bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluating the Impact of Biological Augmentation on Failure Rates and Complications in Acute Patellar Tendon Rupture Surgery Compared With Isolated Repair
Authors: Olivieri Rodrigo , Laso José Ignacio , Franulic Nicolás , Muñoz José T. , Ugarte Jaime , Innocenti Piero
Published: November 2024

Background:

Patellar tendon ruptures are infrequent but disabling injuries. Surgical treatment is the gold standard to obtain good outcomes, and numerous techniques have been described. Biomechanical studies report better results when augmented techniques are used. However, there is a lack of consensus regarding the best standard technique.

Purpose/Hypothesis:

The purpose of this study was to assess a cohort of patients with acute patellar tendon rupture that was surgically treated and to compare the clinical outcomes of 2 groups: isolated repair and biological augmentation techniques with autograft or allograft. It was hypothesized that the biological augmentation group would have better clinical outcomes than the isolated repair group.

Study Design:

Cohort study; Level of evidence, 3.

Methods:

All patients with acute patellar tendon rupture surgically treated in our center between 2016 and 2022 were retrospectively reviewed. Patient and rupture characteristics, surgical technique, clinical outcomes, and complications were recorded. The primary outcome was rerupture rate, and secondary outcomes were infection rate, stiffness >15° of knee flexion deficit, and extensor mechanism lag >5°.

Results:

The study included 34 patients with 36 operated knees (2 patients with bilateral rupture). The mean age was 44.9 years. Isolated repair was performed in 20 knees (55.6%), and 16 knees underwent repair and biological augmentation with autograft or allograft. Both groups were comparable in terms of their demographic characteristics. A statistically significant association was found between the type of surgery and tendon rerupture. Of the patients in the isolated repair group, 5 of 20 (25%) experienced a failure, whereas in the biological augmentation group, no reruptures were recorded ( P = .031). However, no statistically significant associations were found between the type of surgery and other complications, such as the development of stiffness ( P = .54), residual extension lag >5° ( P = .87), or the development of infection ( P = .25).

Conclusion:

In this cohort of patients, biological augmentation reduced the rate of surgical failure for acute patellar tendon rupture without being associated with a higher risk of complications such as stiffness, residual extension lag, or the development of infection.
Differential Racialization of Filipino College Students
Authors: Colond Jay , Beattie Irenee R.
Published: November 2024

Filipino college students report more negative experiences on their campuses than other Asian groups in qualitative studies, but such variation is obscured in quantitative research combining all Asian students together. Little is known about Filipino American racialization in higher education. Theories of racial liminality and racial hierarchies suggest that Filipino student’s interpersonal racialized experiences will differ from those of White and Asian students while being more similar to those of Black and Latinx students. Using a large survey of early college undergraduates, we examine Filipino students’ reports of racial microaggressions compared with other racial groups. We run ordered logit regression to predict student exposure to peer, staff, and faculty microaggressions, net of controls. We find Filipino students are significantly more likely than White and Asian students to report experiencing racial microaggressions from both student peers and campus staff. Filipino students also reported significantly more faculty microaggressions than White (but not Asian) students. Black students reported significantly more student microaggressions than any other racial group but were otherwise not significantly different from Filipino students. Compared with Latinx students, Filipino students reported significantly more staff and faculty microaggressions, but similar rates of student microaggressions. We discuss theoretical and practical implications.
The Association Between Maternal Age at Childbirth and Child Nutritional Outcomes: A Cross-sectional Study From Serbian Roma Communities
Authors: Čvorović Jelena
Published: November 2024

Objectives. Extremes of maternal age at childbirth may influence child nutritional outcomes, but this is under-researched in Roma populations. Methods. The study was a secondary data analysis of Multiple Indicator Cluster Surveys for Serbian Roma settlements and included 2564 children aged 0 to 59 months. Results. About 19% of children were stunted, 9% underweight, 16% were unwanted and born with a low birth weight. Logistic and linear regressions show that maternal age at childbirth had no association with either nutritional or growth outcomes of Roma children ( P > .05). Instead, child characteristics: being born as a boy, low birth weight, unwanted, younger age, and maternal characteristics: short birth spacing, higher parity and low socioeconomic status were associated with children’s malnutrition. Conclusion. Maternal age at childbirth per se does not increase the chances of poor child health outcomes, as the risks seem to be related more to individual child and maternal characteristics and maternal behavioral patterns.
Which Factors Explain the Effectiveness of School-Based Interventions to Prevent Dating and Relationship Violence and Gender-Based Violence? Systematic Review of Mediation Analyses in Randomized Trials
Authors: Rizzo Andrew J. , Shaw Naomi , Farmer Caroline , Orr Noreen , Chollet Annah , Rigby Emma , Hagell Ann , Young Honor , Berry Vashti , Bonell Chris , Melendez-Torres G. J.
Published: November 2024

Adolescent interpersonal violence, particularly gender-based violence (GBV) and dating and relationship violence (DRV), are important public health issues frequently addressed through school-based interventions. This brief report systematically reviews the published evidence on mediational pathways for school-based interventions to effectively reduce GBV and DRV. As part of a larger systematic review funded by the National Institute for Health and Care Research, we identified six randomized trials in which mediation analyses of either DRV or GBV perpetration or victimization outcomes for four different interventions were conducted. We synthesize findings narratively by outcome, type of mediator, and follow-up period (short term or longitudinal). A total of eight mediators were analyzed across all studies. We found clear support for mediation through violence acceptance and delinquent behaviors; inconsistent support for mediation through knowledge, school belonging, belief in the need for help, and gender-inequitable beliefs; and no support for mediation through conflict management skills or bystander actions. These findings provide helpful suggestions on effective pathways for intervention efficacy. Overall, however, there is a need for mediation analyses to be conducted more often in GBV/DRV intervention evaluations. We discuss implications of these findings and suggest areas for future research on mediated pathways for GBV/DRV reduction.
Project Management Office Typologies, Types, and Functions: A Systematic Analysis of the Literature and Directions for Research
Authors: Monteiro António , Varajão João , Santos Vitor
Published: November 2024

Project management offices (PMOs) connect the complex relationships of strategies, projects, and organizational structures to boost the success of business. However, PMOs face significant challenges in clearly defining their roles and responsibilities due to the variety of potential functions that can be assigned to them. This study presents a systematic analysis of PMO typologies, types, and respective functions, providing an in-depth understanding of the dynamic PMO role. We found 16 typologies and 60 PMO types in the literature, showing that PMOs are complex and evolving entities that can assume various forms and organizational responsibilities.
Configuration Design and Size Optimization of a High-Precision Novel Parallel Pointing Mechanism Based on Interference Separation
Authors: Wang Sen , Li Shihua , Han Xueyan , Wei Jiahao , Gao Xueyuan , Xu Hongyu
Published: November 2024

Pointing mechanism is widely used in aerospace field, and its pointing accuracy and stability have high requirements. The pointing mechanism will be affected by external interference when it works. In order to eliminate the impact of interference forces on the output accuracy of the mechanism, firstly, this paper proposes a design method for high-precision pointing mechanisms based on interference separation, aiming at the high-precision pointing requirements of pointing mechanisms. Based on the screw theory, a synthesis method for inner compensation mechanisms has been proposed. And a new type of double-layer parallel mechanism has been designed to compensate for interference forces. Then, the kinematics and dynamics of the mechanism are carried out. An evaluation index for compensating external interference forces is proposed. The interference compensation analysis is conducted for the pointing mechanism. The correctness of the proposed interference force compensation coefficient is verified. Finally, in order to find the optimal solution for the workspace and interference force compensation coefficient of the pointing mechanism, multi-objective optimization design of the structural parameters of the mechanism was carried out based on the particle swarm optimization algorithm. This provides a theoretical basis for the prototype design of the subsequent double-layer parallel mechanism. This double-layer parallel mechanism combines the advantages of large load-bearing capacity, large workspace, and high output accuracy. It can be better applied in the aerospace field where high-precision pointing and force interference compensation are integrated.
Analysis of Water Film Distribution and Aerodynamic Performances of High-Speed Train Under Rainfall Environment
Authors: Li Meixiang , Yu Mengge , Liu Jiali , Sheng Xugao
Published: November 2024

The current research on the aerodynamic performance of the train running in rainy weather is primarily concerned with the trajectory of the raindrops and the aerodynamic variation of trains caused by raindrops. In fact, water film will generate on the train body when raindrops hit the train, which interacts with the flow field around the train, and would probably affect the aerodynamic performance of the train. In this paper, based on shear stress transport (SST) k-w turbulence model and Euler-Lagrange discrete phase model, the aerodynamic calculation model of a high-speed train under rainfall environment is established. The LWF (Lagrangian wall film) is used to simulate the water film distribution of the high-speed train under different rainfall intensities, and the aerodynamic performance of the train are studied. The calculation results show that raindrops will gather on the train surface and form water film under rainfall environment. With the extension of rainfall time, the thickness and coverage range of water film expand, and the maximum thickness of water film can reach 4.95 mm under the working conditions in this paper. The average thickness of water film on the train body increases with the rainfall intensity. When the rainfall intensity increases from 100 mm/h to 500 mm/h, the average water film thickness will increase by 3.26 times. The velocity of water film in the streamlined area of head car is larger than that in other areas, and the maximum velocity is 22.14 m/s. Compared with the rainless environment condition, the skin friction coefficient of the high-speed train increases and the average value will increase by 10.74% for a rainfall intensity of 500 mm/h. The positive pressure and resistance coefficient of the head car increase with the rainfall intensity. This research proposes a methodology to systematically analyze the generation of water film on the train surface and its influence on the train aerodynamic performance; the analysis can provide more practical results and can serve as a reference basis for the design and development of high-speed trains.
Experimental Investigation of the Micro-Milling of Additively Manufactured Titanium Alloys: Selective Laser Melting and Wrought Ti6Al4V
Authors: Rehan Muhammad , He Tao , Khalil Ahmed K. , Tahir Danish , Yip Wai Sze , To Sandy Suet
Published: November 2024

In recent years, additive manufacturing (AM) has gained popularity in the aerospace, automobile, and medical industries due to its ability to produce complex profiles with minimal tolerances. Micro-milling is recommended for machining AM-based parts to improve surface quality and form accuracy. Therefore, the machinability of a titanium alloy (Ti6Al4V) manufactured using selective laser melting (SLM) is explored and compared to that of wrought Ti6Al4V in micro-milling. The experimental results reveal the surface topology, chip morphology, burr formation, and tool wear characteristics of both samples. The micro-milling of AM-based Ti6Al4V generates a surface roughness of 19.2 nm, which is 13.9% lower than that of wrought workpieces, and this component exhibits less tool wear. SLM-based Ti6Al4V produces continuous chips, while wrought Ti6Al4V yields relatively short chips. Additionally, SLM-fabricated Ti6Al4V exhibits smaller burrs after micro-milling than wrought Ti6Al4V. Despite the higher hardness of SLM-based Ti6Al4V, it demonstrates better machinability than wrought Ti6Al4V, resulting in better surface quality with lower tool wear levels and shorter burr heights. This study provides valuable insights into future research on postprocessing AM-based titanium parts, especially using micro-milling.
Cognitive impact and brain structural changes in long COVID patients: a cross-sectional MRI study two years post infection in a cohort from Argentina
Authors: Cataldo Sol A. , Micciulli Andrea , Margulis Laura , Cibeyra Melina , Defeo Sabrina , Horovitz Silvina G. , Martino Analía , Melano Raul , Mena Milagros , Parisi Francisco , Santoro Diego , Sarmiento Florencia , Belzunce Martin A.
Published: November 2024

Objective

Long COVID is a condition characterised by persistent symptoms after a SARS-CoV-2 infection, with neurological manifestations being particularly frequent. Existing research suggests that long COVID patients not only report cognitive symptoms but also exhibit measurable cognitive impairment. Neuroimaging studies have identified structural alterations in brain regions linked to cognitive functions. However, most of these studies have focused on patients within months of their initial infection. This study aims to explore the longer-term cognitive effects and brain structural changes in long COVID patients, approximately two years post-infection, in a cohort from San Martín, Buenos Aires, Argentina.

Methods

We conducted a cross-sectional study involving 137 participants: 109 with long COVID symptoms and 28 healthy controls. The participants underwent an initial clinical assessment, completed a structured questionnaire and standardised scales, underwent a cognitive assessment, and had a brain MRI scan. Structural MRI images were processed via FreeSurfer and FSL to obtain volumetric measures for subcortical and cortical regions, along with regional cortical thickness. Differences between groups for these variables were analysed using ANCOVA, with permutation tests applied to correct for multiple comparisons.

Results

Long COVID patients reported persistent cognitive symptoms such as memory problems and brain fog, with higher levels of fatigue and reduced quality of life compared to controls. Despite subjective cognitive complaints, cognitive tests did not reveal significant differences between groups, except for the TMT-A (p = 0.05). MRI analysis revealed decreased volume in the cerebellum (p = 0.03), lingual gyrus (p = 0.04), and inferior parietal regions (p = 0.03), and reduced cortical thickness in several areas, including the left and right postcentral gyri (p = 0.02,p = 0.03) and precuneus (p = 0.01,p = 0.02).

Conclusions

This study highlights the enduring impact of long COVID on quality of life and physical activity, with specific brain structural changes identified two years post-infection. Although cognitive tests did not show clear impairment, the observed brain atrophy and significant reduction in quality of life emphasize the need for comprehensive interventions and further longitudinal studies to understand the long-term effects of long COVID on cognition and brain health.
Exploring what works well and less well in a community-based drop-in hub providing health and wellbeing services for people experiencing homelessness: a participatory action evaluation of service coordination
Authors: Adams Emma A. , Ramsay Sheena E.
Published: November 2024

Background

People experiencing homelessness often face obstacles accessing health and social care support. Challenges are further exacerbated when support provision for multiple unmet needs are not integrated or coordinated. To overcome these challenges, there has been growing attention on integrating and co-locating health and wellbeing services for people experiencing homelessness. In an urban area of North East England, a long-standing Hub or ‘drop-in centre’ offers a range of health and wellbeing support by bringing together the different health and care system agencies in one space. However, little is known about the perspectives of providers on what works well and less well in how the different services are coordinated.

Methods

Using a participatory action research approach, a qualitative service evaluation was undertaken between June and September 2023. Fourteen interviews were conducted with providers who work in a paid or voluntary capacity operating some of their service offerings or support in the Hub. Interview transcripts were analysed using inductive reflexive thematic analysis.

Results

Three themes were evident from the evaluation: 1) location and space matter, 2) co-location and relationships make a difference, and 3) service consistency and flexibility are paramount.

Conclusion

Co-locating support to cover the breadth of health and care needs has the potential to increase engagement and access for people experiencing homelessness, and to enhance trust with service users and between agencies. This model provides a unique example of co-location and integration of support, particularly with it being operated by a community housing organisation.
The impact of direct health facility financing on MNCH service provision: results from a comparative, before-after study in Pwani Region, Tanzania
Authors: Oh Kyoung Kyun , Ferdinand Joy G. , Kapologwe Ntuli A. , Ngaiza Benedicto M. , Gordon Joyce M. , Lim Doowon , Ngowi Alfred E. , Yusuph Swabaha A. , Kim Hayoung , Park Hansol , Ahn Sooyoung , Nam Bok Hyun , Kim Chang-yup
Published: November 2024

Background

Pwani Regional Secretariat in Tanzania implemented the Maternal, Neonatal, and Child Health Project (2016–2022) through Direct Health Facility Financing (DHFF), which allocates funds directly to health facilities. This study assessed the impact of the six-year DHFF project in Pwani region.

Methods

The study utilised District Health Information Software 2 data from 18 intervention health facilities in Pwani region. Control groups comprised an equal number of facilities from Pwani and Dodoma regions where the project was not implemented. Key indicators assessed included ‘ANC 4 + Rate (%)’, ‘Percentage of Mothers tested for Anaemia during ANC’, ‘Caesarean Section Delivery Rate (%)’, ‘Percentage of Mothers and Newborns receiving PNC services within 48 hours’, ‘Delivery Complication Rate (%)’, and ‘SBA Delivery Rate (%)’ which are associated with the project interventions. The impact of the project was analysed using a paired sample t-test comparing baseline and endline data. We evaluated the significance of the dependent variables using one-way ANOVA with control groups, with the Tukey-Kramer test for post hoc analysis. Chi-square test assessed the significance of Caesarean Section Delivery Rate and the relationship between variables and health facility conditions. Pearson correlation test was used for significance between funding size and the change of MNCH variables. Statistical significance at 0.05 was calculated.

Results

The project showed limited positive impacts, only in the ‘Percentage of Mothers tested for Anaemia during ANC’ (****p < 0.0001), ‘Percentage of Newborns receiving PNC within 48 hours’ (**p = 0.0095), and ‘SBA Delivery Rate’ (***p = 0.0043). The health facility assessment identified positively influencing factors on service delivery, such as facility type (*p = 0.0347), distance to the facility (****p < 0.0001), and internet connectivity (*p = 0.0186). We found that the project did not improve most MNCH indicators, including the CEmONC coverage (χ2 = 2.82, p = 0.2448, df = 2), which was known to be the leading outcome.

Conclusion

The project had limited impacts on MNCH outcomes due to various factors. While the health facility assessment highlighted positive influences on service delivery, significant areas for improvement remain, including referral systems and infrastructure. Operational research findings indicate that the effectiveness of the DHFF could be enhanced by refining its management and governance structures.
Assessing coronary artery stenosis exacerbated impact on left ventricular function and deformation in metabolic syndrome patients by 3.0 T cardiac magnetic resonance imaging
Authors: Jiang Yi-Ning , Gao Yue , Min Chen-Yan , Guo Ying‑Kun , Xu Rong , Shen Li-Ting , Qian Wen-lei , Li Yuan , Yang Zhi-Gang
Published: November 2024

Background

Metabolic syndrome (MetS) and coronary artery stenosis (CAS) independently increase the risk of cardiovascular events, while the impact of CAS on left ventricular (LV) function and deformation in MetS patients remains unclear. This study investigates how varying degrees of CAS exacerbate LV function and myocardial deformation in MetS patients.

Methods

One hundred thirty-one MetS patients who underwent CMR examinations were divided into two groups: the MetS(CAS−) group (n = 47) and the MetS(CAS+) group (n = 84). The MetS(CAS+) group was divided into MetS with non-obstructive CAS(NOCAS+) (n = 30) and MetS with obstructive CAS(OCAS+) group (n = 54). Additionally, 48 age- and sex-matched subjects were included as a control group. LV functional and deformation parameters were measured and compared among subgroups. The determinants of decreased LV global peak strains in all MetS patients were identified using linear regression. The receiver operating characteristic (ROC) curve and logistic regression model (LRM) evaluated the diagnostic accuracy of the degree of CAS for identifying impaired LV strain.

Results

Compared to MetS(CAS−), MetS(NOCAS+) showed a significantly increased LV mass index (p < 0.05). Global longitudinal peak strain was decreased gradually from MetS(CAS−) through MetS(NOCAS+) to MetS(OCAS+) (− 13.02 ± 2.32% vs. − 10.34 ± 4.05% vs. − 7.55 ± 4.48%, p < 0.05). MetS(OCAS+) groups showed significantly decreased LV global peak strain (GPS), PSSR and PDSR in radial and circumferential directions compared with MetS(NOCAS+) (all p < 0.05). The degree of CAS was independently associated with impaired global radial peak strain (GRPS) (β =  − 0.289, p < 0.001) and global longitudinal peak strain (GLPS) (β = 0.254, p = 0.004) in MetS patients. The ROC analysis showed that the degree of CAS can predict impaired GRPS (AUC = 0.730) and impaired GLPS (AUC = 0.685).

Conclusion

Besides traditional biochemical indicators, incorporating CAS assessment and CMR assessment of the LV into routine evaluations ensures a more holistic approach to managing MetS patients. Timely intervention of CAS is crucial for improving cardiovascular outcomes in this high-risk population.
Cooperative participation of CagA and NFATc1 in the pathogenesis of antibiotics-responsive gastric MALT lymphoma
Authors: Tsai Hui-Jen , Yeh Kun-Huei , Lin Chung-Wu , Wu Ming-Shiang , Liou Jyh-Ming , Hsu Ping-Ning , Zeng Yi-Shin , Wei Ming-Feng , Shun Chia-Tung , Wang Hsiu-Po , Chen Li-Tzong , Cheng Ann-Lii , Kuo Sung-Hsin
Published: November 2024

Background

This study aimed to explore whether cytotoxin-associated gene A (CagA) can inhibit cell cycle progression by activating nuclear factor of activated T cells (NFAT) in lymphoma B cells and contribute to Helicobacter pylori eradication (HPE) responsiveness (complete remission [CR] after HPE) in gastric mucosa-associated lymphoid tissue (MALT) lymphoma.

Materials and Methods

We co-cultured three B-lymphoma cell lines (MA-1, OCI-Ly3, and OCI-Ly7) with HP strains (derived from HPE-responsive gastric MALT lymphoma) and evaluated the expression patterns of CagA, phosphorylated (p)-CagA (CagAP−Tyr), and CagA-signaling molecules, cell-cycle inhibitors, p-NFATc1 (Ser172), and NFATc1 using western blotting. Furthermore, we evaluated the association between nuclear NFATc1 expression in the tumor cells of 91 patients who received first-line HPE (59 patients with HPE responsiveness and 32 without HPE responsiveness) and HPE responsiveness and CagA expression in tumor cells.

Results

In HP strains co-cultured with B cell lymphoma cell lines, CagA was translocated to the nucleus through tyrosine phosphorylation (CagAP−Tyr) and simultaneously dephosphorylated NFATc1, subsequently causing nuclear NFATc1 translocation and stimulating the expression of p-SHP-2/p-ERK/Bcl-xL. Activated NFATc1 causes G1 cell cycle retardation in both MA-1 and OCI-Ly3 cells by triggering p21 and p27 production. Nuclear NFATc1 localization was significantly associated with the presence of CagA in gastric MALT lymphomas (80% [41/51] vs. 33% [13/40]; p < 0.001) and with HPE responsiveness (73% [43/59] vs. 25% [8/32]; p < 0.001). Patients exhibiting both the presence of CagA and nuclear NFATc1 localization responded more rapidly to HPE than those without (median interval to CR, 4.00 vs. 6.00 months, p = 0.003).

Conclusions

Our findings indicated that CagA and NFATc1 cooperatively participate in the lymphomagenesis of HPE-responsive gastric MALT lymphoma.
Physical, biochemical, and biological characterization of olive-derived lipid nanovesicles for drug delivery applications
Authors: Zhao Zhu , Lacombe Jerome , Simon Laurianne , Sanchez-Ballester Noelia M. , Khanishayan Ashkan , Shaik Naina , Case Kallie , Dugas Pierre-Yves , Repellin Mathieu , Lollo Giovanna , Soulairol Ian , Harris Ashlee F. , Gordon Michael , Begu Sylvie , Zenhausern Frederic
Published: November 2024

Extracellular vesicles (EVs) have shown great promise as drug delivery system (DDS). However, their complex and costly production limit their development for clinical use. Interestingly, the plant kingdom can also produce EV-like nanovesicles that can easily be isolated and purified from a large quantity of raw material at a high yield. In this study, olive-derived nanovesicles (ODNVs) were isolated from raw fruits using serial centrifugations and their physical and biological features characterized to demonstrate their promising potential to be used as a DDS. Nanotracking particle analysis indicated an average size of 109.5 ± 3.0 nm and yield of 1012 ODNVs/mL for the purest fraction. Microscopy imaging, membrane fluidity assay and lipidomics analysis showed the presence of a rich lipid bilayer that significantly varied between different sources of ODNVs but showed a distinct signature compared to human EVs. Moreover, ODNVs were enriched in PEN1 and TET8 compared to raw fruits, suggesting an extracellular origin. Interestingly, ODNVs size and yield stayed unchanged after exposure to high temperature (70 °C for 1 h), wide pH range (5–10), and 50–100 nm extrusion, demonstrating high resistance to physical and chemical stresses. This high resistance allowed ODNVs to stay stable in water at 4 °C for a month, or with the addition of 25 mM trehalose for long-term freezing storage. Finally, ODNVs were internalized by both 2D and 3D cell culture without triggering significant cytotoxicity and immunogenicity. Importantly, the anticancer drug doxorubicin (dox) could be loaded by passive incubation within ODNVs and dox-loaded ODNVs decreased cell viability by 90% compared to only 70% for free dox at the same concentration, indicating a higher efficiency of drug delivery by ODNVs. In addition, this high cytotoxicity effect of dox-loaded ODNVs was shown to be stable after a 2-week storage at 4 °C. Together, these findings suggested that ODNVs represent a promising candidate as drug nanocarrier for various DDS clinical applications, as demonstrated by their biocompatibility, high resistance to stress, good stability in harsh environment, and improvement of anticancer drug efficacy.
The patient’s voice: a cross-sectional study of physical health and disability in juvenile idiopathic arthritis
Authors: Arneng Sofie Mikalsen , Jenssen Isabelle Pignatel , Lundestad Anette , Cetrelli Lena , Angenete Oskar , Nordal Ellen , Tylleskär Karin B. , Romundstad Pål Richard , Rygg Marite
Published: November 2024

Background

With increasing focus on patient-reported outcome measures (PROMs) in chronic rheumatic diseases, we aimed to evaluate the self-reported physical and psychosocial health in children with juvenile idiopathic arthritis (JIA) compared to matched population-based controls. Furthermore, we aimed to study the association of patient- and physician-reported outcome measures in JIA with patient-reported physical disability.

Methods

We used data from a Norwegian JIA cohort study (NorJIA), including clinical characteristics and outcome measures in participants with JIA and sex- and age-matched population-based controls. Self-reported physical and psychosocial health were assessed using the generic Child Health Questionnaire (CHQ). Comparisons between children with JIA and controls were performed by test of proportions for categorical variables and t-test for continuous variables. To evaluate the association of patient- and physician-reported outcome measures with patient-reported physical disability, assessed with the Child Health Assessment Questionnaire (CHAQ) in children with JIA, we used logistic regression to estimate adjusted odds ratio (OR) with 95% confidence interval (CI).

Results

In total, 221 participants with JIA (59.3% females, median age 12.7 years) and 207 controls with available data were included. In the JIA group, 24.3% scored below the norm for physical health (CHQ PhS < 40) and 8.7% scored below the norm for psychosocial health (CHQ PsS < 40). The corresponding numbers for the control group were 0.5% and 1.9%, respectively. In the JIA group, 57.9% reported physical disability (CHAQ > 0). Several patient-reported outcome measures, such as poor physical health (CHQ PhS < 40), disease-related pain, and the patient’s global assessment of disease impact on wellbeing, were strongly associated with self-reported physical disability (CHAQ > 0), adjusted OR 19.0 (95% CI 5.6, 64.1), 14.1 (95% CI 6.8, 29.2), and 14.0 (95% CI 6.2, 31.6), respectively.

Associations were also found for active disease according to Wallace (adjusted OR 36.3, 95% CI 10.3, 128.1), and physician-reported global assessment of disease activity (adjusted OR 6.2, 95% CI 3.1, 12.6).

Conclusions

The strong association between patient- and physician-reported outcome measures and patient-reported physical disability strengthens the importance of including the patient’s voice in a comprehensive evaluation of patient outcome in JIA.

Trial registration

ClinicalTrials.gov (No: NCT03904459).
Psychotropic drug-induced adverse drug reactions in 462,661 psychiatric inpatients in relation to age: results from a German drug surveillance program from 1993–2016
Authors: Seifert Johanna , Reinhard Matthias A. , Bleich Stefan , Erfurth Andreas , Greil Waldemar , Toto Sermin , Grohmann Renate , Glocker Catherine
Published: November 2024

Background

Clinical practice suggests that older adults (i.e., ≥ 65 years of age) experience adverse drug reactions (ADRs) more often than younger patients (i.e., < 65 years of age). ADRs such as falls, extrapyramidal symptoms (EPS), metabolic disorders, sedation, and delirium are particularly worrisome and often associated with psychotropic drugs.

Methods

This observational study investigated the risk for psychotropic drug-related ADRs in older (n = 99,099) and younger adults (n = 363,562) in psychiatric inpatients using data from the German pharmacovigilance program “Arzneimittelsicherheit in der Psychiatrie” (AMSP) from 1993–2016. The aim was to assess whether age influenced the risk of specific ADR types and if certain psychotropic drugs posed particular concerns.

Results

The risk for ADRs did not differ between older and younger patients (relative risk 0.98, 95% confidence interval 0.92–1.05). However, older patients had a higher risk for delirium (2.35, 1.85–2.99), hyponatremia (3.74, 2.85–4.90), and orthostatic syncope (2.37, 1.72–3.26), as well as certain types of EPS, e.g., parkinsonism (1.89, 1.45–2.48) and Pisa-/metronome syndrome (3.61, 2.51–5.18). The risk for other ADRs, such as acute dystonia (0.20, 0.10–0.37), akathisia (0.47, 0.29–0.76), liver dysfunction (0.63, 0.48–0.82), weight gain (0.07, 0.04–0.14), sexual dysfunction (0.03, CI 0.00–0.25), and hyperprolactinemia/galactorrhea (0.05, 0.02–0.17) was significantly lower for older patients. Older patients treated with any type of antidepressant drug (1.33, 1.26–1.40)—especially selective serotonin reuptake inhibitors (1.57, 1.26–1.40) and selective serotonin-norepinephrine reuptake inhibitors (2.03, 1.80–2.29)—and lithium (1.74, 1.52–2.00) had a higher ADR risk than younger patients. Second-generation antipsychotic drugs had a lower (0.74, 0.71–0.77) and low-potency first-generation antipsychotic drugs a higher (1.19, 1.07–1.33) ADR risk in older patients. The risk for ADRs involving multiple drugs was higher in older patients (1.28, 1.22–1.34). ADRs in older patients were 6.4 times more likely to result in death.

Conclusions

Clinicians and pharmacists should be aware of the types of ADRs and high-risk drugs across age groups and provide appropriate monitoring. Pharmacovigilance is crucial in psychiatric patients of all ages and should not be neglected, even for drugs generally considered “safe”.
The KLF16/MYC feedback loop is a therapeutic target in bladder cancer
Authors: Zheng Lisi , Wang Jingxuan , Han Shan , Zhong Li , Liu Zefu , Li Bin , Zhang Ruhua , Zhou Liwen , Zheng Xianchong , Liu Zhenhua , Zeng Cuiling , Li Ruonan , Zou Yezi , Wang Liqin , Wu Yuanzhong , Kang Tiebang
Published: November 2024

Background

Bladder cancer (BLCA) is a common malignancy characterized by dysregulated transcription and a lack of effective therapeutic targets. In this study, we aimed to identify and evaluate novel targets with clinical potential essential for tumor growth in BLCA.

Methods

CRISPR-Cas9 screening was used to identify transcription factors essential for bladder cancer cell viability. The biological functions of KLF16 in bladder cancer were investigated both in vitro and in vivo. The regulatory mechanism between KLF16 and MYC was elucidated through a series of analyses, including RNA sequencing, quantitative polymerase chain reaction (qPCR), RNA immunoprecipitation, Western blotting, Mass spectrometry, Dual-luciferase reporter assays, Cleavage Under Targets and Tagmentation (CUT&Tag) sequencing, OptoDroplets assays, and RNA stability assay. The clinical relevance of KLF16 and MYC in bladder cancer was evaluated through analyses of public databases and immunohistochemistry.

Results

Krüppel-like factor 16 (KLF16) was essential for BLCA cell viability. Elevated expression of KLF16 was observed in bladder cancer tissues, and higher expression levels of KLF16 were correlated with poor progression-free survival (PFS) and cancer-specific survival (CSS) probabilities in BLCA patients. Mechanistically, KLF16 mRNA competed with the mRNA of dual-specificity phosphatase 16 (DUSP16) for binding to the RNA-binding protein, WW domain binding protein 11 (WBP11), resulting in destabilization of the DUSP16 mRNA. This, in turn, led to activation of ERK1/2, which stabilized the MYC protein. Furthermore, KLF16 interacted with MYC to form nuclear condensates, thereby enhancing MYC’s transcriptional activity. Additionally, MYC transcriptionally upregulated KLF16, creating a positive feedback loop between KLF16 and MYC that amplified their oncogenic functions. Targeting this loop with bromodomain inhibitors, such as OTX015 and ABBV-744, suppressed the transcription of both KLF16 and MYC, resulting in reduced BLCA cell viability and tumor growth, as well as increased sensitivity to chemotherapy.

Conclusions

Our study revealed the crucial role of the KLF16/MYC regulatory axis in modulating tumor growth and chemotherapy sensitivity in BLCA, suggesting that combining bromodomain inhibitors, such as OTX015 or ABBV-744, with DDP or gemcitabine could be a promising therapeutic intervention for BLCA patients.
Permissive weight bearing versus restrictive weight bearing in surgically treated trauma patients with displaced intra-articular calcaneal fractures (the PIONEER study): study protocol for a multicenter randomized controlled trial
Authors: Verstappen Coen , Driessen Mitchell L. S. , Kalmet Pishtiwan H. S. , Brandts Lloyd , Kimman Merel , Edwards Michael , Hermans Erik , Poeze Martijn
Published: November 2024

Background

Following successful treatment, displaced intra-articular calcaneal fractures (DIACFs) necessitate an extensive rehabilitation regimen, significantly influencing functional and socio-economic outcomes. Apart from surgical intervention, the implementation of a comprehensive rehabilitation protocol is crucial to optimize foot stability and functional recovery. The objective of this study is to ascertain the optimal rehabilitation protocol for patients with surgically treated DIACFs, either permissive weight bearing (PWB) or Restricted Weight Bearing, focusing on functional outcomes, health-related quality of life (HRQoL), radiographic parameters, cost-effectiveness, and incidence of complications.

Methods

Study design: A prospective multicenter randomized controlled trial. Study population: Presence of surgically (extended lateral, sinus tarsi, or percutaneous approach) treated unilateral DIACFs (Sanders type II to IV), aged 18–67 years (labor force). Patients must be able to understand and follow weight bearing instructions. N = 115 patients with DIACFs will be included. Interventions: Patients with DIACFs will be randomly allocated to one of the rehabilitation protocols, either PWB or RWB. Primary outcome measure: Functional outcome, measured with the American Orthopaedic Foot & Ankle Society Score (AOFAS)). Secondary outcomes: Functional outcome (Maryland Foot Score, MFS), HRQoL (EuroQol-5D, EQ-5D), differences in radiographic parameters, cost-effectiveness, and complications. Nature and extent of burden: The PWB protocol is aimed to be non-inferior to the RWB protocol. Previous analysis of this protocol in other lower extremity fractures has shown a safe complication rate. Follow-up is standardized according to current trauma guidelines, namely at time points 2, 6, 12 weeks, and 6 months. The radiation exposure for both groups will differ from standard care (one extra CT scan of the foot will be made). Therefore, the burden for participants is considered minimal, with no significant health risks.

Discussion

This study will be the first study to define an optimal rehabilitation regime for surgically treated patients with DIACFs. The limitations of this study include the absence of patient blinding, as this is impossible in rehabilitation. Additionally, the primary outcome measure (AOFAS) has limited validity for DIACFs. However, it is the most commonly used questionnaire in the literature on DIACFs. There is an apparent need since current literature is lacking on this specific topic.

Trial registration

ClinicalTrials.gov NCT05721378, accepted on February 7, 2023.
Improving onchocerciasis elimination surveillance: trials of odour baited Esperanza Window Traps to collect black fly vectors and real-time qPCR detection of Onchocerca volvulus in black fly pools
Authors: Adeleke Monsuru A. , Opara Kenneth N. , Mafuyai Hayward B. , Nwoke Bertram Ekejiuba Bright , Surakat Olabanji A. , Akinde Sunday B. , Nwoke Murphy , Chikezie Friday M. , Yaro Clement A. , Mmaduabuchi Ugagu , Igbe Michael , Makata Emeka , Oyediran Fatai , Anyaike Chukwuma , Tongjura Joseph , Hawkes Frances , Iwalewa Zahra O.
Published: November 2024

Background

Entomological data for onchocerciasis surveillance relies on sampling black flies through human landing collectors in the field and laboratory testing of the flies for infection using pooled screening O-150 PCR-ELISA assay. Both techniques require improvements. This study aimed to optimize the Esperanza Window Trap (EWT) for black fly collection. We tested alternative carbon dioxide (CO2) mimics to attract black flies to the traps. Additionally, we evaluated new quantitative PCR (qPCR) methods that target mitochondrial DNA markers and have been proposed to enhance the sensitivity and specificity for detecting Onchocerca volvulus infections in blackflies.

Methods

Traps baited with low, medium and high release rates of either 2-butanone or cyclopentanone as CO2 mimics were field tested against traps baited with organically generated CO2 in four ecological zones in Nigeria: Guinea savannah, derived savannah, rainforest and montane forest. The performance of EWTs baited with CO2 or in combination with 2-butanone (low release) were subsequently evaluated against the human landing collection (HLC). Trap scaling was also pilot tested by comparing two EWTs to a single HLC team. Collected black flies were used to test detection of O. volvulus in black flies using Ov ND5 real-time PCR (qPCR) compared to the conventional pool screening O-150 PCR.

Results

EWTs baited with 2-butanone caught similar numbers of black flies (Simulium damnosum s.l.) to those baited with CO2, while cyclopentanone collected significantly fewer flies in all locations. The low release of 2-butanone was the most effective overall, although HLCs collected higher numbers of black flies than EWT baited with CO2 either singly or in combination with low-release 2-butanone. The combination of two EWTs baited with CO2 and deployed 100 m apart from each other collected similar numbers of flies as one HLC. More black fly pools were positive for O. volvulus by Ov ND5 qPCR compared with O-150 PCR in derived savannah (31.15 vs. 15.57%), montane forest (11.54 vs. 0%) and rainforest (23.08 vs. 2.56%), with only one positive pool in Guinea savannah detected by both methods.

Conclusions

The 2-butanone has potential to be used in xenomonitoring as a standardized replacement for organically generated CO2. Ov ND5 qPCR detected more positive pools than O-150 PCR. The positive pools found in foci hitherto considered to have interrupted/eliminated onchocerciasis highlight the need for more sensitive and specific methods that support programmatic assessments to identify and combat recrudescence.

Graphical Abstract
Ascorbate peroxidase modulation confirms key role in Leishmania infantum oxidative defence
Authors: Santos Isabella Fernandes Martins , Moreira Douglas de Souza , Costa Karla Ferreira , Ribeiro Juliana Martins , Murta Silvane Maria Fonseca , Santi Ana Maria Murta
Published: November 2024

Background

Ascorbate peroxidase (APX) has emerged as a promising target for chemotherapy because of its absence in humans and crucial role in the antioxidant defence of trypanosomatids. APXs, which are class I haeme-containing enzymes, reduces hydrogen peroxide using ascorbate to produce water and monodehydroascorbate, thereby preventing cell damage caused by H2O2.

Methods

We aimed to create an APX-knockout L. infantum line using CRISPR/Cas9. Despite unsuccessful attempts at full knockouts, we achieved deletion of chromosomal copies post-APX episomal insertion, yielding LiΔchrAPX::LbAPX parasites. We performed phenotypic characterization to assess the impact of these genetic modifications, which included the determination of APX transcript expression levels using quantitative PCR, drug sensitivity, infectivity, and parasite survival in macrophages.

Results

Quantitative polymerase chain reaction (PCR) analysis revealed a 10- to 13-fold reduction in APX transcript expression in LiΔchrAPX::LbAPX compared with wild-type (LiWT) and APX-overexpressing (Li::Cas9::LbAPX) parasites, respectively. The episomes in those knockdown parasites remained stable even after 20 drug-free passages in vitro. Li::Cas9::LbAPX parasites showed increased resistance to trivalent antimony (SbIII) and isoniazid, reduced tolerance to H2O2, and unchanged macrophage infectivity compared with LiWT. In contrast, LiΔchrAPX::LbAPX parasites were more sensitive to SbIII and isoniazid, exhibited greater susceptibility to H2O2-induced oxidative stress, and 72 h post-infection, showed fewer infected macrophages and intracellular amastigotes compared with LiWT parasites.

Conclusions

Our findings hint at the indispensability of APX in L. infantum and raise the possibility of its potential as a therapeutic target for leishmaniasis.

Graphical Abstract
Pre-diagnosis blood DNA methylation profiling of twin pairs discordant for breast cancer points to the importance of environmental risk factors
Authors: Bode Hannes Frederik , He Liang , Hjelmborg Jacob V. B. , Kaprio Jaakko , Ollikainen Miina
Published: November 2024

Background

Assessment of breast cancer (BC) risk generally relies on mammography, family history, reproductive history, and genotyping of major mutations. However, assessing the impact of environmental factors, such as lifestyle, health-related behavior, or external exposures, is still challenging. DNA methylation (DNAm), capturing both genetic and environmental effects, presents a promising opportunity. Previous studies have identified associations and predicted the risk of BC using DNAm in blood; however, these studies did not distinguish between genetic and environmental contributions to these DNAm sites. In this study, associations between DNAm and BC are assessed using paired twin models, which control for shared genetic and environmental effects, allowing testing for associations between DNAm and non-shared environmental exposures and behavior.

Results

Pre-diagnosis blood samples of 32 monozygotic (MZ) and 76 dizygotic (DZ) female twin pairs discordant for BC were collected at the mean age of 56.0 years, with the mean age at diagnosis 66.8 years and censoring 75.2 years. We identified 212 CpGs (p < 6.4*10–8) and 15 DMRs associated with BC risk across all pairs using paired Cox proportional hazard models. All but one of the BC risks associated with CpGs were hypomethylated, and 198/212 CpGs had their DNAm associated with BC risk independent of genetic effects. According to previous literature, at least five of the top CpGs were related to estrogen signaling. Following a comprehensive two-sample Mendelian randomization analysis, we found evidence supporting a dual causal impact of DNAm at cg20145695 (gene body of NXN, rs480351) with increased risk for estrogen receptor positive BC and decreased risk for estrogen receptor negative BC.

Conclusion

While causal effects of DNAm on BC risk are rare, most of the identified CpGs associated with the risk of BC appear to be independent of genetic effects. This suggests that DNAm could serve as a valuable biomarker for environmental risk factors for BC, and may offer potential benefits as a complementary tool to current risk assessment procedures.