bluuebunny/crossref_metadata_2025 huggingface dataset:
Management of Indeterminate Thyroid Nodules: A Model Comparing Surgery, Molecular Testing, and Observation
Authors: Welschmeyer Alexandra , Kligerman Maxwell , Noel Julia
Published: August 2024

Objective

Optimal management of indeterminate nodules remains a controversial area of endocrine surgery. The purpose of this study is to compare observation, molecular testing, and immediate thyroid surgery for the management of Bethesda Classes III and IV nodules in patients age 50 to 90 years.

Study Design

A decision analysis was performed from April 22, 2021, to September 29, 2023, using a Markov model constructed with TreeAgePro 2023. Model variables and ranges were selected based on literature review data.

Setting

TreeAgePro.

Methods

A 1‐way sensitivity analysis was performed to evaluate the age threshold at which each management pathway, immediate thyroid surgery, additional molecular testing, or observation, would be favored. A Monte Carlo probabilistic sensitivity analysis was performed 5 times with model patients assigned starting ages of 50, 60, 70, 80, and 90 years to assess how age at diagnosis would impact model results. Outcomes were measured with quality‐adjusted life‐years and accounted for perioperative complications including permanent recurrent laryngeal nerve injury, permanent hypoparathyroidism, and medical complications.

Results

In the study models, molecular testing was more beneficial than surgery and observation across all ages. The age threshold at which observation became more beneficial than surgery as the next best option was 83.1 years. However, the clinical difference between all 3 treatment algorithms was relatively minimal.

Conclusions

Decision‐making regarding indeterminate thyroid nodules is complex. Given the clinically similar results across all 3 treatment algorithm, this study reinforces that treatment modalities should be individually tailored and based on shared physician‐patient decision making.
A legal cure for news choice overload: Regulating algorithms and AI with ‘light patterns’ to foster autonomy and democracy
Authors: Molitorisz Sacha
Published: August 2024

Despite an unprecedented abundance of news content, both news avoidance and dissatisfaction are rising. Blending journalism, philosophy and law scholarship, this paper argues that ‘news choice overload’ causes paralysis and poor outcomes as it transfers power to algorithms, thereby harming autonomy and, in turn, democracy. An analysis of Australian and European regulatory responses shows the need for an algorithmic regulator and a transparency requirement for digital platforms. Further, people's ability to choose autonomously can be fostered by positive interventions, or ‘light patterns’, including ‘diversity nudges’ and a shift from caveat emptor to a caveat venditor approach, in which digital platforms are assigned legal responsibility. Recognising that it is autonomy and democracy—not choice per se—that are valuable, such interventions can shift meaningful decision‐making back to citizens at a moment when the rise of generative artificial intelligence is giving algorithms yet more power.
Editor's Note
Authors: Mick Connie S.
Published: August 2024

This note from the editor provides a brief summary of the articles contained in this issue and invites readers to respond and submit their own articles.
Revisiting the nexus between governance and poverty in Sub‐Saharan Africa
Authors: Abdulhakeem A. Kilishi
Published: August 2024

The aim of this study is to investigate the influence of different components of governance on poverty. Hence, the study investigates the direct impact of four pillars of governance and 16 subindicators of governance on poverty in Sub‐Saharan Africa (SSA). This is unlike most previous studies that use a composite index of governance which does not have a bearing on specific policy variables. A panel data set of 41 SSA countries over a period from 2012 to 2022 is analyzed using the System GMM (Generalised Method of Moment) estimation technique. The findings show that improvement in the four pillars of governance (security and rule of law; participation, rights and inclusion; foundation for economic opportunity; and human development) would yield significant reduction of poverty in SSA. However, not all the sub‐indicators have a direct impact on poverty, those that show significant effects are: (a) rule of law and justice, (b) accountability and transparency, (c) anticorruption, (d) public administration, (e) infrastructure, (f) rural development, (g) social welfare, and (h) sustainable environment. All the significant indicators have bearing on the creation and protection of an enabling environment and opportunity for productive activities. Hence, it is recommended that policymakers should undertake judicial system reforms including reforms of the police services. Civil service reform is also recommended, while the business of government should be carried out transparently with zero tolerance for corruption.
The medicinal plant Buddleja asiatica and its relation to the welfare of local people in the Pan‐Himalayan region: Past, present, and future perspectives
Authors: Gurung Bishal , Yang Fengmao , Chen Gao , Ge Jia
Published: August 2024

Societal Impact Statement

Globalization and rapid shifts in culture and economy threaten indigenous and local knowledge (ILK) systems, and large intergenerational gaps in this knowledge already exist. Buddleja asiatica is a deciduous shrub or small tree with traditional medicinal applications but is currently largely overlooked as a medicinal resource. This study investigates the traditional uses of B. asiatica in indigenous communities in the Pan‐Himalayan region through ethnobotanical field surveys, with a view to preserving cultural heritage and strengthening economic resilience in these communities, as well as developing B. asiatica as a medicinal resource. Prioritizing the well‐being of mountain communities, this study aims to bridge community development with nature.

Buddleja asiatica Lour. (Scrophulariaceae) is widely distributed across the Pan‐Himalayan region. It has traditional medicinal applications and cultural value, as well as ecological significance. We conducted an ethnobotanical study combining field surveys from Nepal and Xizang, China with a literature review using Web of Science (WoS) to review the ethnobotanical, phytochemical, and pharmacological aspects of this species. Our study highlights the cultural significance of B. asiatica within indigenous communities and, in particular, the use of the leaves to make a starter culture for the preparation of wine. However, an evident intergenerational gap in knowledge transfer exists. The phytochemical investigation revealed the presence of various chemical classes (carbohydrates, terpenoids, flavonoids, saponins, esters, steroids, glycosides, and fatty acids), of which 15 phytoconstituents were first reported from various parts of B. asiatica. The potential medicinal properties of these chemicals include anti‐inflammatory, antioxidant, cytotoxic, antihepatotoxic, antimicrobial, and cholinesterase activities. We combine these lines of evidence to show the prospects for the livelihoods of local people across this region and propose future research directions.
A fully automatic tool for development of population pharmacokinetic models
Authors: Chen Xiaomei , Nordgren Rikard , Belin Stella , Hamdan Alzahra , Wang Shijun , Yang Tianwu , Huang Zhe , Carter Simon J. , Buatois Simon , Abrantes João A. , Hooker Andrew C. , Karlsson Mats O.
Published: August 2024

Population pharmacokinetic (PK) models are widely used to inform drug development by pharmaceutical companies and facilitate drug evaluation by regulatory agencies. Developing a population PK model is a multi‐step, challenging, and time‐consuming process involving iterative manual model fitting and evaluation. A tool for fully automatic model development (AMD) of common population PK models is presented here. The AMD tool is implemented in Pharmpy, a versatile open‐source library for pharmacometrics. It consists of different modules responsible for developing the different components of population PK models, including the structural model, the inter‐individual variability (IIV) model, the inter‐occasional variability (IOV) model, the residual unexplained variability (RUV) model, the covariate model, and the allometry model. The AMD tool was evaluated using 10 real PK datasets involving the structural, IIV, and RUV modules in three sequences. The different sequences yielded generally consistent structural models; however, there were variations in the results of the IIV and RUV models. The final models of the AMD tool showed lower Bayesian Information Criterion (BIC) values and similar visual predictive check plots compared with the available published models, indicating reasonable quality, in addition to reasonable run time. A similar conclusion was also drawn in a simulation study. The developed AMD tool serves as a promising tool for fast and fully automatic population PK model building with the potential to facilitate the use of modeling and simulation in drug development.
Modeling multiple‐criterion diagnoses by heterogeneous‐instance logistic regression
Authors: Yang Chun‐Hao , Li Ming‐Han , Wen Shu‐Fang , Chang Sheng‐Mao
Published: August 2024

Mild cognitive impairment (MCI) is a prodromal stage of Alzheimer's disease (AD) that causes a significant burden in caregiving and medical costs. Clinically, the diagnosis of MCI is determined by the impairment statuses of five cognitive domains. If one of these cognitive domains is impaired, the patient is diagnosed with MCI, and if two out of the five domains are impaired, the patient is diagnosed with AD. In medical records, most of the time, the diagnosis of MCI/AD is given, but not the statuses of the five domains. We may treat the domain statuses as missing variables. This diagnostic procedure relates MCI/AD status modeling to multiple‐instance learning, where each domain resembles an instance. However, traditional multiple‐instance learning assumes common predictors among instances, but in our case, each domain is associated with different predictors. In this article, we generalized the multiple‐instance logistic regression to accommodate the heterogeneity in predictors among different instances. The proposed model is dubbed heterogeneous‐instance logistic regression and is estimated via the expectation‐maximization algorithm because of the presence of the missing variables. We also derived two variants of the proposed model for the MCI and AD diagnoses. The proposed model is validated in terms of its estimation accuracy, latent status prediction, and robustness via extensive simulation studies. Finally, we analyzed the National Alzheimer's Coordinating Center‐Uniform Data Set using the proposed model and demonstrated its potential.
The Pattern of Copper Release in Copper‐Based Nanoparticles Regulates Tumor Proliferation and Invasiveness in 3D Culture Models
Authors: Garcia‐Peiro Jose I. , Guerrero‐López Paula , Hornos Felipe , Hueso Jose L. , Garcia‐Aznar J. Manuel , Santamaria Jesus
Published: August 2024

Cancer is a leading cause of death worldwide. Glioblastoma (GBM) is a major challenge in oncology due to its highly invasive nature and limited treatment options. GBM's aggressive migration beyond tumor margins and rapid tumor growth hinders success in patient treatment. Localized therapeutic delivery, such as the use of transition metals like copper, is highlighted as a novel therapeutic agent for many potential biomedical applications. Herein, it is aimed to study the effects of Cu release on the proliferation and invasiveness of cancer cells. To this end, novel copper‐based nanostructures with different release patterns are designed. Using a complex 3D cell culture model to mimic the tumor microenvironment, it is shown that different patterns of copper ion release have a strong impact on GBM progression and invasiveness. The findings highlight the importance of optimizing localized copper release patterns to tailor different tumor treatment strategies. They also show the potential and suitability of 3D microchips as instruments to study the behavior of tumor spheroids. In spite of their limitations, these 3D microdevices enable a controlled and close monitoring of the influence of environmental factors (such as the presence of Cu ions) on the proliferation and invasiveness of the cells, with a better approach to reality compared to 2D models and with a more controlled environment, compared to an in vivo model.
Allometric shifts in foraging site selection and area increase energy intake for Yellowstone Cutthroat Trout but are constrained by functional limits to prey capture
Authors: Hallbert Tyson B. , Keeley Ernest R.
Published: August 2024

Objective

For foraging animals, energy acquisition is often influenced by an interaction of prey abundance and the amount of space needed to capture sufficient food. Suitable habitat includes those locations where prey capture rates are sufficient to meet energetic requirements for growth and reproduction. Hence, quantifying how space use changes with energy requirements and how prey densities affect prey capture rates in foraging animals provides insight into the mechanisms that create suitable habitat. Here, we were interested in assessing how body size influences foraging site selection, space use, and energy intake by Yellowstone Cutthroat Trout Oncorhynchus virginalis bouvieri. Furthermore, we sought to quantify how foraging rates changed with increasing levels of food.

Methods

We recorded Yellowstone Cutthroat Trout foraging behavior in natural streams and measured space use and foraging rates using three-dimensional videography.

Result

We found that physical habitat features, such as current velocity, water depth, and foraging distance, were positively correlated with fish body size, but when foraging area was compared to a model of space use, we found that Yellowstone Cutthroat Trout used less space to capture prey than the model predicted. Fish foraging rates and estimated energy intake also increased with increasing prey availability; however, trout captured prey according to a type II functional response, indicating an upper limit to prey capture from handling time constraints.

Conclusion

These data demonstrate that Yellowstone Cutthroat Trout display allometric changes in foraging habitat use: larger fish can occupy deeper and faster areas that increase prey encounter rates, but as prey encounter rates increase, the foraging rates become limited by an individual's ability to identify, pursue, and handle prey items.
Evaluation of the effect of sustained‐release progesterone injection on the expression of interferon‐related genes in repeat‐breeder dairy cows
Authors: Modaresi Jahangir , Kadivar Ali , Esfandabadi Naser Shams , Khosravian Pegah , Mohebbi Abdonnaser
Published: August 2024

Background

Repeat‐breeder cows repeatedly fail to conceive after at least three attempts and return to oestrus at apparently normal intervals. Repeat‐breeder cows cause economic losses in dairy farms in different ways.

Objective

In the present study, we investigated the effect of sustained‐release progesterone injection in two different doses on the expression of interferon‐related genes in repeat‐breeder dairy cows.

Methods

A total of 96 repeat‐breeder primiparous and multiparous cows were assigned among three groups: control group, inseminated and do not receive progesterone treatment; P400 and P600 groups, inseminated and received a single‐intramuscular injection of 400 and 600 mg slow‐release progesterone 5 days after insemination, respectively. Blood sampling was carried out on Day 20 after AI for progesterone measurement and evaluation of gene expression for ISG15, MX1 and MX2 genes.

Results

One injection of sustained‐release progesterone increased the expression of ISG15, MX1 and MX2 genes with differences between two different progesterone concentrations. For all three genes, the level of gene expression was higher in progesterone‐supplemented group than in control group, when P400 and P600 groups considered together. The level of MX2 gene expression was significantly higher in pregnant cows than non‐pregnant cows. There was a significant positive correlation between expression level of all three genes and blood progesterone concentration. The expression level of ISG15 gene showed a significant positive correlation with MX1 and MX2 gene expression.

Conclusion

The use of this sustained‐release progesterone is simple and can be used in repeat‐breeder cows to improve fertility.
Quantitative experimental study on the apparent contact angle of unsaturated loess and its application in soil–water characteristics curve modeling
Authors: Fu Yingpeng , Xu Ling , Liao Hongjian
Published: August 2024

Advancing and receding water contact angles, often denoted as the maximum and minimum apparent water contact angles, are crucial parameters reflecting a soil's water holding capacity. These parameters play an important role in establishing theoretical soil–water characteristic curves (SWCCs) for unsaturated soils. However, pre‐assuming constant advancing and receding contact angles during soil wetting and drying processes may be erroneous due to their close correlations with the water content and void ratio. To address this research gap, systematic laboratory measurements were conducted on a loess with different void ratios and water contents. Apparent water contact angles were acquired using an axisymmetric drop shape analyzer, enabling a comprehensive dataset. Analysis of variance was employed to assess the statistically significant differences between void ratios and water contents. The results reveal a significant increase in the observed water contact angle as the void ratio decreases and a decrease with increasing water content. Although both the void ratio and water content influence the water contact angle, the latter has a more pronounced effect. The relationship between the receding water contact angle and water content/void ratio is observed to be linear. The identification of this linear relationship offers insights into the fitting of the SWCC for loess across varying void ratios. This study serves to enhance theoretical methodologies, particularly in the adaptation of contact angles, thus facilitating the development of more precise SWCC models.
Bring digital twins back to Earth
Authors: Saltelli Andrea , Gigerenzer Gerd , Hulme Mike , Katsikopoulos Konstantinos V. , Melsen Lieke A. , Peters Glen P. , Pielke Roger , Robertson Simon , Stirling Andy , Tavoni Massimo , Puy Arnald
Published: August 2024

We reflect on the development of digital twins of the Earth, which we associate with a reductionist view of nature as a machine. The projects of digital twins deviate from contemporary scientific paradigms in the treatment of complexity and uncertainty, and does not engage with critical and interpretative social sciences. We contest the utility of digital twins for addressing climate change issues and discuss societal risks associated with the concept, including the twins' potential to reinforce economicism and governance by numbers, emphasizing concerns about democratic accountability. We propose a more balanced alternative, advocating for independent institutions to develop diverse models, prioritize communication with simple heuristic‐based models, collect comprehensive data from various sources, including traditional knowledge, and shift focus away from physics‐centered variables to inform climate action. We argue that the advancement of digital twins should hinge on stringent controls, favoring a nuanced, interdisciplinary, and democratic approach that prioritizes societal well‐being over blind pursuit of computational sophistication.

This article is categorized under:

Climate Models and Modeling > Earth System Models

Climate Models and Modeling > Knowledge Generation with Models

Climate, History, Society, Culture > Disciplinary Perspectives
Alterations of the AKT Pathway in Sporadic Human Tumors, Inherited Susceptibility to Cancer, and Overgrowth Syndromes
Authors: Menges Craig W. , Hassan Dalal , Cheung Mitchell , Bellacosa Alfonso , Testa Joseph R.
Published: August 2024

The AKT kinases are critical signaling molecules that regulate cellular physiology upon the activation of tyrosine kinase receptors and phosphatidylinositol 3-kinases (PI3K). AKT kinases govern many cellular processes considered hallmarks of cancer, including cell proliferation and survival, cell size, tumor invasion, metastasis, and angiogenesis. AKT signaling is regulated by multiple tumor suppressors and oncogenic proteins whose loss or activation, respectively, leads to dysregulation of this pathway, thereby contributing to oncogenesis. Herein, we review the enormous body of literature documenting how the AKT pathway becomes hyperactivated in sporadic human tumors and various hereditary cancer syndromes. We also discuss the role of activating mutations of AKT pathway genes in various chimeric overgrowth disorders, including Proteus syndrome, hypoglycemia with hypertrophy, CLOVES and SOLAMEN syndromes, and hemimegalencephaly.
The Dirty, Working-Class Problem
Authors: Brugge Doug , Datesman Aaron
Published: August 2024

Discussions of nuclear power frequently leave out consideration of the necessity of mining and processing uranium ore. When people claim nuclear power has not killed anyone, they ignore the proof of thousands of deaths of miners and the likely harm to health of nearby residents. A particularly disturbing aspect of uranium mining is that it often affects indigenous people disproportionately.
Protracted Exposures May Be Misunderstood
Authors: Brugge Doug , Datesman Aaron
Published: August 2024

The accepted “Linear No Threshold” model of risk from exposure to ionizing radiation is likely not suitable to describe protracted exposures at environmental dose rates. Assessments of the safety of operating nuclear power plants may not be valid as a result.
Introduction
Authors: Jolly Stellina , Ahmad Nafees , Scott Matthew
Published: August 2024

This edited volume brings together academics from Indonesia, Thailand, Sri Lanka, Vietnam, Bangladesh, Bhutan, India, the Solomon Islands, Papua New Guinea, Australia and the Philippines, to examine lived experiences of and actual as well as potential responses to the varieties of migration, displacement, planned relocation as well as voluntary and involuntary immobility (collectively termed human mobility) that take place in the context of disasters and climate change that increasingly impact the lives of people living across Asia and the Pacific. A product of the editorial collaboration between the South Asian University and the Raoul Wallenberg Institute for Human Rights and Humanitarian Law (RWI), the volume represents the collective efforts of members of the Asia Pacific Academic Network on Disaster Displacement. This academic network was formed in 2018 as part of a regional thematic study on human rights and disaster displacement.
BCFT One-point Functions of Coulomb Branch Operators
Authors: Bason Davide , Di Pietro Lorenzo , Valandro Roberto , van Muiden Jesse
Published: August 2024

Abstract

We show that supersymmetry can be used to compute the BCFT one-point function coefficients for chiral primary operators, in 4d $$ \mathcal{N} $$
N
= 2 SCFTs with $$ \frac{1}{2} $$

1
2

-BPS boundary conditions. The main ingredient is the hemisphere partition function, with the boundary condition on the equatorial S3. A supersymmetric Ward identity relates derivatives with respect to the chiral coupling constants to the insertion of the primaries at the pole of the hemisphere. Exact results for the one-point functions can be then obtained in terms of the localization matrix model. We discuss in detail the example of the super Maxwell theory in the bulk, interacting with 3d $$ \mathcal{N} $$
N
= 2 SCFTs on the boundary. In particular we derive the action of the SL(2,ℤ) duality on the one-point functions.
Discontinuous peripheral enhancement of focal liver lesions on CT and MRI: outside the box of typical cavernous hemangioma
Authors: Matteini Francesco , Cannella Roberto , Dioguardi Burgio Marco , Torrisi Chiara , Sartoris Riccardo , Brancatelli Giuseppe , Vilgrain Valérie , Ronot Maxime , Vernuccio Federica
Published: August 2024

The discontinuous peripheral enhancement is a pattern of enhancement usually attributed to typical cavernous hemangioma, that is the most common benign solid lesion of the liver. The discontinuous peripheral enhancement, however, may be encountered in many other benign and malignant focal liver lesions as an atypical presentation or evolution, and hemangiomas with discontinuous peripheral hyperenhancement on hepatic arterial phase may not always have the typical post-contrast pattern on portal venous and delayed phases. Therefore, abdominal radiologists may be challenged in their practice by lesions with discontinuous peripheral enhancement. This pictorial essay aims to review the spectrum of benign and malignant focal liver lesions that may show discontinuous peripheral enhancement. A particular point of interest is the diagnostic tree pathway that may guide the radiologists in the differential diagnosis.

Graphical abstract
Analysis and forecast of crop water demand in irrigation districts across the eastern part of the Ebro river basin (Catalonia, Spain): estimation of evapotranspiration through copernicus-based inputs
Authors: Bellvert Joaquim , Pamies-Sans Magí , Quintana-Seguí Pere , Casadesús Jaume
Published: August 2024

The agricultural sector is currently facing the uncertainty that accompanies climate change in terms of the availability of water resources, as well as the need to balance the water demand for agricultural irrigation with other uses in river basins. In Spain, irrigation districts (IDs) play a very important role in the management of water resources. The efficiency of ID water management involves finding an equilibrium between supply and demand. It is in relation to the latter where the uncertainty is greatest, because until now no tools have been available to characterize water demands with sufficient precision throughout irrigation campaigns. ID managers need precise information and the development of tools to support decision making in planning and water management. Therefore, this study aims to identify, compare and analyse the differences between the demands, allocations and consumptions of water for irrigation in different IDs of the eastern part of the Ebro basin during six consecutive growing seasons. In addition, projections of water demands up to 2100 are conducted using a dataset of six global climate models under different climate scenarios. Novel advances in remote sensing for evapotranspiration approaches using Copernicus-based inputs were used in this study. Large variabilities in water demands among IDs and in the adjustments between demands and allocations were observed, suggesting there is still much room for the improvement of water management. All climate projections have a very clear pattern indicating an upward trend in water demands until the end of the century.
High-intensity resistance training improves quality of life, muscle endurance and strength in patients with myositis: a randomised controlled trial
Authors: Jensen Kasper Yde , Aagaard Per , Suetta Charlotte , Nielsen Jakob Lindberg , Bech Rune Dueholm , Schrøder Henrik Daa , Christensen Jan , Simonsen Casper , Diederichsen Louise Pyndt
Published: August 2024

Myositis is associated with reduced quality of life, which is accompanied by significant impairments in muscle endurance and strength, altogether representing cardinal traits in patients with myositis. This randomised controlled trial aimed to investigate the effect of high-intensity resistance training on quality of life in patients with myositis. Thirty-two patients with established, stable myositis were randomised to 16 weeks of high-intensity resistance training (intervention group) or 16 weeks of usual care (control group). Primary outcome was quality of life assessed as the change in the physical component summary score (PCS) of the Short Form-36 health questionnaire from baseline to post-intervention. Secondary outcomes included functional capacity measures, such as functional index 3, and International Myositis Assessment and Clinical Studies Group (IMACS) disease activity and damage core set measures, including manual muscle testing 8 (MMT8). The primary outcome PCS showed an improvement in favour of high-intensity resistance training with a between-group difference of 5.33 (95% CI 0.61; 10.05) (p = 0.03). Additionally, functional index 3 showed a between-group difference indicating greater gains with high-intensity resistance training 11.49 (95% CI 3.37; 19.60) (p = 0.04), along with a between-group improvement in MMT8 1.30 (95% CI 0.09; 2.51) (p = 0.04). High-intensity resistance training for 16 weeks effectively improved quality of life in patients with myositis. Clinical measures of muscle endurance and muscle strength were also found to improve with high-intensity resistance training, while patients stayed in disease remission. Consequently, progressively adjusted high-intensity resistance training is feasible and causes no aggravation of the disease, while benefitting patients with myositis.

Clinical trial registration: Clinicaltrials.gov ID: NCT04486261—https://clinicaltrials.gov/study/NCT04486261.
Predictive markers for head and neck cancer treatment response: T1rho imaging in nasopharyngeal carcinoma
Authors: Ai Qi Yong H. , King Ann D. , Tsang Yip Man , Yu Ziqiang , Mao Kaijing , Mo Frankie K. F. , Wong Lun M. , Leung Ho Sang , So Tiffany Y. , Hui Edwin P. , Ma Brigette B. Y. , Chen Weitian
Published: August 2024

Objectives

To investigate the potential of T1rho, a new quantitative imaging sequence for cancer, for pre and early intra-treatment prediction of treatment response in nasopharyngeal carcinoma (NPC) and compare the results with those of diffusion-weighted imaging (DWI).

Materials and methods

T1rho and DWI imaging of primary NPCs were performed pre- and early intra-treatment in 41 prospectively recruited patients. The mean preT1rho, preADC, intraT1rho, intraADC, and % changes in T1rho (ΔT1rho%) and ADC (ΔADC%) were compared between residual and non-residual groups based on biopsy in all patients after chemoradiotherapy (CRT) with (n = 29) or without (n = 12) induction chemotherapy (IC), and between responders and non-responders to IC in the subgroup who received IC, using Mann–Whitney U-test. A p-value of < 0.05 indicated statistical significance.

Results

Significant early intra-treatment changes in mean T1rho (p = 0.049) and mean ADC (p < 0.01) were detected (using paired t-test), most showing a decrease in T1rho (63.4%) and an increase in ADC (95.1%). Responders to IC (n = 17), compared to non-responders (n = 12), showed higher preT1rho (64.0 ms vs 66.5 ms) and a greater decrease in ΔT1rho% (− 7.5% vs 1.3%) (p < 0.05). The non-residual group after CRT (n = 35), compared to the residual group (n = 6), showed higher intraADC (0.96 vs 1.09 × 10−3 mm2/s) and greater increase in ΔADC% (11.7% vs 27.0%) (p = 0.02).

Conclusion

Early intra-treatment changes are detectable on T1rho and show potential to predict tumour shrinkage after IC. T1rho may be complementary to DWI, which, unlike T1rho, did not predict response to IC but did predict non-residual disease after CRT.

Clinical relevance statement

T1rho has the potential to complement DWI in the prediction of treatment response. Unlike DWI, it predicted shrinkage of the primary NPC after IC but not residual disease after CRT.

Key Points

Changes in T1rho were detected early during cancer treatment for NPC.

Pre-treatment and early intra-treatment change in T1rho predicted response to IC, but not residual disease after CRT.

T1rho can be used to complement DWI with DWI predicting residual disease after CRT.
Comparative analysis of femoral bone loss: uncemented vs. cemented aseptic stem loosening in first-time revision surgery—a retrospective evaluation of 215 patients
Authors: Wagener Nele , Hardt Sebastian , Pumberger Matthias , Schömig Friederike
Published: August 2024

Introduction

The integrity of the femoral bone is crucial when considering reconstructive options for the first-time revision of a total hip arthroplasty (THA). Aseptic loosening of primary stems, whether cemented or uncemented, significantly affects the volume and quality of resultant femoral bone loss. This study evaluates the impact of the initial fixation method on femoral bone defect patterns by comparing the extent of bone loss.

Materials and methods

A retrospective cohort of 215 patients with either cemented or uncemented stems, indicated for aseptic stem loosening, and undergoing first-time stem revision from 2010 to 2022 at our institution was analyzed. Femoral bone loss extent at first-time revision was preoperatively gauged using radiographs and categorized by the Paprosky classification. Survival probabilities pre-first-time revision for both stem types were calculated using Kaplan–Meier methods. Hazard ratios were applied to compare the risk of initial revision for uncemented versus cemented stems within the first and subsequent 2nd to 10th years post-primary implantation.

Results

Cemented stems were associated with a higher occurrence of significant bone defects of type 3a (23.53% vs. 14.02%, p = .108), 3b (39.22% vs. 1.22%, p < .001), and 4 (3.92% vs. 0.00%) compared to uncemented stems. Conversely, smaller defects of type 1 and 2 were more prevalent in uncemented stem loosening (84.76% vs. 33.33%, p < .001). Notably, cemented stems exhibited a significantly prolonged revision-free period over the complete decade following primary insertion (p < .001). The unadjusted risk of first-time revision due to stem loosening showed a tendency to an increase in uncemented stems within the initial postoperative year (HR 5.55, 95% CI 0.74; 41.67, p = .096), and an adjusted risk of 2.1 (95% CI 0.26; 16.53, p = .488). However, these differences did not reach statistical significance. In the subsequent 2nd-10th years, the risk was lower compared to cemented stems (HR 2.35, 95% CI 1.39; 3.99, p = .002).

Conclusions

Uncemented primary stems necessitating first-time revision due to aseptic loosening demonstrated notably smaller femoral bone defects in comparison to primary cemented stems.
Clinical forensic medicine in emergency departments: a pilot study of a forensic training and evaluation of its effectiveness in an Italian hospital
Authors: Tambuzzi Stefano , Rossi Cecilia , Pavanello Donatella , Primavera Riccardo , Costantino Giorgio , Cattaneo Cristina
Published: August 2024

Because emergency departments are often the first point of contact for victims of violence, it is critical to provide the appropriate treatment in compliance with all necessary medicolegal precautions. For this reason, a randomized controlled trial was conducted at the Policlinico Hospital of Milan (Italy) in which an intervention group (12 physicians) received a 6-h course on clinical forensic medicine and their performance in medicolegal procedures in claimed cases of violence was compared with that of a control group (13 physicians) by means of a 16-item assessment scale over the 3 months before and the 3 months after the course. Overall, 195 medical records were included in the statistical analysis. Out of these cases, 105 occurred before the course (60 analyzed by the control group and 45 by the intervention group) and 90 occurred after the course (45 analyzed by the control group and 45 by the intervention group). The results showed that the overall mean score of physicians who participated to the course increased from 14.0 (IQR 7.0) to 19.0 (IQR 8.0) with a p-value < 0.0001 and that the comparison between the intervention group and the control group after the course was 19.0 (IQR = 8.0) and 14.0 (IQR = 7.0), respectively, with a p-value < 0.0001. The improvement was very little and below the expectations pointing out that educational courses, although they can be a first step towards raising the ED physicians’ awareness of clinical forensics, may not be enough and that more structured training and new strategies should be implemented.
Active and non-active secondary progressive multiple sclerosis patients exhibit similar disability progression: results of an Italian MS registry study (ASPERA)
Authors: Chisari Clara Grazia , Amato Maria Pia , Di Sapio Alessia , Foschi Matteo , Iaffaldano Pietro , Inglese Matilde , Fermo Salvatore Lo , Lugaresi Alessandra , Lus Giacomo , Mascoli Nerina , Montepietra Sara , Pesci Ilaria , Quatrale Rocco , Salemi Giuseppe , Torri Clerici Valentina , Totaro Rocco , Valentino Paola , Filippi Massimo , Patti Francesco
Published: August 2024

‘Active’ and ‘non-active’ secondary progressive MS (SPMS) have distinct pathophysiological mechanisms and clinical characteristics, but there is still no consensus regarding the frequency of these MS forms in the real-world setting. We aimed to evaluate the frequency of ‘active’ and ‘non-active’ SPMS in a large cohort of Italian MS patients and the differences in terms of clinical and MRI characteristics and disease progression. This multicenter study collected data about MS patients who have transitioned to the SP form in the period between 1st January 2014 and 31st December 2019 and followed by the MS centers contributing to the Italian MS Registry. Patients were divided into ‘active SPMS’ and ‘non-active SPMS’, based on both reported MRI data and relapse activity in the year before conversion to SPMS. Out of 68,621, 8,316 (12.1%) patients were diagnosed with SPMS. Out of them, 872 (10.5%) were classified into patients with either ‘active’ or ‘non-active’ SPMS. A total of 237 were classified into patients with ‘active SPMS’ (27.2%) and 635 as ‘non-active SPMS’ (72.8%). ‘Non-active SPMS’ patients were older, with a longer disease duration compared to those with ‘active SPMS’. The percentages of patients showing progression independent of relapse activity (PIRA) at 24 months were similar between ‘active’ and ‘non-active’ SPMS patients (67 [27.4%] vs 188 [29.6%]; p = 0.60). In the ‘active’ group, 36 (15.2%) patients showed relapse-associated worsening (RAW). Comparison of the survival curves to EDSS 6 and 7 according to disease activity did not show significant differences (p = 0.68 and p = 0.71). ‘Active’ and ‘non-active’ SPMS patients had a similar risk of achieving disability milestones, suggesting that progression is primarily attributed to PIRA and only to a small extent to disease activity.
Solving Mathematical Programs with Complementarity Constraints Arising in Nonsmooth Optimal Control
Authors: Nurkanović Armin , Pozharskiy Anton , Diehl Moritz
Published: August 2024

This paper examines solution methods for mathematical programs with complementarity constraints (MPCC) obtained from the time-discretization of optimal control problems (OCPs) subject to nonsmooth dynamical systems. The MPCC theory and stationarity concepts are reviewed and summarized. The focus is on relaxation-based methods for MPCCs, which solve a (finite) sequence of more regular nonlinear programs (NLP), where a regularization/homotopy parameter is driven to zero. Such methods perform reasonably well on currently available benchmarks. However, these results do not always generalize to MPCCs obtained from nonsmooth OCPs. To provide a more complete picture, this paper introduces a novel benchmark collection of such problems, which we call . The problem set includes 603 different MPCCs and we split it into a few representative subsets to accelerate the testing. We compare different relaxation-based methods, NLP solvers, homotopy parameter update and relaxation parameter steering strategies. Moreover, we check whether the obtained stationary points allow first-order descent directions, which may be the case for some of the weaker MPCC stationarity concepts. In the best case, the Scholtes’ relaxation (SIAM J. Optim. 11, 918–936, 2001) with  (Math. Program. 106, 25–57, 2006) as NLP solver manages to solve 73.8% of the problems. This highlights the need for further improvements in algorithms and software for MPCCs.
From the latin “re-cordis, passing through the heart”: autonomic modulation differentiates migraineurs from controls when recounting a significant life event
Authors: Guidotti Sara , Torelli Paola , Ambiveri Giordano , Fiduccia Alice , Castaldo Matteo , Pruneti Carlo
Published: August 2024

Objective

The literature on clinical psychophysiology highlights the possibility of using Heart Rate Variability (HRV) as an index of psychophysical balance and resilience to stress. This study investigates the differences in stress reactivity and subsequent recovery between a group of migraineurs and healthy controls.

Methods

Socio-demographic (i.e., sex, age, profession, marital status, and level of education) and psychophysiological (HR and HRV) measures of a group of thirty subjects with migraine (26 migraineurs without aura (86.7%), 2 migraineurs with aura (6.7%), and 2 migraineurs with and without aura (6.7%)) and from thirty healthy control subjects were collected. In particular, HRV was analyzed through frequency-domain parameters, including Low-Frequency (LF; 0.04–0.15 Hz) and High-Frequency (HF; 0.15–0.4 Hz) bands as well as LF/HF ratio during a Psychophysiological Stress Profile (PSP) structured in seven phases: (1) Baseline, (2) Objective stressor 1 (Stroop Test), (3) Rest 1, (4) Objective stressor 2 (Mental Arithmetic Task), (5) Rest 2, (6) Subjective stressor (recount a significant life event), and (7) Rest 3. The LF, HF, and LF/HF ratio values were transformed into a logarithmic scale (i.e., log-LF, log-HF, and log LF/HF ratio). Additionally, LF and HF were converted into normalized units (0-100) (i.e., LF% and HF%) which, in turn, were used to obtain reactivity and recovery to stress through delta values (Δ) calculation.

Results

Subjects with migraine reported greater ΔLF% levels of reactivity and recovery to subjective stressor, demonstrating a prevalence of sympathetic activity while recounting a personal life event. At the same time, a lowering of the same values was found in the subjects of the group control.

Discussion

Our results underline the importance of conducting a psychophysiological assessment in patients with headaches because reduced stress management skills could influence the clinical manifestations of the disease, considering stress as one of the most common triggers for migraine patients.
A phase 2 study of mobocertinib as first-line treatment in Japanese patients with non-small cell lung cancer harboring EGFR exon 20 insertion mutations
Authors: Yoh Kiyotaka , Azuma Koichi , Hayashi Hidetoshi , Nishio Makoto , Chikamori Kenichi , Ichihara Eiki , Watanabe Yasutaka , Asato Takayuki , Kitagawa Tadayuki , Fram Robert J. , Ohe Yuichiro
Published: August 2024

Background

Mobocertinib is a novel, synthetic, orally administered tyrosine kinase inhibitor that inhibits many activated forms of epidermal growth factor receptor (EGFR), including those containing exon 20 insertion (ex20ins) mutations. This study aimed to assess the efficacy of mobocertinib in Japanese patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring EGFR ex20ins mutations.

Methods

This was a phase 2, open-label study. Patients with NSCLC harboring EGFR ex20ins mutations who had not had previous systemic treatment received mobocertinib 160 mg once daily. The primary endpoint was the confirmed objective response rate. A planned interim analysis was completed for the first 14 patients with a centrally confirmed EGFR ex20ins mutation, with enrollment stopped if the number of patients with an objective response was five or fewer.

Results

In total, 33 patients were enrolled into the study (63.6% women; median age: 66 years). At the interim analysis, the objective response rate evaluated by a central independent review committee was 28.6% (4/14, 90% confidence interval: 10.4–54.0); therefore, enrollment was stopped for futility. In the full analysis set, the objective response rate was 18.2% (6/33, 95% confidence interval: 7.0–35.5); of the six responders, one patient (3.0%) had a complete response and five patients (15.2%) had partial responses. The most common treatment-related adverse events were diarrhea, paronychia, stomatitis, and nausea.

Conclusion

Although study enrollment was terminated early owing to futility, our results showed modest activity of mobocertinib in Japanese patients with NSCLC with EGFR ex20ins mutations with no additional safety concerns.
Cost effectiveness of a GP delivered medication review to reduce polypharmacy and potentially inappropriate prescribing in older patients with multimorbidity in Irish primary care: the SPPiRE cluster randomised controlled trial
Authors: Gillespie Paddy , Moriarty Frank , Smith Susan M. , Hobbins Anna , Walsh Sharon , Clyne Barbara , Boland Fiona , McEnteggart Tara , Flood Michelle , Wallace Emma , McCarthy Caroline ,   for the SPPiRE Study team
Published: August 2024

Background

Evidence on the cost effectiveness of deprescribing in multimorbidity is limited.

Objective

To investigate the cost effectiveness of a general practitioner (GP) delivered, individualised medication review to reduce polypharmacy and potentially inappropriate prescribing in older patients with multimorbidity in Irish primary care.

Methods

Within trial economic evaluation, from a healthcare perspective and based on a cluster randomised controlled trial with a 6 month follow up and 403 patients (208 Intervention and 195 Control) recruited between April 2017 and December 2019. Intervention GPs used the SPPiRE website which contained educational materials and a template to support a web-based individualised medication review. Control GPs delivered usual care. Incremental costs, quality adjusted life years (QALYs) generated using the EQ-5D-5L instrument, and expected cost effectiveness were estimated using multilevel modelling and multiple imputation techniques. Uncertainty was explored using parametric, deterministic and probabilistic methods.

Results

On average, the SPPiRE intervention was dominant over usual care, with non-statistically significant mean cost savings of €410 (95% confidence interval (CI): − 2211, 1409) and mean health gains of 0.014 QALYs (95% CI − 0.011, 0.039). At cost effectiveness threshold values of €20,000 and €45,000 per QALY, the probability of SPPiRE being cost effective was 0.993 and 0.988. Results were sensitive to missing data and data collection period.

Conclusions

The study observed a pattern towards dominance for the SPPiRE intervention, with high expected cost effectiveness. Notably, observed differences in costs and outcomes were consistent with chance, and missing data and related uncertainty was non trivial. The cost effectiveness evidence may be considered promising but equivocal.

Trial registration

ISRCTN: 12752680, 20th October 2016.