation carrier with five malignancies: a case report
Authors: Su Elena , Christinat Yann , McKee Thomas , Azzarello-Burri Silvia , Jochum Wolfram , Fischer Stefanie , Rothermundt Christian
Published: December 2024

Background

BRCA2 germline mutations are known to predispose carriers to various cancer types, including breast, ovarian, pancreatic and prostate cancer. An association with melanoma has also been reported. However, the full tumour spectrum associated with BRCA2 mutations, particularly in patients with other concurrent pathogenetic mutations, is unexplored.

Case presentation

We present a 70-year-old female patient with a pathogenic BRCA2 c.5946del variant. Over a period of 15 years, she has developed two independent breast cancers, well-differentiated liposarcoma, clear cell renal cell carcinoma and myeloproliferative neoplasia. This unusual tumour spectrum and the staggered occurrence of these tumours required multiple rounds of genetic testing and led to a delayed diagnosis of the BRCA2-associated tumour predisposition. In addition to the BRCA2 mutation, extended germline testing revealed an APC c.3920T > A variant and variants of unknown significance in the BRIP1 and ATR genes. The molecular analysis of the tumours revealed distinct profiles with differences in HRD status and in copy number variations, indicating no common origin.

Conclusions

Our case study revealed that the pathogenic BRCA2 c.5946del germline variant can be associated with an unusual tumour spectrum, which may lead to a delayed diagnosis of a hereditary tumour predisposition. Thus, upfront genetic testing using large multigene panels or whole-genome sequencing in encouraged, especially in cases with a prominent family history.
SARS-CoV-2 introductions to the island of Ireland: a phylogenetic and geospatiotemporal study of infection dynamics
Authors: Rice Alan M. , Troendle Evan P. , Bridgett Stephen J. , Firoozi Nejad Behnam , McKinley Jennifer M. ,   The COVID-19 Genomics UK consortium,   National SARS-CoV-2 Surveillance & Whole Genome Sequencing (WGS) Programme, Bradley Declan T. , Fairley Derek J. , Bamford Connor G. G. , Skvortsov Timofey , Simpson David A.
Published: December 2024

Background

Ireland’s COVID-19 response combined extensive SARS-CoV-2 testing to estimate incidence, with whole genome sequencing (WGS) for genome surveillance. As an island with two political jurisdictions―Northern Ireland (NI) and Republic of Ireland (RoI)―and access to detailed passenger travel data, Ireland provides a unique setting to study virus introductions and evaluate public health measures. Using a substantial Irish genomic dataset alongside global data from GISAID, this study aimed to trace the introduction and spread of SARS-CoV-2 across the island.

Methods

We recursively searched for 29,518 SARS-CoV-2 genome sequences collected in Ireland from March 2020 to June 2022 within the global SARS-CoV-2 phylogenetic tree and identified clusters based on shared last common non-Irish ancestors. A maximum parsimony approach was used to assign a likely country of origin to each cluster. The geographic locations and collection dates of the samples in each introduction cluster were used to map the spread of the virus across Ireland. Downsampling was used to model the impact of varying levels of sequencing and normalisation for population permitted comparison between jurisdictions.

Results

Six periods spanning the early introductions and the emergence of Alpha, Delta, and Omicron variants were studied in detail. Among 4439 SARS-CoV-2 introductions to Ireland, 2535 originated in England, with additional cases largely from the rest of Great Britain, United States of America, and Northwestern Europe. Introduction clusters ranged in size from a single to thousands of cases. Introductions were concentrated in the densely populated Dublin and Belfast areas, with many clusters spreading islandwide. Genetic phylogeny was able to effectively trace localised transmission patterns. Introduction rates were similar in NI and RoI for most variants, except for Delta, which was more frequently introduced to NI.

Conclusions

Tracking individual introduction events enables detailed modelling of virus spread patterns and clearer assessment of the effectiveness of control measures. Stricter travel restrictions in RoI likely reduced Delta introductions but not infection rates, which were similar across jurisdictions. Local and global sequencing levels influence the information available from phylogenomic analyses and we describe an approach to assess the ability of a chosen WGS level to detect virus introductions.
Neutrophil extracellular traps and oxidative stress in systemic lupus erythematosus patients with and without renal involvement
Authors: Liu Lu , de Leeuw Karina , van Goor Harry , Doornbos-van der Meer Berber , Arends Suzanne , Westra Johanna
Published: December 2024

Objectives

To investigate the levels of plasma neutrophil extracellular traps (NETs) and free thiols, the latter reflecting systemic oxidative stress (OS), and to explore the relationship between NETs and OS in quiescent systemic lupus erythematosus (SLE) patients with and without renal involvement.

Methods

Plasma levels of NETs and free thiols were measured cross-sectionally in 100 SLE patients with low disease activity (SLEDAI < 5), of whom 73 patients had no renal involvement (non-LN) and 27 patients had lupus nephritis (LN). Additionally, 22 healthy controls (HCs) were included. NETs were measured using a myeloperoxidase-DNA complex ELISA and free thiols were measured using a thiol assay kit.

Results

NETs levels were significantly higher in both non-LN and LN patients compared to HCs (p < 0.001, p = 0.013), with no difference between the two patient groups (p = 0.799). Free thiol levels were not significantly different between groups. Interestingly, NETs were negatively correlated with free thiols in all 100 SLE patients (rho = -0.32) and non-LN patients (rho = -0.38), but not in LN patients. Levels of free thiols were significantly lower in subgroups of patients with estimated glomerular filtration rate (eGFR) < 60, serum creatinine (sCr) ≥ 90, C reactive protein (CRP) levels ≥ 5 and body mass index (BMI) ≥ 30. In multivariable regression, disease duration, NETs levels, and eGFR were independently associated with free thiol levels.

Conclusions

Levels of NETs were increased in quiescent SLE patients. Although free thiol levels did not differ among the groups. The levels of NETs and free thiols were independently associated in SLE patients, suggesting a potential role of OS in NETs formation. Therefore, reducing OS might be an additional therapeutic target for SLE treatment.
Structural validity of the Brazilian version of the quality care questionnaire-palliative care for use in individuals with diabetes mellitus eligible for palliative care
Authors: Mendes-Júnior Abraão Albino , Santos-de-Araújo Aldair Darlan , de Oliveira Silva Santos Leonel Richard , Ladeira Lorena Lúcia Costa , Ferreira Meire Coelho , Godim Louise Aline Romão , Maia Mariana Campos , de Farias Diniz Marinete Rodrigues , Dibai-Filho Almir Vieira , Bassi-Dibai Daniela
Published: December 2024

Background

The Brazilian version of the Quality Care Questionnaire-Palliative Care (QCQ-PC) is an instrument designed to assess the quality of care provided in palliative care from the user’s perspective, featuring easy comprehension and applicability. It has demonstrated validity for use in individuals with cancer, but there is a need for validation in other populations due to the scarcity of instruments with this purpose.

Objective

To structurally validate the Brazilian version of the QCQ-PC for use in individuals with diabetes mellitus (DM) eligible for palliative care.

Methods

This is a structural validation study of a questionnaire according to the Consensus-based Standards for the Selection of Health Measurement Instruments (COSMIN). The study was conducted with 100 individuals with DM. Data collection occurred in differents care services in São Luís (northeast Brazil) by means of the application of the QCQ-PC and a form with sociodemographic, clinical, and daily habit data. Descriptive data analysis was performed using absolute values, relative frequencies, and measures of central tendency and dispersion. Structural validity was assessed by means of exploratory factor analysis (EFA).

Results

Of the 100 participants included in the study, 66% were female, 54% were single, with a median age of 64 years, 44% were overweight (44%), 77% were on polypharmacy, and 70% were physically inactive. We found that one domain is the most appropriate for use of the QCQ-PC in individuals with DM eligible for palliative care, according to the parallel analysis implemented in the EFA. This domain was named “quality of care”. The fit indices for this one-dimensional internal structure were adequate: Kaiser–Meyer–Olkin test = 0.71, p value < 0.01 in Bartlett’s test, chi-square/degree of freedom = 1.07, comparative fit index = 0.993, Tucker-Lewis index. = 0.991, root mean square error of approximation = 0.028. The QCQ-PC presented factor loadings ranging from 0.480 to 0.883, maintaining a total of 12 items, which demonstrates the adequate relationship between the quality of care domain and its items.

Conclusion

Therefore, the internal structure with one domain (quality of care) is the most suitable for use in individuals with DM eligible for palliative care by means of the QCQ-PC.
SDG 18 for sustainable space exploration
Authors: Zimon Dominik , Lysenko-Ryba Kateryna , Szocik Konrad
Published: December 2024

The aim of this study is to fill out the gap that exists in the literature by discussing the main problems and barriers to sustainable development in space and the initial proposal to adopt SDG 18. Despite the fact that the subject of the sustainable development of space is little researched, it seems that in order to be able to properly prepare for it, a broader debate on this subject should now be undertaken. This is due to the fact that this issue is undoubtedly complex and multifaceted. The starting point for the development of SDG 18 seems to be the discussion of issues such as: sustainable financing of space exploration, laws and treaties. The considerations undertaken in the article may be helpful for government organizations in creating future sustainable development strategies. Business representatives will receive valuable information on the constraints associated with the implementation of space programs. On the other hand, scientists can treat the article as a starting point for deliberations on the 18 SDG and pose further questions to deepen the issues outlined in the article, and develop the 18 goal with further aspects omitted in this study.
3D analysis of soft tissue dimensional changes after dental implant placement with butt-joint vs. conical connection: a 12-month randomized control trial
Authors: Derakhshani André-Joubin , Beuer Florian , Wernfried Heinrich Böse Mats , Herklotz Insa , Unkovskiy Alexey
Published: December 2024

Purpose

to quantify the soft tissue dimensional changes after single-gap implant placement, during healing abutment and crown delivery phase for butt-joint and conical implant-abutment connection type.

Methods

forty patients were enrolled in the study and received randomly allocated implants with butt-joint and conical implant-abutment connection type. A standard healing abutment was placed after 6 months for two weeks. The definitive screw retained full-ceramic crowns were manufactured in a digital workflow. The soft tissue profile was digitized using IOS on following stages: pre-op, immediately, two, 7 and 14 days post-op, pre-exposure, immediately after exposure, two weeks after exposure (pre-delivery), immediately after crown delivery, 6 and 12 months after delivery. The intraoral scans were matched in the metrology software (Geomagic Control X). The mean maximum and mean average differences in mm were gathered to assess the soft tissues change. Various anamnesis parameters have been taken into account.

Results

the conical connection implant system exhibited more soft tissue gain and less recession, compared to the butt-joint connection type within the 12 months follow-up period. A higher loss of soft tissue was observed in the distal papilla than in the mesial one.

Conclusions

the implant-abutment connection type may influence the reaction of peri-implant soft tissue within the 12 months follow-up period.