bluuebunny/crossref_metadata_2025 huggingface dataset:
Foundational artificial intelligence models and modern medical practice
Authors: Medetalibeyoglu Alpay , Velichko Yury S , Hart Eric M , Bagci Ulas
Published: December 2024

Our opinion piece pays homage to the evolution of medical practices, tracing back to the era of Hippocrates, through significant historical milestones, and drawing parallels with the principles underpinning foundational artificial intelligence (AI) models. It emphasizes the shared ethos of both domains: a commitment to comprehensive care that values diverse data integration and individualized patient treatment. The excitement surrounding foundation models in medical imaging is understandable. However, a critical and cautious approach is crucial before widespread adoption. By addressing the present 4 major limitations (ie, data bias and generalizability, interpretability of AI models, data scarcity and diversity, and computational resources and infrastructure) and fostering a culture of rigorous research, we can unlock the true potential of these models and revolutionize medical care. This critique (opinion) paper highlights the need for a more measured approach in the field of foundation AI models for medicine in general and for medical imaging in particular. It emphasizes the importance of tackling core challenges before rushing toward clinical applications. By focusing on robust methodologies and addressing limitations, researchers can ensure the development of truly impactful and trustworthy models for the betterment of healthcare.
Definition of a disability weight for human exposure to ionizing radiation and its application to the justification of medical exposure
Authors: Kotre Colin John
Published: December 2024

Objectives

To establish a link between radiation dosimetry and disability-adjusted life-years (DALY) with the aim of quantifying the justification of medical exposures.

Methods

The health detriment, defined as lifetime loss of DALY at age of exposure to ionizing radiation for a US-European population was calculated. A simple model of the relationship was fitted to the results. Apart from in late life within the latency period for radiation-induced cancers, most of the relationship can be adequately fitted to a straight line of negative gradient. The gradient of this line corresponds to a loss of DALY per year following exposure to radiation and is therefore equivalent to a disability weight (DW) used in the calculation of DALY.

Results

Radiation dose-dependent DWs for radiation exposure to a US-European population are estimated as 0.020 DALY/yr/Sv for males and 0.022 DALY/yr/Sv for females.

Conclusions

By comparing a range of 66 radiological examinations in terms of the DWs of the disease or injury states with the DWs resulting from the associated radiological exposures, it is demonstrated graphically that the resulting benefit is far greater than the detriment in every case.

Advances in knowledge

The definition of a DW for ionizing radiation, proportional to effective dose as currently defined, can link radiation exposure to the existing large body of data on the DALY burden and DWs for a wide range of diseases and injuries, providing a means for the quantitative justification of the benefit-detriment balance of medical exposures.
The challenge of scaling-up social work innovations: A case study of Shared Lives schemes in England
Authors: Purcell Carl , Manthorpe Jill , Malley Juliette
Published: December 2024

Innovation is routinely presented as a response to pressure on public services. This article considers the development of Shared Lives (SL) schemes in English adult social care (ASC), a model of care that has been consistently promoted as innovative. SL seeks to replicate ‘ordinary family life’ for adults who need support. Evidence of positive outcomes for people supported, and of cost-effectiveness compared to other models, has attracted the attention of national policymakers and local authority (LA) ASC leaders. Most LAs now operate or commission a SL scheme. Despite this wide ‘spread’, SL remains a very small model that has not yet been ‘scaled-up’ to the extent that many have hoped. Drawing on interviews with fifty people involved in SL, including from four contrasting local schemes in 2021–2023, we highlight four interconnected sets of ‘organisational capabilities’ and resources needed for schemes to grow: (1) collaborative working with social workers; (2) leadership at different levels; (3) mechanisms to harness knowledge and evidence; and (4) investment in the workforce of scheme staff and carers. We propose these factors help schemes become locally embedded in communities. However, our study also highlights the fragility of the model to socio-economic changes and social work practice imperatives.
Global prevalence of mental health comorbidity in patients with acne: an analysis of trends from 1961 to 2023
Authors: Chen Yiran , Sun Suting , Yang Han , Fei Xiaoya , Zhang Ying , Song Jiankun , Ru Yi , Zhao Hang , Luo Ying , Kuai Le , Luo Yue , Li Bin , Xie Mengji , Fan Bin , Ding Xiaojie
Published: December 2024

Background

Patients with acne increasingly face mental health challenges such as anxiety, depression and suicidal thoughts. However, no global systematic analysis exists on this topic.

Objectives

To examine the prevalence of mental disorders – specifically, anxiety, depression and suicidal thoughts – among patients with acne.

Methods

An exhaustive search of six databases was conducted up to May 2023. Data analysis was performed using Python and Stata MP 17, including subgroup evaluations, metaregression and sensitivity analyses.

Results

Forty-three studies were analysed. The findings indicate that depression, anxiety and suicidal thoughts in patients with acne are prevalent at rates of 22%, 29% and 12%, respectively. Rates of depression were highest in Asia at 42%, led by India (53%) and Saudi Arabia (51%). Anxiety was also most common in Asia, at 45%, notably in Singapore (60%) and Iran (58%). Suicidal thoughts were highest in Oceania, specifically New Zealand at 24%. The study is limited by the inclusion of only Chinese- and English-language research, potentially introducing selection bias.

Conclusions

The results of this study highlight the incidence of mental health disorders coexisting with acne. This study may help to foster greater understanding and awareness among both medical professionals and patients regarding the psychological complexities tied to acne.
Bridging the Gap: Unveiling the Potential of Tanzania’s SMEs through VAT Insights
Authors: Ebrahim Amina , Castillo Sebastián , Leyaro Vincent , Swema Ezekiel , Haule Oswald
Published: December 2024

The collection of value added tax (VAT) is essential for achieving domestic revenue objectives, yet VAT gap estimation is rarely performed in developing countries. This study utilizes innovative tax declaration and audit data to estimate VAT misreporting in Tanzania, applying a machine learning approach to predict evasion in unaudited firms and periods. We measure the underreporting component of the compliance gap, quantifying potential revenue losses due to inaccurate reporting. Our findings indicate that firms often avoid excessive audits, leading to increased evasion, with those firms showing the largest VAT gaps. We estimate a 62% VAT gap among small and medium-sized enterprises in Tanzania. Finally, we present a cost-benefit ratio, suggesting that while auditing sectors with large VAT gaps is cost-effective, those contributing significantly to the overall VAT gap should also be prioritized for revenue generation. (JEL codes: H25, H26, and H32)
Diagnostic Accuracy of Chest X-ray Computer-Aided Detection Software for Detection of Prevalent and Incident Tuberculosis in Household Contacts
Authors: Macpherson Liana , Kik Sandra V , Quartagno Matteo , Lakay Francisco , Jaftha Marche , Yende Nombuso , Galant Shireen , Aziz Saalikha , Daroowala Remy , Court Richard , Taliep Arshad , Serole Keboile , Goliath Rene T , Davies Nashreen Omar , Jackson Amanda , Douglass Emily , Sossen Bianca , Mukasa Sandra , Thienemann Friedrich , Song Taeksun , Ruhwald Morten , Wilkinson Robert J , Coussens Anna K , Esmail Hanif ,   Imaging of TB Household Contacts Group, Barry Clifton E , Ellner Jerrold J , Flynn JoAnne L , Heinsohn Torben , Horsburgh C Robert , Jacobson Karen R , Malherbe Stephanus T , Salgame Padmini , Sheerin Dylan , Streicher Elizabeth , Tlala Mpho , Via Laura E , Walzl Gerhard , Warren Robin , Warwick James
Published: December 2024

Background

World Health Organization (WHO) tuberculosis (TB) screening guidelines recommend computer-aided detection (CAD) software for chest radiograph (CXR) interpretation. However, studies evaluating their diagnostic and prognostic accuracy are limited.

Methods

We conducted a prospective cohort study of household contacts of rifampicin-resistant TB in South Africa. Participants underwent baseline CXR and sputum investigation (routine [single spontaneous] and enhanced [additionally 2–3 induced]) for prevalent TB and follow-up for incident TB. Three CXR-CAD software products (CAD4TBv7.0, qXRv3.0.0, and Lunit INSIGHT v3.1.4.111) were compared. We evaluated their performance to detect routine and enhanced prevalent and incident TB, comparing performance with blood tests (Xpert MTB host-response, erythrocyte sedimentation rate, C-reactive protein, QuantiFERON) in a subgroup.

Results

483 participants were followed up for 4.6 years (median). There were 23 prevalent (7 routinely diagnosed) and 38 incident TB cases. The AUC ROCs (95% CIs) to identify prevalent TB for CAD4TBv7.0, qXRv3.0.0, and Lunit INSIGHT v3.1.4.111 were .87 (.77–.96), .88 (.79–.97), and .91 (.83–.99), respectively. More than 30% with scores above recommended CAD thresholds who were bacteriologically negative on routine baseline sputum were subsequently diagnosed by enhanced sputum investigation or during follow-up. The AUC performance of baseline CAD to identify incident cases ranged between .60 and .65. Diagnostic performance of CAD for prevalent TB was superior to blood testing.

Conclusions

Our findings suggest that the potential of CAD-CXR screening for TB is not maximized as a high proportion of those above current thresholds, but with a negative routine confirmatory sputum, have true TB disease that may benefit intervention.
Management, Outcomes, and Predictors of Mortality of Cryptococcus Infection in Patients Without Human Immunodeficiency Virus: A Multicenter Study in 46 Hospitals in Australia and New Zealand
Authors: Coussement Julien , Heath Christopher H , Roberts Matthew B , Lane Rebekah J , Spelman Tim , Smibert Olivia C , Longhitano Anthony , Morrissey C Orla , Nield Blake , Tripathy Monica , Davis Joshua S , Kennedy Karina J , Lynar Sarah A , Crawford Lucy C , Crawford Simeon J , Smith Benjamin J , Gador-Whyte Andrew P , Haywood Rose , Mahony Andrew A , Howard Julia C , Walls Genevieve B , O’Kane Gabrielle M , Broom Matthew T , Keighley Caitlin L , Bupha-Intr Olivia , Cooley Louise , O’Hern Jennifer A , Jackson Justin D , Morris Arthur J , Bartolo Caroline , Tramontana Adrian R , Grimwade Katherine C , Au Yeung Victor , Chean Roy , Woolnough Emily , Teh Benjamin W , Slavin Monica A , Chen Sharon C A ,   the Australian and New Zealand Study Group for Cryptococcosis in Patients Without HIV Infection, Alcorn Kylie , Beardsley Justin , Bloch Aaron , Crowe Amy , Doyle Wendy , England Michelle , Griffin David , Hamilton Kate , Korman Tony M , Madigan Victoria , McGann Hugh , Pratt William , Sparham Sarah , Van Hal Sebastiaan , Waters Prue , Williams Eloise
Published: December 2024

Background

Limited data exist regarding outcomes of cryptococcosis in patients without human immunodeficiency virus (HIV), and few studies have compared outcomes of Cryptococcus gattii versus Cryptococcus neoformans infection.

Methods

We conducted a retrospective study in 46 Australian and New Zealand hospitals to determine the outcomes of cryptococcosis in patients without HIV diagnosed between 2015 and 2019 and compared outcomes of C. gattii versus C. neoformans infections. Multivariable analysis identified predictors of mortality within 1 year.

Results

Of 426 patients, 1-year all-cause mortality was 21%. Cryptococcus gattii infection was associated with lower mortality than C. neoformans (adjusted odds ratio [OR], 0.47; 95% confidence interval [CI], .23–.95), while severe neurological symptoms at presentation were the strongest predictor of death (adjusted OR, 8.46; 95% CI, 2.99–23.98). Almost all (99.5%) patients with central nervous system (CNS) infection received induction antifungal therapy versus 27.7% with isolated pulmonary cryptococcosis. The most common regimen in CNS disease was liposomal amphotericin B with flucytosine (93.8%; mean duration, 31 ± 13 days). Among patients with CNS cryptococcosis, C. gattii infection was associated with higher risk of immune reconstitution inflammatory response (C-IRIS) than C. neoformans (21% versus 3%, P < .001). Nineteen patients received amphotericin B-based re-induction therapy for suspected relapse, but none had microbiological relapse. Serum cryptococcal antigen positivity and lung imaging abnormalities resolved slowly (resolution at 1 year in 25% and 34% of patients, respectively).

Conclusions

Compared with C. neoformans, C. gattii infection demonstrated lower mortality but higher C-IRIS risk in CNS infection. Severe neurological symptoms were the strongest predictor of mortality.
Meis transcription factors regulate cardiac conduction system development and adult function
Authors: Muñoz-Martín Noelia , Simon-Chica Ana , Díaz-Díaz Covadonga , Cadenas Vanessa , Temiño Susana , Esteban Isaac , Ludwig Andreas , Schormair Barbara , Winkelmann Juliane , Olejnickova Veronika , Sedmera David , Filgueiras-Rama David , Torres Miguel
Published: December 2024

Aims

The cardiac conduction system (CCS) is progressively specified during development by interactions among a discrete number of transcription factors (TFs) that ensure its proper patterning and the emergence of its functional properties. Meis genes encode homeodomain TFs with multiple roles in mammalian development. In humans, Meis genes associate with congenital cardiac malformations and alterations of cardiac electrical activity; however, the basis for these alterations has not been established. Here, we studied the role of Meis TFs in cardiomyocyte development and function during mouse development and adult life.

Methods and results

We studied Meis1 and Meis2 conditional deletion mouse models that allowed cardiomyocyte-specific elimination of Meis function during development and inducible elimination of Meis function in cardiomyocytes of the adult CCS. We studied cardiac anatomy, contractility, and conduction. We report that Meis factors are global regulators of cardiac conduction, with a predominant role in the CCS. While constitutive Meis deletion in cardiomyocytes led to congenital malformations of the arterial pole and atria, as well as defects in ventricular conduction, Meis elimination in cardiomyocytes of the adult CCS produced sinus node dysfunction and delayed atrio-ventricular conduction. Molecular analyses unravelled Meis-controlled molecular pathways associated with these defects. Finally, we studied in transgenic mice the activity of a Meis1 human enhancer related to an single-nucleotide polymorphism (SNP) associated by Genome-wide association studies (GWAS) to PR (P and R waves of the electrocardiogram) elongation and found that the transgene drives expression in components of the atrio-ventricular conduction system.

Conclusion

Our study identifies Meis TFs as essential regulators of the establishment of cardiac conduction function during development and its maintenance during adult life. In addition, we generated animal models and identified molecular alterations that will ease the study of Meis-associated conduction defects and congenital malformations in humans.
Transjugular transcatheter edge-to-edge mitral valve repair in a patient with functional mitral regurgitation: a case report
Authors: Enta Yusuke , Munehisa Yoshiko , Satomi Natsuko , Hayatsu Yukihiro , Tada Norio
Published: December 2024

Background

Transcatheter edge-to-edge mitral valve repair (M-TEER) using the MitraClip system is primarily performed using the transfemoral approach. However, when this approach is not feasible, the transjugular approach can be used as an alternative.

Case summary

A 57-year-old man presented with heart failure and persistent New York Heart Association class IV symptoms, refractory to guideline-directed medical therapy, intravenous therapy, and intra-aortic balloon pumping. His medical history included pulmonary embolism secondary to deep vein thrombosis, which occluded the inferior vena cava (IVC). Transthoracic echocardiography (TTE) revealed severe functional mitral regurgitation (FMR). The IVC occlusion made the transfemoral approach impossible; hence, transjugular M-TEER was planned. Transseptal puncture was performed via the right internal jugular (RIJ), 32 mm above the mitral annulus. A Confida wire was positioned in the left ventricle, and a steerable guiding catheter was introduced with 180° clockwise rotation of the +knob for septal crossing through the stiff wire. The MitraClip XTW was inserted into the catheter with a 90° counterclockwise rotation. After adjusting to a straddle position to move the clip laterally, additional knob rotations were performed to position the clip at A2/P2. Once the clip was placed, only trivial mitral regurgitation (MR) remained. No complications occurred, and the patient improved, allowing discharge. Transthoracic echocardiography at 1-year post-procedure demonstrated sustained MR reduction.

Discussion

We have described the successful completion of M-TEER using the RIJ approach in a patient with severe FMR. Technical considerations in M-TEER require special attention because of limited reports on the M-TEER procedure via the RIJ.
Comparative cardiovascular effectiveness of glucagon-like peptide-1 receptor agonists and sodium–glucose cotransporter-2 inhibitors in atherosclerotic cardiovascular disease phenotypes: a systematic review and meta-analysis
Authors: Lin Yu-Min , Wu Jheng-Yan , Lee Mei-Chuan , Su Chen-Lun , Toh Han Siong , Chang Wei-Ting , Chen Sih-Yao , Kuo Fang-Hsiu , Tang Hsin-Ju , Liao Chia-Te
Published: December 2024

Background

Atherosclerotic cardiovascular disease (ASCVD) encompasses various phenotypes with elevated risks of major adverse cardiovascular events (MACEs). This study aimed to assess the comparative cardiovascular effectiveness of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium–glucose cotransporter-2 inhibitors (SGLT2is) across diverse ASCVD phenotypes.

Methods and results

We conducted a systematic review and meta-analysis of randomized controlled trials evaluating GLP-1 RAs or SGLT2is against placebo or standard care in ASCVD patients. Primary outcomes included MACE, defined as cardiovascular mortality, non-fatal myocardial infarction, and non-fatal stroke. Risk ratios (RRs) with 95% confidence interval (CI) were calculated using a random-effects model.

Twenty-six trials (151 789 patients) were included. Both GLP-1 RAs and SGLT2is significantly reduced MACE rates in ASCVD patients (RR 0.85; 95% CI 0.80–0.91 for both). GLP-1 RAs showed significant effectiveness in peripheral artery disease (RR 0.86; 95% CI 0.76–0.98) and post-acute cardiovascular events (RR 0.90; 95% CI 0.83–0.97). In ASCVD with heart failure, both drug classes reduced MACE (GLP-1 RAs: RR 0.73; 95% CI 0.63–0.84; SGLT2is: RR 0.86; 95% CI 0.78–0.95). SGLT2is significantly reduced MACE in ASCVD with chronic kidney disease (RR 0.84; 95% CI 0.72–0.99), particularly in severe albuminuria (RR 0.61; 95% CI 0.37–0.99).

Conclusion

GLP-1 RAs and SGLT2is exhibit distinct cardiovascular effectiveness profiles across ASCVD phenotypes. GLP-1 RAs show particular benefits in peripheral artery disease and post-acute cardiovascular events, while SGLT2is demonstrate unique advantages in ASCVD with comorbid chronic kidney disease. Both are effective in heart failure. These findings support tailored treatment strategies for diverse ASCVD participants based on specific comorbidities and risk factors.
Deep learning model to diagnose cardiac amyloidosis from haematoxylin/eosin-stained myocardial tissue
Authors: Tohyama Takeshi , Iwasaki Takeshi , Ikeda Masataka , Katsuki Masato , Watanabe Tatsuya , Misumi Kayo , Shinohara Keisuke , Fujino Takeo , Hashimoto Toru , Matsushima Shouji , Ide Tomomi , Kishimoto Junji , Todaka Koji , Oda Yoshinao , Abe Kohtaro
Published: December 2024

Aims

Amyloid deposition in myocardial tissue is a definitive feature for diagnosing cardiac amyloidosis, though less invasive imaging modalities such as bone tracer cardiac scintigraphy and cardiac magnetic resonance imaging have been established as first steps for its diagnosis. This study aimed to develop a deep learning model to support the diagnosis of cardiac amyloidosis from haematoxylin/eosin (HE)-stained myocardial tissue.

Methods and results

This single-centre retrospective observational study enrolled 166 patients who underwent myocardial biopsies between 2008 and 2022, including 76 patients diagnosed with cardiac amyloidosis and 90 with other diagnoses. A deep learning model was developed to output the probabilities of cardiac amyloidosis for all the small patches cutout from each myocardial specimen. The developed model highlighted the area in the stained images as highly suspicious, corresponding to where Dylon staining marked amyloid deposition, and discriminated the patches in the evaluation dataset with an area under the curve of 0.965. Provided that the diagnostic criterion for cardiac amyloidosis was defined as a median probability of cardiac amyloidosis >50% in all patches, the model achieved perfect performance in discriminating patients with cardiac amyloidosis from those without it, with an area under the curve of 1.0.

Conclusion

A deep learning model was developed to diagnose cardiac amyloidosis from HE-stained myocardial tissue accurately. Although further prospective validation of this model using HE-stained myocardial tissues from multiple centres is needed, it may help minimize the risk of missing cardiac amyloidosis and maximize the utility of histological diagnosis in clinical practice.
What’s the cardiac rhythm at the time of cardiac arrest? Disputed dogma or true fact?
Authors: Maury Philippe , Marimpouy Nathan , Beneyto Maxime
Published: December 2024

It was widely accepted that malignant ventricular arrhythmias (VA) are the main direct initial cause for cardiac arrest and sudden cardiac death (SCD), but diverging data tended to demonstrate that asystole or pulseless activity were becoming the most prevalent cardiac rhythms at the time of cardiac arrest. We challenge here these conceptions and reinforce the persisting prominent role of VA in SCD.
French socialism in the Argentine Partido Socialista: political dimensions of an uncomfortable presence (1890–1915)
Authors: Herrera Carlos M , Reyes Francisco J
Published: December 2024

The presence of French socialism in the Argentine Socialist Party is something of a paradox: the cultural weight of France in Argentina’s intellectual and artistic life from the nineteenth century until the first decades of the twentieth century had no equivalent impact on Argentine socialism. This is even more striking if we consider the intensity of personal exchanges, including a visit by Jean Jaurès to Buenos Aires in 1911. Of course, Francophilia was not unknown to these socialists, but their main leaders adopted a mostly critical approach towards French traditions, and later towards the Section française de l’Internationale ouvrière (SFIO), at least when compared to the Belgian and German socialist parties. This difference becomes even more perceptible when we compare the Partido Socialista (PS) in Argentina to other socialist parties from the same region. The thesis of this article is that the influence of French socialism served, in the early years of the PS in Argentina, to feed the leftist currents that opposed the leadership, promoting a revolutionary attitude on its part instead of its integration into the political system. At the same time, Jaurès’ immense international status as a socialist meant that his 1911 visit would facilitate the eventual integration of the Argentine party into the political system.
Detecting gene expression in Caenorhabditis elegans
Authors: Calarco John A , Taylor Seth R , Miller David M
Published: December 2024

Reliable methods for detecting and analyzing gene expression are necessary tools for understanding development and investigating biological responses to genetic and environmental perturbation. With its fully sequenced genome, invariant cell lineage, transparent body, wiring diagram, detailed anatomy, and wide array of genetic tools, Caenorhabditis elegans is an exceptionally useful model organism for linking gene expression to cellular phenotypes. The development of new techniques in recent years has greatly expanded our ability to detect gene expression at high resolution. Here, we provide an overview of gene expression methods for C. elegans, including techniques for detecting transcripts and proteins in situ, bulk RNA sequencing of whole worms and specific tissues and cells, single-cell RNA sequencing, and high-throughput proteomics. We discuss important considerations for choosing among these techniques and provide an overview of publicly available online resources for gene expression data.
Characterizing selection on complex traits through conditional frequency spectra
Authors: Patel Roshni A , Weiß Clemens L , Zhu Huisheng , Mostafavi Hakhamanesh , Simons Yuval B , Spence Jeffrey P , Pritchard Jonathan K
Published: December 2024

Natural selection on complex traits is difficult to study in part due to the ascertainment inherent to genome-wide association studies (GWAS). The power to detect a trait-associated variant in GWAS is a function of its frequency and effect size – but for traits under selection, the effect size of a variant determines the strength of selection against it, constraining its frequency. Recognizing the biases inherent to GWAS ascertainment, we propose studying the joint distribution of allele frequencies across populations, conditional on the frequencies in the GWAS cohort. Before considering these conditional frequency spectra, we first characterized the impact of selection and non-equilibrium demography on allele frequency dynamics forwards and backwards in time. We then used these results to understand conditional frequency spectra under realistic human demography. Finally, we investigated empirical conditional frequency spectra for GWAS variants associated with 106 complex traits, finding compelling evidence for either stabilizing or purifying selection. Our results provide insights into polygenic score portability and other properties of variants ascertained with GWAS, highlighting the utility of conditional frequency spectra.
Motor pool selectivity of neuromuscular degeneration in type I spinal muscular atrophy is conserved between human and mouse
Authors: Lee Justin C , Chung Wendy K , Pisapia David J , Henderson Christopher E
Published: December 2024

Spinal muscular atrophy (SMA) is caused by low levels of the survival motor neuron (SMN) protein. Even though SMN is ubiquitously expressed, the disease selectively affects motor neurons, leading to progressive muscle weakness. Even among motor neurons, certain motor units appear more clinically resistant to SMA. To quantitatively survey selective resistance, we studied extensive neuromuscular autopsies of Type I SMA patients and age-matched controls. We found highly divergent degrees of degeneration of neighboring motor units, even within individual cranial nerves or a single anatomical area such as the neck. Examination of a Type I SMA patient maintained on life support for 17 years found that most muscles were atrophied, but the diaphragm was strikingly preserved. Nevertheless, some resistant human muscles with preserved morphology displayed nearly complete conversion to slow Type I myofibers. Remarkably, a similar pattern of selective resistance was observed in the SMNΔ7 mouse model. Overall, differential motor unit vulnerability in human Type I SMA suggests the existence of potent, motor unit-specific disease modifiers. Mechanisms that confer selective resistance to SMA may represent therapeutic targets independent of the SMN protein, particularly in patients with neuromuscular weakness refractory to current treatments.
Marine heatwaves in the Subarctic and the effect of acute temperature change on the key grazer Strongylocentrotus droebachiensis (Echinoidea, Echinodermata)
Authors: Koch Marie , Jungblut Simon , Götze Sandra , Bock Christian , Saborowski Reinhard
Published: December 2024

Subarctic fjord systems are facing a continuous temperature increase as well as more frequent and more intense marine heatwaves (MHWs). MHWs are periods of exceptionally high temperatures above the long-term average. In the Porsangerfjord (Northern Norway), the average water temperature ranges from 2.5°C in March to 10°C in August. MHWs frequently exceed the summer maximum by up to 6°C with so far unknown ecological effects. The green sea urchin, Strongylocentrotus droebachiensis, is a key grazer on habitat-forming kelp in Subarctic fjord systems. At high abundances, sea urchins transform productive kelp beds through pronounced grazing into depleted sea urchin barrens. In a laboratory experiment, we investigated the influence of acute temperature change on the grazing activity and the metabolic performance of the green sea urchin. Grazing rates increased continuously from 2 to 10°C but decreased again at 14°C. At 22°C, rapid decay of sea urchins were associated with changes of the metabolic energy state from aerobiosis to anaerobiosis. We propose two scenarios: Moderate warming might lead to the proliferation of the sea urchin population and increased grazing pressure on kelp forests, while extreme warming, as predicted by the end of the century, as well as the occurrence of extreme MHWs, may severely impair the sea urchin population and, in turn, might favour the proliferation of adaptable kelp species.
The weighted and shifted seven-step BDF method for parabolic equations
Authors: Akrivis Georgios , Chen Minghua , Yu Fan
Published: December 2024

Stability of the BDF methods of order up to 5 for parabolic equations can be established by the energy technique via Nevanlinna–Odeh multipliers. The nonexistence of Nevanlinna–Odeh multipliers makes the six-step BDF method special; however, the energy technique was recently extended by the authors in Akrivis et al. (2021, SIAM J. Numer. Anal., 59, 2449–2472) and covers all six stable BDF methods. The seven-step BDF method is unstable for parabolic equations, since it is not even zero-stable. In this work, we construct and analyze a stable linear combination of two non zero-stable schemes, the seven-step BDF method and its shifted counterpart, referred to as WSBDF7 method. The stability regions of the WSBDF$q, q\leqslant 7$, with a weight  $\vartheta \geqslant 1$, increase as $\vartheta $ increases and are larger than the stability regions of the classical $q$-step BDF methods, corresponding to $\vartheta =1$. We determine novel and suitable multipliers for the WSBDF7 method and establish stability for parabolic equations by the energy technique. The proposed approach is applicable for mean curvature flow, gradient flows, fractional equations and nonlinear equations.
Dynamic quinone repertoire accompanied the diversification of energy metabolism in Pseudomonadota
Authors: Chobert Sophie-Carole , Roger-Margueritat Morgane , Flandrin Laura , Berraies Safa , Lefèvre Christopher T , Pelosi Ludovic , Junier Ivan , Varoquaux Nelle , Pierrel Fabien , Abby Sophie S
Published: December 2024

It is currently unclear how Pseudomonadota, a phylum that originated around the time of the Great Oxidation Event, became one of the most abundant and diverse bacterial phyla on Earth, with metabolically versatile members colonizing a wide range of environments with different O2 concentrations. Here, we address this question by studying isoprenoid quinones, which are central components of energy metabolism covering a wide range of redox potentials. We demonstrate that a dynamic repertoire of quinone biosynthetic pathways accompanied the diversification of Pseudomonadota. The low potential menaquinone (MK) was lost in an ancestor of Pseudomonadota while the high potential ubiquinone (UQ) emerged. We show that the O2-dependent and O2-independent UQ pathways were both present in the last common ancestor of Pseudomonadota, and transmitted vertically. The O2-independent pathway has a conserved genetic organization and displays signs of positive regulation by the master regulator “fumarate and nitrate reductase” (FNR), suggesting a conserved role for UQ in anaerobiosis across Pseudomonadota. The O2-independent pathway was lost in some lineages but maintained in others, where it favoured a secondary reacquisition of low potential quinones (MK or rhodoquinone), which promoted diversification towards aerobic facultative and anaerobic metabolisms. Our results support that the ecological success of Pseudomonadota is linked to the acquisition of the largest known repertoire of quinones, which allowed adaptation to oxic niches as O2 levels increased on Earth, and subsequent diversification into anoxic or O2-fluctuating environments.
High prevalence of reverse transcriptase inhibitors associated resistance mutations among people living with HIV on dolutegravir-based antiretroviral therapy in Francistown, Botswana
Authors: Choga Ontlametse T , Lemogang Goitseone M , Choga Wonderful T , Muzanywa Gaonyadiwe , Shadreck Thembinkosi M , Ralegoreng Charity , Maruapula Dorcas , Moraka Natasha O , Koofhethile Catherine K , Mokgethi Patrick T , Seru Kedumetse , Zuze Boitumelo J L , Montshosi Patience , Gobe Irene , Motswaledi Modisa S , Musonda Rosemary , Mbulawa Mpaphi B , Makhema Joseph , Shapiro Roger , Lockman Shahin , Chebani Tony , Nawa Judith , Bochena Lindani , Moyo Sikhulile , Gaseitsiwe Simani
Published: December 2024

Objectives

We assessed HIV-1 drug resistance profiles among people living with HIV (PLWH) with detectable viral load (VL) and on dolutegravir-based antiretroviral therapy (ART) in Botswana.

Methods

The study utilised available 100 residual HIV-1 VL samples from unique PLWH in Francistown who had viraemia at-least 6 months after initiating ART in Botswana’s national ART program from November 2023 to January 2024. Viraemia was categorized as low-level viraemia (LLV) (VL: 200–999 copies/mL) or virologic failure (VF) (VL ≥1000 copies/mL). HIV-1 protease, reverse transcriptase and integrase genes were sequenced using an in-house next-generation sequencing Oxford nanopore technology. HIV-1 drug resistance mutations (DRMs) were identified using the HIVdb Program in the Stanford HIV drug resistance database and compared between VL groups.

Results

Among 100 participants, 83.0% were on dolutegravir-based, 10.0% were on non-dolutegravir-based ART and 7.0% had unknown/undocumented ART regimens. Thirty (30%) participants had LLV and 70 (70%) had VF. Among 58 successfully sequenced, 32.8% [95% Confidence Interval (CI): 21.8–46.0] had DRMs to any drug class, 33.3% (4/12) in the LLV group and 32.6% (15/46) in the VF group. Among individuals on dolutegravir-based ART, the overall HIV DRMs were 34.8% (95% CI: 22.7–49.2). By VL groups, 40.0% (95% CI: 16.8–68.7) and 33.3% (95% CI: 20.2–50.0) had DRMs at LLV and VF, respectively.

Conclusions

A high but similar prevalence of any DRMs was observed among individuals with LLV and those with VF on dolutegravir-based therapy. Monitoring DRMs in individuals with detectable VL is crucial for preserving dolutegravir-based ART.
Drug-resistant tuberculosis treatment success predictors in Namibia
Authors: Nangombe Vulika , Amkongo Mondjila , Godman Brian , Kibuule Dan
Published: December 2024

Background

Drug-resistant tuberculosis (DR-TB) is a considerable barrier to ending TB globally by 2035. In most high TB-burden countries in the sub-Saharan region, drivers of DR-TB treatment success are unknown.

Objectives

To determine predictors and patterns of treatment success rates (TSRs) in DR-TB in Namibia to inform strategies of national TB programmes.

Methods

A nationwide retrospective observational cohort study of a 6 year DR-TB database, 2014–19, was carried out. Independent predictors of successful treatment outcome in DR-TB were determined by multivariate logistic regression.

Results

Of the 1494 DR-TB patients included, 56.3% (n = 841) were male, the mean (±SD) age was 35.6 ± 14.2 years, and 8.3% had TB/HIV coinfection. The overall TSR was 66.5% (n = 994) and it increased marginally between implementation of the second and third medium-term plans for TB and leprosy (MTP-II and MTP-III). Being female was associated with lower odds of treatment success [adjusted OR (aOR) = 0.6; 95% CI: 0.34–0.89; P = 0.015), as was a young age (under 5 years) (aOR = 0.1; 95% CI: 0.0007–0.421; P = 0.005) and ages of 5–14 years (aOR = 0.0; 95% CI: 0.002–0.269; P = 0.002). Namibian nationality also showed a reduced likelihood of treatment success (aOR = 0.3; 95% CI: 0.089–0.961; P = 0.043). Among clinical predictors, bilateral pulmonary forms were inversely associated with treatment success (aOR = 0.2; 95% CI: 0.057–0.498; P = 0.001). Conversely, baseline monoresistance was linked to an increased likelihood of treatment success (aOR = 7.6; 95% CI: 1.427–40.631; P = 0.018).

Conclusions

Whilst DR-TB TSRs improved, they are below the global target and vary by clinical and patient demographics. Targeted interventions for high-risk patients, including female patients, those aged under 15 years, locals and those with bilateral pulmonary disease using community-based approaches to boost adherence, alongside leveraging the skills of clinical pharmacists, should now be explored.
Quantifying phenotypic and genetic variation for cow fertility phenotypes in American Simmental using total herd reporting data
Authors: Catrett Cassidy C , Moorey Sarah E , Beever Jon E , Rowan Troy N
Published: December 2024

Reproduction plays a major role in the production efficiency of livestock species. However, cow-centric reproductive traits tend to be lowly heritable and are not expressed until later in an animal’s lifetime, making phenotypic selection alone inefficient at generating genetic gain. Genetic progress can be accelerated by focusing selection on the predicted genetic component of reproductive traits using Expected Progeny Differences. We used the American Simmental Association’s performance and Total Herd Enrollment data, made up of 533,155 calving records from 303,158 females (132,403 cows and 170,755 heifers), 33,732 of which are genotyped, to explore three continuous and two discrete phenotypes focused on quantifying early and sustained fertility in beef cows. We analyzed calving date (CD) (cow’s CD relative to the start of the calving season), calving interval (CI) (days between calves), first calving interval (FCI) (CI observation between the first and second calving record for a female), heifer pregnancy (HP) (did the animal calve as 2-yr-old), and discrete early calving (DEC) (did animal calve in the first 30 d of the calving season) as distinct, but correlated measures of fertility. This dataset provides insight into population-wide trends related to cow attrition, calving season lengths, and phenotypic variation in fertility. We used pedigree and genomic REML to estimate these six phenotypes’ genetic, permanent environment, and temporary environmental variance components. Pedigree-estimated heritabilities were 0.06 (± 0.000011) for CD, (0.04 ± 0.000005) for CI, 0.07 (± 0.000016) for DEC, 0.05 ± 0.000041 for FCI, and 0.23 (± 0.000099) for HP, consistent with other fertility traits across beef and dairy cattle. The incorporation of genomics increased the heritability estimate for HP (0.24 ± 0.000098) and decreased the estimate for FCI (0.04 ± 0.000029). Positive phenotypic and genetic correlations were found among these phenotypes (rG = 0.01 to 0.96). These results call for further work in optimizing genetic predictions and exploration of the genetic architecture through genome-wide studies. Whole herd reporting date frameworks represent opportunities for measuring new reproductive phenotypes, but their utility in genetic evaluations will rely on novel trait initiatives and consistent recording that captures more detailed data.
Upgrade Rate of Exclusively MRI-Detected Papillomas in Asymptomatic Patients Undergoing Screening or Extent of Disease Examinations
Authors: Zamora Kathryn Watts , Yalniz Ceren , Brar Kudratjot , Li Yufeng , Zalasin Stefanie , Woodard Stefanie
Published: December 2024

Objective

To determine the upgrade rate of exclusively MRI-detected benign papillomas in asymptomatic high-risk patients, patients with a history of cancer, or patients with known malignancy.

Methods

This IRB-approved retrospective study reviewed all breast MRI–guided biopsies yielding papilloma on pathology for all asymptomatic patients undergoing breast MRI for high-risk screening, newly diagnosed breast cancer, or a personal history of breast cancer. All cases were followed by excision or 2-year imaging follow-up. The upgrade rate was determined. Fisher’s exact test was used to determine the significance of associated factors, including lesion type, lesion size, and ipsilateral malignancy.

Results

Of the 258 MRI-guided biopsies, 117 met the inclusion criteria. A 4% (5/117) upgrade rate was found with a 3% (4/117) upgrade rate to ductal carcinoma in situ (DCIS) and a 1% (1/117) upgrade rate to invasive malignancy for all identified papillomas. When evaluating all papillomas, the only associated feature identified to be statically significant for risk of upgrade was ipsilateral malignancy with a 60% (3/5) upgrade rate with a P-value of .0057. When separately evaluating benign papillomas only by excluding those with atypia or additional high-risk lesion at biopsy, a 4% (3/80) upgrade rate to DCIS was found. There was no upgrade to invasive malignancy.

Conclusion

Upgrade of MRI-detected papillomas in asymptomatic high-risk patients, patients with a history of cancer, or patients with known malignancy is 4% in this population, which suggests these lesions may warrant surgical excision.
Reinventing trade, environment and development interlinkages: lessons from the EU–Mercosur Association Agreement
Authors: Harrison James , Paulini Sophia
Published: December 2024

The trade pillar of the EU–Mercosur Association Agreement (EUMAA) has demonstrated critical problems with the way in which the EU handles interlinkages between trade, environment and development in its free trade agreements, particularly through its Sustainability Impact Assessments and Trade and Sustainable Development Chapters. But instead of prompting fundamental change, key EU actors have responded by merely tinkering with the existing model. This article explores why such an approach is insufficient to address the urgent ecological and developmental challenges which EUMAA specifically, and EU trade agreements more generally, currently ignore. It argues that the sustainable development paradigm underlying the EU’s trade and sustainability agenda must be strengthened through the explicit incorporation and then operationalization of the concepts of planetary boundaries and socio-economic equality. It utilizes the example of EUMAA to demonstrate the kind of concrete changes that could flow from this strengthened sustainable development paradigm including (I) the creation of radically different negotiating processes (II) the utilization of trade measures within FTAs to achieve key environmental and developmental goals and (III) the redistribution of environmental and developmental responsibilities among key actors who are the subjects and objects of trade governance.
Evaluating the intersection of climate vulnerability and cancer burden in North Carolina
Authors: Pak Joyce , Le Ngan , Metwally Eman M , Wang Jeanny , Planey Arrianna Marie , Lowman Amy M , Jackson Bradford E , Butler Eboneé N , Lund Jennifer L
Published: December 2024

Climate-related extreme weather events disrupt health-care systems and exacerbate health disparities, particularly affecting individuals diagnosed with cancer. This study explores the intersection of climate vulnerability and cancer burden in North Carolina (NC). Using county-level data from the US Climate Vulnerability Index (CVI) and the NC Department of Health and Human Services, we analyzed cancer incidence and mortality rates from 2017 to 2021. Our findings reveal a robust correlation between CVI percentiles and cancer mortality (r = 0.72). Counties with high area deprivation like Scotland, Robeson, and Halifax had the highest CVI percentiles of 0.68, 0.67, and 0.66, with respective cancer mortality rates of 193, 195, and 196 per 100 000 person-years. Correlations between CVI and cancer incidence were modest (r = 0.22). These results underscore the need for targeted public health interventions to mitigate climate-related health disparities. Future work could focus on exploring specific climate hazards and cancer outcomes to enhance preparedness and resilience in cancer care.
Piperlongumine inhibits glioblastoma proliferation by inducing ferroptosis
Authors: Qiu Jianting , Guo Fangzhou , Shi Ji , Guo Tangjun , Piao Haozhe
Published: December 2024

Objectives

This study aimed to investigate the effects of Piperlongumine on Glioblastoma multiforme.

Methods

The effects of Piperlongumine on the viability and proliferation of glioma cells LN229 and A172 were measured. Changes in mitochondrial structure were observed. Cell proliferative capacity was assessed using immunofluorescence. The levels of glutathione, malondialdehyde, 4-hydroxynonenal, and intracellular reactive oxygen species were detected. The levels of ferroptosis-related proteins were detected. A plasmid transfection was performed to overexpress the nuclear factor erythroid 2-related factor 2 gene; a subcutaneous tumor model was established in nude mice to observe the in vivo inhibitory effects of Piperlongumine on Glioblastoma multiforme and the recovery effect of Fer-1. The expression levels of ferroptosis-related proteins were detected using immunohistochemistry.

Key findings

Piperlongumine inhibited the viability of glioma cells, as well as their proliferation. The ferroptosis inhibitors were able to restore the inhibitory effect of Piperlongumine on glioma cell proliferation. Forced overexpression of nuclear factor erythroid 2-related factor 2 partially reversed Piperlongumine-induced ferroptosis; Piperlongumine exhibited a significant inhibitory effect on Glioblastoma multiforme cells in vivo, which could be restored by Fer-1.

Conclusions

Piperlongumine inhibits Glioblastoma multiforme proliferation by inducing ferroptosis in vitro and vivo model.
A case of isolated SMA dissection with failed initial conservative management
Authors: Emara Salma , Kropp Madison , Akbari Masoud , Cook Kristin
Published: December 2024

Isolated superior mesenteric dissection (ISMAD) is an uncommon condition, often diagnosed incidentally for presentations of acute abdominal pain. Early identification and treatment are crucial as complications such as bowel ischemia or vessel rupture can occur. There remain no established treatment guidelines, making surgical and endovascular indications controversial. A 60-year-old male presented with acute abdominal pain, and was diagnosed with ISMAD via computed tomography imaging. He was initially managed conservatively which progressed to worsening abdominal pain, hypertensive crisis, and hemoperitoneum on follow-up computed tomography angiography (CTA). A mesenteric angiogram revealed a pseudoaneurysm in the superior mesenteric artery (SMA) which was subsequently treated with coil embolization. The absence of long-term evidence on relapse rates questions the overall effectiveness of nonoperative therapy. Further research is needed to establish clear guidelines and to determine whether early intervention might be more advantageous in managing complications and preventing recurrence.