bluuebunny/crossref_metadata_2025_split huggingface dataset:
Early tumour necrosis factor antagonist treatment prevents perianal fistula development in children with Crohn’s disease: post hoc analysis of the RISK study
Authors: Adler Jeremy , Gadepalli Samir , Rahman Moshiur , Kim Sandra 
Published: December 2024

BackgroundOne in three children with Crohn’s disease develop perianal fistula complications (PFCs), among the most disturbing and difficult-to-treat disease-related complications. Retrospective evidence suggests PFCs may be preventable.ObjectiveWe aimed to determine if early antitumour necrosis factor-alpha (anti-TNF⍺) therapy prevents PFC development in a well-characterised prospective cohort of paediatric patients with Crohn’s disease who were free from PFC at enrolment.DesignRISK was a multicentre inception cohort of children newly diagnosed with Crohn’s disease. We included all patients who had never experienced PFCs 30 days after study enrolment. We conducted nearest-neighbour propensity score-matched triad analyses. Matching was performed to balance patient characteristics across three mutually exclusive treatment groups based on therapy prior to either PFC development or the end of the observation period.ResultsAmong 873 patients without perianal fistula, 447 matched patients were included (149 per treatment group). The presence of non-penetrating perianal lesions (large skin tags, ulcers and/or fissures) was significantly associated with PFC development, with 4-fold greater odds of PFC (OR 4.08, 95% CI (95% CI) 1.70 to 9.78; p=0.0016). Early anti-TNF⍺ therapy was associated with an 82% decrease in the odds of PFC (OR 0.18, 95% CI 0.05 to 0.66; p=0.01). Among those with perianal lesions, anti-TNF⍺ therapy was associated with 94% reduced odds of PFC development (OR 0.055, 95% CI 0.006 to 0.50; p=0.010). No other treatment group was associated with reduced risk of PFC.ConclusionEarly anti-TNF therapy prevents perianal fistula development, especially among patients at increased risk.
Clinicopathological characteristics of light chain proximal tubulopathy: a multicentre case series
Authors: Lin Yao , Xing Guolan , Hu Ruimin , Liu Shaojun , Li Guisen , Zhang Ping , Xu Feng , Liang Dandan , Zhu Xiaodong , Zhang Mingchao , Yang Fan , Yao Xinchen , Liu Feng , Wang Yujie , Dong Shihui , Liang Shaoshan , Zeng Caihong 
Published: December 2024

AimsLight chain proximal tubulopathy (LCPT) is a rare complication of paraprotein-related diseases. We report a case series to present the clinicopathological characteristics and outcomes of LCPT.MethodsA multicentre retrospective case series of 47 patients with LCPT, consisting of 36 crystalline, three non-crystalline, and eight mixed LCPTs, was studied between January 2007 and December 2023.ResultsThe median age at diagnosis was 57 years. Presentations included proteinuria (100%), renal insufficiency (62%) and Fanconi syndrome (68%). The underlying haematological diagnoses were monoclonal gammopathy of renal significance in 81% and multiple myeloma in 19%. Monoclonal light chain (LC) was detected in all cases using serum/urine-free LC assays or immunofixation electrophoresis. Among 36 crystalline LCPTs, 34 were κ-restricted and 2 λ-restricted. Three non-crystalline LCPTs were all λ-restricted. In mixed LCPTs, seven were κ-restricted and one was λ-restricted. Notably, 66% frozen-section immunofluorescence failed to reveal restricted LC, requiring paraffin-immunofluorescence or immunoelectron microscopy. The appearance of inclusions displayed intraindividual homogeneity but interindividual heterogeneity in 42 patients and notable intraindividual heterogeneity in the remaining 5 patients. Haematological complete response, very good partial response and partial response occurred in 61%. Kidney function improved or remained stable in 84%, worsened in 8% and progressed to end-stage renal disease in 8%.ConclusionsProteinuria and kidney dysfunction are the most common but less-specific renal manifestations of LCPTs, with most featuring Fanconi syndrome. Crystalline LCPT, primarily associated with κ-LC, is the predominant form. Most inclusions displayed intraindividual homogeneity and interindividual heterogeneity by electron microscopy. Most achieved haematological responses and favourable renal outcomes.
Local cell therapy using CCL19-expressing allogeneic mesenchymal stem cells exerts robust antitumor effects by accumulating CD103+IL-12-producing dendritic cells and priming CD8+T cells without involving draining lymph nodes
Authors: Iida Yuichi , Harada Mamoru 
Published: December 2024

BackgroundImmune checkpoint blockade is a promising anticancer therapy, whereas the presence of T cells in tumor sites is indispensable for its therapeutic efficacy. To promote the infiltration of T cells and dendritic cells (DCs) into the tumor, we previously proposed a local cell therapy using chemokine (C-C motif) ligand 19 (CCL19)-expressing immortalized syngeneic immortalized mesenchymal stem cells (syn-iMSC/CCL19). However, the preparation of syngeneic/autologous MSC from individual hosts limits the clinical application of this cell therapy.MethodsIn this study, we further developed a new cell therapy using allogeneic iMSC/CCL19 (allo-iMSC/CCL19) using several tumor mice models.ResultsThe allo-iMSC/CCL19 therapy exerted drastic antitumor effects, in which the host’s T cells were induced to respond to allogeneic MSC. In addition, the allo-iMSC/CCL19 therapy promoted the infiltration of CD103+interleukin (IL)-12-producing DCs and priming of CD8+T cells at tumor sites compared with that using syn-iMSC/CCL19. The antitumor effect of allo-iMSC/CCL19 therapy was not influenced by fingolimod, a sphingosine 1-phosphate receptor modulator, implying no involvement of draining lymph nodes in the priming of tumor-specific T cells.ConclusionThese results suggest that allo-iMSC/CCL19 therapy exerts dramatic antitumor effects by promoting the infiltration of CD103+IL-12-producing DCs and thereby priming tumor-specific CD8+T cells at tumor sites. This local cell therapy could be a promising approach to anticancer therapy, particularly for overcoming dysfunction in the cancer-immunity cycle.
Telomere length, in vivo Alzheimer’s disease pathologies and cognitive decline in older adults
Authors: Jung Joon Hyung , Byun Min Soo , Yi Dahyun , Ahn Hyejin , Lee Jun Ho , Lee Jang-Seok , Lee Hyun-Seob , Lee Jun-Young , Kim Yu Kyeong , Lee Yun-Sang , Kang Koung Mi , Sohn Chul-Ho , Lee Dong Young 
Published: December 2024

BackgroundWhether telomere length (TL), an indicator of biological ageing, reflects Alzheimer’s disease (AD)-related neuropathological change remains unclear. We investigated the relationships between TL, in vivo AD pathologies, including cerebral beta-amyloid and tau deposition, and cognitive outcomes in older adults.MethodsA total of 458 older adults were included, encompassing both cognitively normal (CN) individuals and those cognitively impaired (CI), with the CI group consisting of individuals with mild cognitive impairment or AD dementia. All participants underwent clinical and neuropsychological assessments, amyloid positron emission tomography (PET) scan and DNA extraction for measuring TL at baseline. A subset of participants (n=140) underwent tau PET scan. At follow-up, the participants underwent neuropsychological assessments annually for up to 4 years.ResultsOverall, longer TL was associated with greater brain tau deposition (B=0.139, 95% CI 0.040, 0.238) and a faster decline in global cognition (B = − 0.371, 95% CI − 0.720, –0.023). In the subgroup analysis, the association between longer TL and greater in vivo AD pathologies, as well as faster cognitive decline, was observed particularly in the CI group. Mediation analysis suggested that longer TL was associated with cognitive decline through increased tau deposition in the CI group.ConclusionOur finding suggests that older adults with relatively longer TL, particularly in the CI group, may have greater in vivo AD pathologies and experience more rapid cognitive decline, potentially mediated by brain tau deposition. Further studies are necessary to elucidate the biological links underlying these associations.
Incidence and prevalence of functional neurological disorder: a systematic review
Authors: Finkelstein Sara A , Diamond Clare , Carson Alan , Stone Jon 
Published: December 2024

BackgroundRobust epidemiological data regarding population incidence and prevalence of functional neurological disorder (FND) would be helpful with regards to resource allocation and planning for this disorder, particularly given high symptom burden and high healthcare utilisation. We therefore aimed to systematically review and synthesise available data on FND incidence and prevalence.MethodsPubMed was searched to identify original research articles that reported on the incidence or prevalence of FND. Risk of bias assessment for each study was conducted. Incidence and prevalence rates of FND were additionally estimated by extrapolating data from low risk of bias studies on functional seizures alone.ResultsThirty-nine articles were included. Nineteen reported on FND incidence, 21 reported on prevalence. Comparison between studies was difficult due to methodological differences and significant heterogeneity of incidence and prevalence estimates was found. The incidence of FND was estimated at 10–22/100 000, while minimum prevalence of FND was estimated at 80–140/100 000, with a possible range of 50–1600/100 000. Incidence of paediatric FND was estimated to be between 1 and 18/100 000.ConclusionsThe range of incidence and prevalence varies widely across studies, with significant heterogeneity among studies and most studies likely provide underestimates due to methodological challenges. However, using our best method as a conservative estimate, there are likely a minimum of 50–100 000 people with FND in the UK, as an example country. Given that FND appears to be more prevalent than many other well-known and well-funded neurological disorders, incidence and prevalence data suggested here indicate the need for greater research and clinical funding allocation to FND programmes.
Real time continuous monitoring of injection pressure at the needle tip is better than ultrasound in early detecting intraneural injection
Authors: Dossi Roberto , Quadri Christian , Capdevila Xavier , Saporito Andrea 
Published: December 2024

IntroductionDuring peripheral nerve blocks, inadvertent intraneural injection is not infrequent. Recently, with sonographic nerve swelling, it has been shown that intraneural injection can be detected as early as 0.4 mL. A new method based on injection pressure monitoring at the needle tip, the real pressure in the tissues, is compared with sonographic performance in early detection of intraneural injection.MethodsThis cadaver study was conducted on the upper limb of fresh cadavers. Senior anesthesiologists performed ultrasound guided intraneural injections of the nerves using a modified Visioplex needle with a fiberoptic sensor embedded. 12 injections were performed, two on each nerve (radial, ulnar, and median) for each anatomical preparation. 3 mL of saline methylene blue mix was injected at 10 mL/min. Recordings of ultrasound screen and pressure curves were blindly analyzed to evaluate nerve swelling and injection pressures.ResultsAn immediate increase in injection pressure from time zero was observed in all 12 intraneural injections, with similar trends. After only 0.2 mL, intraneural injection was clearly identified as the pressure curves had already risen to an average of 120 mm Hg (SD 5). Nerve swelling was observed in 10 of 12 injections (83%). This was evident after an average of 1.2 mL (SD 0.5). Following injections, dissection of specimens confirmed intraneural spread in all cases.ConclusionPressure monitoring at the needle tip consistently showed a pressure rise from the onset of injection and proved to be a more sensitive and earlier indicator of intraneural injection than sonographic nerve swelling.
Evaluation of pheromone- and floral-baited traps for monitoring western corn rootworm (Coleoptera: Chrysomelidae) beetles in Canada
Authors: van Herk Willem G. , Bailey Terisha , Saguez Julien , Smith Jocelyn L. , Farhan Yasmine 
Published: December 2024

Western corn rootworm (WCR), Diabrotica virgifera virgifera, was first detected in British Columbia (BC) in 2016, resulting in the need for a trapping method that can detect beetles at low population levels and that can potentially mass trap beetles in sweet corn processing and distribution outlets. Based on early field experiments run in BC in 2019 and 2020, four trap types, baited with sex pheromone or floral lures, were evaluated in BC, Ontario, and Quebec for two 2-week periods during the swarming period in 2021. Trap captures were scored 0–10 based on relative captures, with the method with greatest captures scored as 10. Captures of male beetles were greatest on pheromone-baited PAL (“cloak”) (mean score of all 2021 experiments = 9.6) and PALs traps (8.6), and significantly lower with pheromone-baited Delta (3.4) and KLP (“hat”) (1.5), or floral-baited PAL (2.1) and PALs traps (1.9). Captures of female beetles were greatest on floral-baited PALs (8.7), PAL (8.4), and Delta traps (5.0), and low on KLP (1.5) and all other trapping methods (<1). In follow-up experiments run in 2023, pheromone-baited PAL traps captured >180× more beetles than non-baited Pherocon AM traps. Together these results indicate that PAL, PALs, and Delta traps can be used for the early detection of male and female WCR when baited with pheromone and floral lures, respectively, in Canada, both to determine the onset of the beetle swarming season for timing of foliar insecticide applications, and to monitor the spread of WCR to new areas.
Phase 1/2 Study of the Indoleamine 2,3-Dioxygenase 1 Inhibitor Linrodostat Mesylate Combined with Nivolumab or Nivolumab and Ipilimumab in Advanced Solid Tumors or Hematologic Malignancies
Authors: Luke Jason J. , Gelmon Karen , Siu Lillian L. , Moreno Victor , Desai Jayesh , Gomez-Roca Carlos A. , Carlino Matteo S. , Pachynski Russell K. , Cosman Rasha , Chu Quincy Siu-Chung , Damian Silvia , Curigliano Giuseppe , Tam Rachel , Wang Xianling , Jeyamohan Chandrika , Wang Lily , Zhu Li , Santucci-Pereira Julia , Greenawalt Danielle M. , Tabernero Josep 
Published: December 2024

Abstract

Purpose:
To evaluate the safety, efficacy, pharmacokinetics, pharmacodynamics, and biomarkers of linrodostat mesylate, a selective, oral indoleamine 2,3-dioxygenase 1 inhibitor combined with nivolumab ± ipilimumab in advanced solid tumors and hematologic malignancies.

Patients and Methods:
In this phase 1/2 study, patients received once-daily linrodostat [part 1 (escalation), 25–400 mg; part 2 (expansion), 100 or 200 mg] plus nivolumab (480 mg every 4 weeks or 240 mg every 2 weeks) or triplet therapy (part 3, linrodostat 20–100 mg once daily; nivolumab 360 mg every 3 weeks or 480 mg every 4 weeks; ipilimumab 1 mg/kg every 6 weeks or every 8 weeks). Endpoints included safety and efficacy (coprimary; parts 2 and 3), pharmacokinetics, pharmacodynamics, biomarkers, and efficacy (part 1).

Results:
A total of 55, 494, and 41 patients were enrolled in parts 1, 2, and 3, respectively. Linrodostat exposures exceeded predicted therapeutic target concentrations starting at 50 mg. Rates of grade 3/4 adverse events were 50.1% to 63.4%. The maximum tolerated linrodostat dose was 200 mg; dose-limiting toxicities were primarily immune-related. Responses were observed across different cohorts, study parts, and tumor types, particularly in immunotherapy-naïve patients. Kynurenine decreased with linrodostat + nivolumab regardless of response. In contrast, IFN-γ gene expression signature was associated with response; in nonmelanoma patients, a composite of low tryptophan 2,3-dioxygenase gene expression plus high IFN-γ signature was associated with response.

Conclusions:
Linrodostat + nivolumab ± ipilimumab demonstrated a manageable safety profile. Kynurenine changes supported indoleamine 2,3-dioxygenase 1 pathway inhibition but did not correlate with response. A composite biomarker of low tryptophan 2,3-dioxygenase expression plus high IFN-γ gene expression may predict response to linrodostat + nivolumab.
Complete Remissions of HER2-Positive Trastuzumab-Resistant Xenografts Using a Potent [225Ac]Ac-Labeled Anti-HER2 Antibody–Drug Radioconjugate
Authors: Pougoue Ketchemen Jessica , Njotu Fabrice Ngoh , Babeker Hanan , Monzer Alissar , Nwangele Emmanuel , Tikum Anjong Florence , Henning Nikita , Hassani Nava , Frye Sarah , Perron Randy , Byrne Chris , Didychuk Candice , Qi Qi , Bannister Laura , Doroudi Alireza , Fonge Humphrey 
Published: December 2024

Abstract

Purpose:
There is overwhelming interest to use actinium-225 ([225Ac]Ac) to develop targeted α therapies. Antibody–drug conjugates (ADC) are highly cytotoxic. Combining [225Ac]Ac with an ADC to develop an antibody–drug radioconjugate [225Ac]Ac–macropa–trastuzumab(T)–PEG6–emtansine (DM1), is expected to be more effective than its ADC (T–PEG6–DM1) against breast cancer.

Experimental Design:
[89Zr]Zr–p-isothiocyanatobenzyl desferrioxamine (DFO)–T–PEG6–DM1 (imaging) and [225Ac]Ac–macropa–T–PEG6–DM1 (radiotherapy) were developed. Biodistribution and safety evaluations of [225Ac]Ac–macropa–T-PEG6–DM1 were carried out in non–tumor-bearing BALB/c mice. MicroPET imaging and biodistribution were done using [89Zr]Zr-DFO–T–PEG6–DM1, and radiotherapy using [225Ac]Ac–macropa–T–PEG6–DM1 was carried out in athymic BALB/c nude mice bearing trastuzumab-resistant HCC1954 and trastuzumab-DM1 (T-DM1)/trastuzumab-resistant JIMT-1 tumor-bearing mice.

Results:
After 7 days of incubation at 37°C, [225Ac]Ac–macropa–T–PEG6–DM1 was stable in both human serum (89.2% ± 0.9%) and PBS (82.8% ± 0.4%). T–PEG6–DM1 (8 mg/kg) and [225Ac]Ac–macropa–T–PEG6–DM1 (3 × 18 kBq) administered separately in non–tumor-bearing mice 10 days apart were well tolerated biochemically and hematologically. Imaging and biodistribution showed high tumor uptake of [89Zr]Zr-DFO–T–PEG6–DM1 in tumor-bearing mice at 120 hours after injection: 38.1% ± 2.8% IA/g (HCC1954) and 14.6% ± 1% IA/g (JIMT-1). In HCC1954 tumor-bearing mice, all treatment groups had complete remission (8/8), indicative of the responsiveness of the xenograft to T-DM1–based treatments, whereas for JIMT-1 xenografts (having 1/8 complete remission) at 23 days after treatment, tumor volumes were 332.1 ± 77.5 vs. 244.6 ± 63 vs. 417.9 ± 62.1 vs. 102.4 ± 18.5 for the saline (negative control), T-DM1 (positive control), T–PEG6–DM1, and [225Ac]Ac–macropa–T–PEG6–DM1, respectively.

Conclusions:
[225Ac]Ac–macropa–T–PEG6–DM1 is more potent than ADC against trastuzumab-resistant breast cancer and necessitates clinical translation.
Baroreflex Sensitivity and Long-Term Dementia Risk in Older Adults
Authors: Ma Yuan , Zhang Yiwen , Hamaya Rikuta , Westerhof Berend E. , Shaltout Hossam A. , Kavousi Maryam , Mattace-Raso Francesco , Hofman Albert , Wolters Frank J. , Lipsitz Lewis A. , Ikram M. Arfan 
Published: December 2024

BACKGROUND:
Increased blood pressure (BP) variability is linked to dementia risk, but the relationship between baroreflex sensitivity (BRS), a fundamental mechanism for maintaining stable BP, and dementia risk is undetermined.

METHODS:
We tested the hypothesis that impaired BRS is associated with increased dementia risk in 1819 older adults (63% women; age, 71.0±6.3 years) from the community-based Rotterdam Study. Cardiac BRS was determined from a 5-minute beat-to-beat BP recording at supine rest between 1997 and 1999. Cardiac BRS measures the correlation between changes in consecutive beat-to-beat systolic BP and subsequent responses in heartbeat intervals, with a higher value indicating better BRS. The primary outcome was incident dementia ascertained from baseline through January 1, 2020; the secondary outcome was all-cause mortality.

RESULTS:

During a median follow-up of 14.8 years, 421 participants developed dementia. The association of cardiac BRS with dementia risk differed by antihypertensive medication use (
P
interaction
=0.03) and was only observed in participants not taking antihypertensives. Specifically, in those not taking antihypertensive medication, reduced BRS was associated with a higher risk of dementia (adjusted hazard ratio comparing bottom versus top quintiles, 1.60 [95% CI, 1.07–2.40];
P
trend
=0.02). Reduced BRS was also associated with an increased risk of death (corresponding hazard ratio, 1.76 [95% CI, 1.32–2.35]). The association remained after adjusting for average BP and BP variability.

CONCLUSIONS:
Impaired BRS partly explains hypertension-related brain damage and excessive dementia risk beyond conventional BP measures, making it a potential novel biomarker for the early detection and prevention of dementia.
Writing Proficiency Development of Spanish Heritage Language Learners: Does Starting Proficiency Matter?
Authors: Gatti Alberta , Graves Syelle , Durán Urrea Evelyn 
Published: December 2024

Abstract
This study investigates to what extent heritage language learners’ (HLL) functional writing proficiency can increase after one semester of instruction. The study assessed 134 Spanish HLLs enrolled in a post-secondary heritage language course at the start and end of one semester, with a standardized measure following protocols of the American Council on the Teaching of Foreign Languages (ACTFL) Writing Proficiency Test (WPT) and Guidelines. Statistically significant results of contingency table analyses indicate that (1) HLLs can make gains in proficiency after one semester of instruction, but that not many do, and (2) a gain is more likely the lower the starting proficiency level of the writer. These results offer a tentative baseline for understanding the development of functional writing proficiency in Spanish HLLs. Implications for instruction are also discussed, including the advantages of placing learners by proficiency.
The Causes and Consequences of Loving International Organizations: A Reply to Jean D’Aspremont
Authors: Daugirdas Kristina 
Published: December 2024

Abstract
In observing a pervasive love for international organizations and prompting readers to notice and to interrogate its causes and consequences, Jean d’Aspremont makes an important and urgent contribution. This essay raises doubts about some of the drivers of love that d’Aspremont identifies while acknowledging that the community of scholars and practitioners whose work focuses on international organizations does seem to share such an affection. D’Aspremont observes that we temper and confine our critcisms of international organizations, seeking reform and incremental change rather than radical disruption. He labels this particular kind of “criticability” of international organizations a driver of love for them. But it is better characterised as a consequence of love—and an important one, because it highlights questions we’re not asking and possibilities we’re not considering. As members of a professional community, we must continuously ask ourselves what we’re assuming, what we’re resisting, and what we’re missing—and make sure that we constitute our professional community in a way that corrects for our individual blind spots instead of replicating them.
International and Regional Organizations: An Asian Perspective
Authors: Gulecha Anmol 
Published: December 2024

Abstract
As Jean d’Aspremont extols the concept of love for international organizations, it’s notable that, unlike the African Union or the European Union, Asia lacks a region-wide international organization. Additionally, from an international perspective, Asia is often seen as under-participating in organizations such as the United Nations. This raises the question: what is the Asian perspective on Jean d’Aspremont’s discourse regarding love for international organizations? An examination of examples from both regional and international organizations reveals that Asian states’ approach to the notion of love for international organizations is marked by ‘mixed feelings’. The perspective of Asian states is characterised by a conflict between the preservation of state sovereignty and the effective functioning of international organizations themselves.