bluuebunny/crossref_metadata_2025 huggingface dataset:
Neutron star mergers and their impact on second generation star formation in the early universe
Authors: Skinner Danielle , Wise John H
Published: February 2024

The exact evolution of elements in the Universe, from primordial to heavier elements produced via the r-process, is still under scrutiny. The supernova deaths of the very first stars led to the enrichment of their local environments, and can leave behind neutron stars (NSs) as remnants. These remnants can end up in binary systems with other NSs, and eventually merge, allowing for the r-process to occur. We study the scenario where a single NS merger (NSM) enriches a halo early in its evolution to understand the impact on the second generation of stars and their metal abundances. We perform a suite of high-resolution cosmological zoom-in simulations using enzo where we have implemented a new NSM model varying the explosion energy and the delay time. In general, an NSM leads to significant r-process enhancement in the second generation of stars in a galaxy with a stellar mass of ∼105 M⊙ at redshift 10. A high explosion energy leads to a Population II (Pop II) mass fraction of 72 per cent being highly enhanced with r-process elements, while a lower explosion energy leads to 80 per cent being enhanced, but only 14 per cent being highly enhanced. When the NSM has a short delay time of 10 Myr, only 5 per cent of the mass fraction of Pop II stars is highly enhanced, while 64 per cent is highly enhanced for the longest delay time of 100 Myr. This work represents a stepping stone towards understanding how NSMs impact their environments and the metal abundances of descendant generations of stars.
The rise and fall of dust in the Universe
Authors: Eales Stephen , Ward Bradley
Published: February 2024

We estimate how the mean density of dust in the Universe varies with redshift, using submillimetre continuum observations and a method designed to minimize the effect of dust temperature. We have used the Herschel Astrophysical Terahertz Large Area Survey (Herschel-ATLAS) to show that the median temperature of dust in galaxies is $\simeq 22\ \mathrm{ K}$ and does not vary significantly with redshift out to z = 1. With this as our estimate of the mass-weighted dust temperature, we have used an 850-μm survey of the field of the Cosmological Evolution Survey (COSMOS) to estimate the mean density of dust in 10 redshift bins over the range 0 < z < 5.5. We find that the mean density of dust increased by a factor of ≃10 from z = 5 to z = 2, declined slightly to z = 1, and then steeply to the present day. The relationship between the mean density of dust and redshift is similar to the relationship between the mean star formation rate and redshift, although the increase for the former is steeper from z = 5 to z = 2. We have also used the submillimetre measurements to estimate the mean density of gas over the same redshift range. The values we estimate for the dust-traced gas are much lower and with a different redshift dependence than those for estimates of the mean density of atomic gas but similar to those for estimates of the mean density of the CO-traced gas. We find that the depletion time for the dust-traced gas in the Universe as a whole declines with redshift in the same way as seen for individual galaxies.
Increased prevalence of kidney cysts in individuals carrying heterozygous COL4A3 or COL4A4 pathogenic variants
Authors: Furlano Mónica , Pilco-Teran Melissa , Pybus Marc , Martínez Víctor , Aza-Carmona Miriam , Rius Peris Asunción , Pérez-Gomez Vanessa , Berná Gerson , Mazon Jaime , Hernández Jonathan , Fayos de Arizón Leonor , Viera Elizabet , Gich Ignasi , Pérez Hugo Vergara , Gomá-Garcés Elena , Albero Dolon José Luis , Ars Elisabet , Torra Roser
Published: February 2024

Background

Clinical variability among individuals with heterozygous pathogenic/likely pathogenic (P/LP) variants in the COL4A3/COL4A4 genes (also called autosomal dominant Alport syndrome or COL4A3/COL4A4-related disorder) is huge; many individuals are asymptomatic or show microhematuria, while others may develop proteinuria and chronic kidney disease (CKD). The prevalence of simple kidney cysts (KC) in the general population varies according to age, and patients with advanced CKD are prone to have them. A possible association between heterozygous COL4A3, COL4A4 and COL4A5 P/LP variants and KC has been described in small cohorts. The presence of KC in a multicenter cohort of individuals with heterozygous P/LP variants in the COL4A3/COL4A4 genes is assessed in this study.

Methods

We evaluated the presence of KC by ultrasound in 157 individuals with P/LP variants in COL4A3 (40.7%) or COL4A4 (53.5%) without kidney replacement therapy. The association between presence of KC and age, proteinuria, estimated glomerular filtration rate (eGFR) and causative gene was analyzed. Prevalence of KC was compared with historical case series in the general population.

Results

Half of the individuals with P/LP variants in COL4A3/COL4A4 showed KC, which is a significantly higher percentage than in the general population. Only 3.8% (6/157) had cystic nephromegaly. Age and eGFR showed an association with the presence of KC (P < .001). No association was found between KC and proteinuria, sex or causative gene.

Conclusions

Individuals with COL4A3/COL4A4 P/LP variants are prone to develop KC more frequently than the general population, and their presence is related to age and to eGFR. Neither proteinuria, sex nor the causative gene influences the presence of KC in these individuals.
Incidence and outcomes of kidney replacement therapy for end-stage kidney disease due to primary glomerular disease in Europe: findings from the ERA Registry
Authors: Abd ElHafeez Samar , Kramer Anneke , Arici Mustafa , Arnol Miha , Åsberg Anders , Bell Samira , Belliere Julie , Corte Carmen Díaz , Fresnedo Gema Fernández , Hemmelder Marc , Heylen Line , Hommel Kristine , Kerschbaum Julia , Naumović Radomir , Nitsch Dorothea , Santamaria Rafael , Finne Patrik , Palsson Runolfur , Pippias Maria , Resic Halima , Rosenberg Mai , de Pablos Carmen Santiuste , Segelmark Mårten , Sørensen Søren Schwartz , Soler Maria Jose , Vidal Enrico , Jager Kitty J , Ortiz Alberto , Stel Vianda S
Published: February 2024

Background

Primary glomerular disease (PGD) is a major cause of end-stage kidney disease (ESKD) leading to kidney replacement therapy (KRT). We aimed to describe incidence (trends) in individuals starting KRT for ESKD due to PGD and to examine their survival and causes of death.

Methods

We used data from the European Renal Association (ERA) Registry on 69 854 patients who started KRT for ESKD due to PGD between 2000 and 2019. ERA primary renal disease codes were used to define six PGD subgroups. We examined age and sex standardized incidence, trend of the incidence and survival.

Results

The standardized incidence of KRT for ESKD due to PGD was 16.6 per million population (pmp), ranging from 8.6 pmp in Serbia to 20.0 pmp in France. Immunoglobulin A nephropathy (IgAN) and focal segmental glomerulosclerosis (FSGS) had the highest incidences, of 4.6 pmp and 2.6 pmp, respectively. Histologically non-examined PGDs represented over 50% of cases in Serbia, Bosnia and Herzegovina, and Romania and were also common in Greece, Estonia, Belgium and Sweden. The incidence declined from 18.6 pmp in 2000 to 14.5 pmp in 2013, after which it stabilized. All PGD subgroups had 5-year survival probabilities above 50%, with crescentic glomerulonephritis having the highest risk of death [adjusted hazard ratio 1.8 (95% confidence interval 1.6–1.9)] compared with IgAN. Cardiovascular disease was the most common cause of death (33.9%).

Conclusion

The incidence of KRT for ESKD due to PGD showed large differences between countries and was highest and increasing for IgAN and FSGS. Lack of kidney biopsy facilities in some countries may have affected accurate assignment of the cause of ESKD. The recognition of the incidence and outcomes of KRT among different PGD subgroups may contribute to a more individualized patient care approach.
A predictive mortality score in ANCA-associated renal vasculitis
Authors: Fage Nicolas , Quéméneur Thomas , Riou Jérémie , Boud'hors Charlotte , Desouche Alice , Vinatier Emeline , Samoreau Clément , Coindre Jean-Philippe , Djema Assia , Henry Nicolas , Gnemmi Viviane , Copin Marie-Christine , Piccoli Giorgina Barbara , Vandenbussche Cyrille , Augusto Jean-François , Brilland Benoit ,   the Maine-Anjou Registry Research Group, Augusto Jean-François , Beauvillain Céline , Coindre Jean-Philippe , Copin Marie-Christine , Cousin Maud , Croué Anne , Djema Assia , Guibert Fanny , Henry Nicolas , Piccoli Giorgina Barbara , Pouteau Lise-Marie , Wacrenier Samuel , Vinatier Emeline
Published: February 2024

Background

Several scores have been developed to predict mortality at anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) diagnosis. Their prognostic value in Caucasian patients with kidney involvement (AAV-GN) remains uncertain as none has been developed in this specific population. We aimed to propose a novel and more accurate score specific for them.

Methods

This multicentric study included patients diagnosed with AAV-GN since January 2000 in four nephrology centers (recorded in the Maine-Anjou AAV-GN Registry). Existing scores and baseline characteristics were assessed at diagnosis before any therapeutic intervention. A multivariable analysis was performed to build a new predictive score for death. Its prognosis performance (area under receiving operating curve and C-index) and accuracy (Brier score) was compared with existing scores. One hundred and eighty-five patients with AAV-GN from the RENVAS registry were used as a validation cohort.

Results

A total of 228 patients with AAV-GN from the Maine-Anjou registry were included to build the new score. It included the four components most associated with death: age, history of hypertension or cardiac disease, creatinine and hemoglobin levels at diagnosis. Overall, 194 patients had all the data available to determine the performance of the new score and existing scores. The new score performed better than the previous ones in the development and in the validation cohort. Among the scores tested, only Five-Factor Score and Japanese Vasculitis Activity Score had good performance in predicting death in AAV-GN.

Conclusions

This original score, named DANGER (Death in ANCA Glomerulonephritis—Estimating the Risk), may be useful to predict the risk of death in AAV-GN patients. Validation in different populations is needed to clarify its role in assisting clinical decisions.
Sustainability of an Opt-Out Electronic-Health Record-Based Tobacco Treatment Consult Service at a Large Safety-Net Hospital: A 6-Year Analysis
Authors: Flores Adriana , Wiener Renda Soylemez , Hon Stephanie , Wakeman Cornelia , Howard Jinesa , Virani Nikita , Mattus Bruce , Foreman Alexis Gallardo , Singh Johar , Rosen Linda , Bulekova Katia , Kathuria Hasmeena
Published: February 2024

Introduction

Our safety-net hospital implemented a hospital-based tobacco treatment intervention in 2016. We previously showed the intervention, an “opt-out” Electronic Health Record (EHR)-based Best Practice Alert (BPA)+ order-set that triggers consultation to an inpatient Tobacco Treatment Consult (TTC) service for all patients who smoke, improves smoking abstinence. We now report on sustainability, 6 years after inception.

Aims and Methods

We analyzed data collected between July 2016–June 2022 of patients documented as “currently smoking” in the EHR. Across the 6 years, we used Pearson’s correlation analysis to compare Adoption (clinician acceptance of the BPA+ order-set, thus generating consultation to the TTC service); Reach (number of consultations completed by the TTC service); and Effectiveness (receipt of pharmacotherapy orders between patients receiving and not receiving consultations).

Results

Among 39 558 adult admissions (July 2016–June 2022) with “currently smoking” status in the EHR for whom the BPA triggered, clinicians accepted the TTC order set on 50.4% (19 932/39 558), though acceptance varied across services (eg, Cardiology [71%] and Obstetrics-Gynecology 12%]). The TTC service consulted on 17% (6779/39 558) of patients due to staffing constraints. Consultations ordered (r = −0.28, p = .59) and completed (r = 0.45, p = .37) remained stable over 6-years. Compared to patients not receiving consultations, patients receiving consultations were more likely to receive pharmacotherapy orders overall (inpatient: 50.8% vs. 35.1%, p < .0001; at discharge: 27.1% vs. 10%, p < .0001) and in each year.

Conclusions

The “opt-out” EHR-based TTC service is sustainable, though many did not receive consultations due to resource constraints. Health care systems should elevate the priority of hospital-based tobacco treatment programs to increase reach to underserved populations.

Implications

Our study shows that opt-out approaches that utilize the EHR are a sustainable approach to providing evidence-based tobacco treatment to all hospitalized individuals who smoke, regardless of readiness to stop smoking and clinical condition.
Do Infectious Diseases After Kidney Retransplantation Differ From Those After First Kidney Transplantation?
Authors: Kusejko Katharina , Neofytos Dionysios , van Delden Christian , Hirsch Hans H , Meylan Pascal , Boggian Katia , Hirzel Cedric , Garzoni Christian , Sidler Daniel , Schnyder Aurelia , Schaub Stefan , Golshayan Déla , Haidar Fadi , Bonani Marco , Kouyos Roger D , Mueller Nicolas J , Schreiber Peter W ,   the Swiss Transplant Cohort Study, Amico P , Aubert J-D , Banz V , Beckmann S , Beldi G , Berger C , Berishvili E , Berzigotti A , Binet I , Bochud P-Y , Branca S , Bucher H , Catana E , Cairoli A , Chalandon Y , De Geest S , De Rougemont O , De Seigneux S , Dickenmann M , Dreifuss J L , Duchosal M , Fehr T , Ferrari-Lacraz S , Garzoni C , Golshayan D , Goossens N , Halter F H J , Heim D , Hess C , Hillinger S , Hirsch H H , Hirt P , Hofbauer G , Huynh-Do U , Immer F , Koller M , Laager M , Laesser B , Lamoth F , Lehmann R , Leichtle A , Manuel O , Marti H P , Martinelli M , McLin V , Mellac K , Merçay A , Mettler K , Müller A , Mueller N J , Müller-Arndt U , Müllhaupt B , Nägeli M , Oldani G , Pascual M , Passweg J , Pazeller R , Posfay-Barbe K , Rick J , Rosselet A , Rossi S , Rothlin S , Ruschitzka F , Schachtner T , Schanz U , Schaub S , Scherrer A , Schnyder A , Schuurmans M , Schwab S , Sengstag T , Simonetta F , Stampf S , Steiger J , Stirnimann G , Stürzinger U , Van Delden C , Venetz J-P , Villard J , Vionnet J , Wick M , Wilhelm M , Yerly P
Published: February 2024

Background

Infectious diseases (IDs) are highly relevant after solid organ transplantation in terms of morbidity and mortality, being among the most common causes of death. Patients undergoing kidney retransplantation (re-K-Tx) have been already receiving immunosuppressive therapy over a prolonged period, potentially facilitating subsequent infections. Comparing ID events after re-K-Tx and first kidney transplantation (f-K-Tx) can delineate patterns and risks of ID events associated with prolonged immunosuppression.

Methods

We included adult patients with records on f-K-Tx and re-K-Tx in the Swiss Transplant Cohort Study. We analyzed ID events after f-K-Tx and re-K-Tx within the same patients and compared infection rates, causative pathogens, and infection sites. Recurrent time-to-event analyses were performed for comparison of infection rates.

Results

A total of 59 patients with a median age of 47 years (range, 18–73) were included. Overall, 312 ID events in 52 patients occurred. In multivariable recurrent event modeling, the rate of ID events was significantly lower after re-K-Tx (hazard ratio, 0.70; P = .02). More bacterial (68.9% vs 60.4%) and fungal (4.0% vs 1.1%) infections were observed after f-K-Tx but fewer viral infections (27.0% vs 38.5%) as compared with re-K-Tx (P = .11). After f-K-Tx, urinary and gastrointestinal tract infections were more frequent; after re-K-Tx, respiratory tract and surgical site infections were more frequent (P < .001).

Conclusions

ID events were less frequent after re-K-Tx. Affected sites differed significantly after f-K-Tx vs re-K-Tx.
Dalba Got Back? Use of Dalbavancin for the Treatment of Vertebral Osteomyelitis
Authors: Streifel Amber C , Strnad Luke C , Sikka Monica K , Varley Cara D , Makadia Jina , Sukerman Ellie , Douglass Alyse H , Mayer Heather , Young Kathleen , Lewis James S
Published: February 2024

Data evaluating dalbavancin use for vertebral osteomyelitis remain limited. In our retrospective cohort, 29 of 34 (85.3%) patients completed their dalbavancin course. Adverse reactions occurred for 6 (17.6%) and infection recurrence in 3 (8.8%) within 90 days. Dalbavancin appears to be safe and well-tolerated for vertebral osteomyelitis.
Burnout, Compassion Fatigue, and the Long Haul of Caring for Long COVID
Authors: Ramers Christian B , Scott John D , Struminger Bruce B
Published: February 2024

The current landscape of clinician burnout is prompting the need for our health care system to revise its approach toward complex conditions such as long coronavirus disease (COVID), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and other postinfectious fatiguing illnesses (PIFIs). We discuss our efforts here at Family Health Center of San Diego (FHCSD) to help share insight and glean perspective from clinicians who have participated in our Centers for Disease Control and Prevention (CDC)–funded 3-year continuing professional development initiative. The Long COVID and Fatiguing Illness Recovery Program uses multidisciplinary team-based case consultation and peer-to-peer sharing of emerging best and promising practices (ie, teleECHO [Extension for Community Healthcare Outcomes]) to support the management of complex cases associated with long COVID, ME/CFS, and other PIFIs. We believe that this perspective captures a key moment in the trajectory of postpandemic clinician burnout and prompts further reflection and action from the health care system to improve clinician- and patient-level outcomes related to the care of patients with postinfectious fatiguing illnesses.
Modeling Invasive Aspergillosis Risk for the Application of Prophylaxis Strategies
Authors: Young Jo-Anne H , Andes David R , Ardura Monica I , Arrieta Antonio , Bow Eric J , Chandrasekar Pranatharthi H , Chen Sharon C A , Hammond Sarah P , Husain Shahid , Koo Sophia , Lavergne Valéry , Nguyen M Hong , Patterson Thomas F , So Miranda , Thompson George R , Morrissey C Orla , Schuster Mindy G
Published: February 2024

The epidemiology of invasive aspergillosis (IA) is evolving. To define the patient groups who will most likely benefit from primary or secondary Aspergillus prophylaxis, particularly those whose medical conditions and IA risk change over time, it is helpful to depict patient populations and their risk periods in a temporal visual model. The Sankey approach provides a dynamic figure to understand the risk of IA for various patient populations. While the figure depicted within this article is static, an internet-based version could provide pop-up highlights of any given flow's origin and destination nodes. A future version could highlight links to publications that support the color-coded incidence rates or other actionable items, such as bundles of applicable pharmacologic or non-pharmacologic interventions. The figure, as part of the upcoming Infectious Diseases Society of America's aspergillosis clinical practice guidelines, can guide decision-making in clinical settings.
The characteristic time scale of cultural evolution
Authors: Wand Tobias , Hoyer Daniel
Published: February 2024

Numerous researchers from various disciplines have explored commonalities and divergences in the evolution of complex social formations. Here, we explore whether there is a “characteristic” time course for the evolution of social complexity in a handful of different geographic areas. Data from the Seshat: Global History Databank is shifted so that the overlapping time series can be fitted to a single logistic regression model for all 23 geographic areas under consideration. The resulting regression shows convincing out-of-sample predictions, and its period of extensive growth in social complexity can be identified via bootstrapping as a time interval of roughly 2,500 years. To analyze the endogenous growth of social complexity, each time series is restricted to a central time interval without major disruptions in cultural or institutional continuity, and both approaches result in a similar logistic regression curve. Our results suggest that these different areas have indeed experienced a similar course in the their evolution of social complexity, but that this is a lengthy process involving both internal developments and external influences.
Male spondyloarthritis patients and those with longer disease duration have less severe disc degeneration: propensity score-matched comparison
Authors: Cheung Samuel Tin Yan , Tsang Helen Hoi Lun , Cheung Prudence Wing Hang , Cheung Jason Pui Yin
Published: February 2024

Objective

Using whole spine sagittal T2 MRI, we aimed to compare the severity and prevalence of disc degeneration (DD) in axial SpA patients vs the general population and to determine any association between spinal inflammation, structural changes, mobility and DD among SpA patients.

Methods

Two prospectively collected cohorts of SpA patients (n = 411) and the general population (n = 2007) were recruited. Eventually, 967 participants from the populational cohort and 304 participants from the SpA cohort were analysed. Two hundred and nineteen matched pairs were generated by propensity score matching. Imaging parameters, including Pfirrmann grading, disc herniation, high-intensity zone, Schmorl’s node, Modic change and anterior marrow change were studied and compared from C2/3 to L5/S1. DD was defined as Pfirrmann grade 4 or 5. Demographic factors, including age, sex and BMI, were collected. Multivariable linear regression was used to determine the association between spinal inflammation [Spondyloarthritis Research Consortium of Canada (SPARCC) spine MRI index], structural changes [modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS)] and mobility (BASMI) with lumbar Pfirrmann score.

Results

SpA patients had lower prevalence of DD (P < 0.001). The disease stage-stratified regression model showed that SPARCC spinal MRI index was associated with higher lumbar Pfirrmann scores in early disease (β = 0.196, P = 0.044), whereas mSASSS was associated with lower lumbar Pfirrmann scores in later disease (β = −0.138, P = 0.038). Males had higher mSASSS (P < 0.001) and lower odds of whole spine DD (odds ratio = 0.622, P = 0.028).

Conclusion

SpA patients had lower DD severity than the general population. Males had higher mSASSSs, and increased mSASSS at later disease was associated with less severe DD.
Enhancing cartilage regeneration and repair through bioactive and biomechanical modification of 3D acellular dermal matrix
Authors: Gao Wei , Cheng Tan , Tang Zhengya , Zhang Wenqiang , Xu Yong , Han Min , Zhou Guangdong , Tao Chunsheng , Xu Ning , Xia Huitang , Sun Weijie
Published: February 2024

Acellular dermal matrix (ADM) shows promise for cartilage regeneration and repair. However, an effective decellularization technique that removes cellular components while preserving the extracellular matrix, the transformation of 2D-ADM into a suitable 3D scaffold with porosity and the enhancement of bioactive and biomechanical properties in the 3D-ADM scaffold are yet to be fully addressed. In this study, we present an innovative decellularization method involving 0.125% trypsin and 0.5% SDS and a 1% Triton X-100 solution for preparing ADM and converting 2D-ADM into 3D-ADM scaffolds. These scaffolds exhibit favorable physicochemical properties, exceptional biocompatibility and significant potential for driving cartilage regeneration in vitro and in vivo. To further enhance the cartilage regeneration potential of 3D-ADM scaffolds, we incorporated porcine-derived small intestinal submucosa (SIS) for bioactivity and calcium sulfate hemihydrate (CSH) for biomechanical reinforcement. The resulting 3D-ADM+SIS scaffolds displayed heightened biological activity, while the 3D-ADM+CSH scaffolds notably bolstered biomechanical strength. Both scaffold types showed promise for cartilage regeneration and repair in vitro and in vivo, with considerable improvements observed in repairing cartilage defects within a rabbit articular cartilage model. In summary, this research introduces a versatile 3D-ADM scaffold with customizable bioactive and biomechanical properties, poised to revolutionize the field of cartilage regeneration.
Revisiting Event-Study Designs: Robust and Efficient Estimation
Authors: Borusyak Kirill , Jaravel Xavier , Spiess Jann
Published: February 2024

We develop a framework for difference-in-differences designs with staggered treatment adoption and heterogeneous causal effects. We show that conventional regression-based estimators fail to provide unbiased estimates of relevant estimands absent strong restrictions on treatment-effect homogeneity. We then derive the efficient estimator addressing this challenge, which takes an intuitive “imputation” form when treatment-effect heterogeneity is unrestricted. We characterize the asymptotic behaviour of the estimator, propose tools for inference, and develop tests for identifying assumptions. Our method applies with time-varying controls, in triple-difference designs, and with certain non-binary treatments. We show the practical relevance of our results in a simulation study and an application. Studying the consumption response to tax rebates in the U.S., we find that the notional marginal propensity to consume is between 8 and 11% in the first quarter—about half as large as benchmark estimates used to calibrate macroeconomic models—and predominantly occurs in the first month after the rebate.
Anticoagulant and non-anticoagulant therapy in thrombotic antiphospholipid syndrome: old drugs and new treatment targets
Authors: Ruiz-Irastorza Guillermo , Tektonidou Maria G , Khamashta Munther
Published: February 2024

In this review, we discuss the current evidence on classic and newer oral anticoagulant therapy, older drugs such as HCQ and statins, and new potential treatment targets in APS. Vitamin K antagonists (VKAs) remain the cornerstone treatment for thrombotic events in APS. In patients fulfilling criteria for definite APS presenting with a first venous thrombosis, treatment with VKAs with a target international normalized ratio (INR) 2.0–3.0 is recommended. In patients with arterial thrombosis, treatment with VKA with target INR 2.0–3.0 or 3.0–4.0 is recommended by recent guidelines, considering the individual’s bleeding and thrombosis recurrence risk. A combination of VKAs and low-dose aspirin (75–100 mg/daily) may also be considered. According to available evidence direct oral anticoagulants should be avoided in patients with arterial thrombosis and/or those with triple aPL positivity. Adjunctive treatment with HCQ and/or statins can be considered, especially in anticoagulation treatment–refractory APS. Potential targeted treatments in APS include B-cell targeting, complement inhibition, mammalian target of rapamycin inhibition, IFN targeting, adenosine receptors agonists, CD38 targeting or chimeric antigen receptor T-cell therapy. The safety and efficacy of these treatment targets needs to be examined in well-designed randomized controlled trials.
New advances in genomics and epigenetics in antiphospholipid syndrome
Authors: López-Pedrera Chary , Cerdó Tomás , Jury Elizabeth C , Muñoz-Barrera Laura , Escudero-Contreras Alejandro , Aguirre M A , Pérez-Sánchez Carlos
Published: February 2024

APS patients exhibit a wide clinical heterogeneity in terms of the disease’s origin and progression. This diversity can be attributed to consistent aPL profiles and other genetic and acquired risk factors. Therefore, understanding the pathophysiology of APS requires the identification of specific molecular signatures that can explain the pro-atherosclerotic, pro-thrombotic and inflammatory states observed in this autoimmune disorder. In recent years, significant progress has been made in uncovering gene profiles and understanding the intricate epigenetic mechanisms and microRNA changes that regulate their expression. These advancements have highlighted the crucial role played by these regulators in influencing various clinical aspects of APS. This review delves into the recent advancements in genomic and epigenetic approaches used to uncover the mechanisms contributing to vascular and obstetric involvement in APS. Furthermore, we discuss the implementation of novel bioinformatics tools that facilitate the investigation of these mechanisms and pave the way for personalized medicine in APS.
Viewpoint: Provoked thrombosis in antiphospholipid syndrome
Authors: Wahl Denis , Pengo Vittorio
Published: February 2024

Unprovoked thrombosis (thrombosis occurring without an established environmental factor favouring the episode) is a classic feature of APS. In the general population, provoked venous thromboembolism (VTE) is clearly defined and has clinical and therapeutic differences compared with unprovoked VTE. Whether provoked VTE in the context of APS may lead to a limited treatment duration is not well established. Therefore, careful clinical and laboratory evaluation is needed to identify patients eligible for a limited duration of anticoagulation treatment after provoked VTE. Given the uncertainties of available data, the risks and benefits of treatment decisions should be clearly explained. Decisions should be shared by both the patient and physician. Cardiovascular risk factors are common in patients with APS with arterial thrombosis. There are insufficient data suggesting that cardiovascular risk factor control would allow the cessation of anticoagulation. In most instances, arterial thrombosis will require prolonged anticoagulants. A careful analysis of clinical characteristics and laboratory evaluation, particularly the aPL antibody profile, is needed to make decisions on a case-by-case basis.
Identification of the VLDLR locus associated with giant cell arteritis and the possible causal role of low-density lipoprotein cholesterol in its pathogenesis
Authors: Iwasaki Takeshi , Watanabe Ryu , Zhang Hui , Hashimoto Motomu , Morinobu Akio , Matsuda Fumihiko
Published: February 2024

Objectives

To elucidate the association between genetic variants and the risk of GCA via large-scale genome-wide association studies (GWAS). In addition, to assess the causal effect of a specific molecule by employing the obtained GWAS results as genetic epidemiological tools.

Methods

We applied additional variant quality control to the publicly available GWAS results from the biobanks of the UK (UKBB) and Finland (FinnGen), which comprised 532 cases vs 408 565 controls and 884 cases vs 332 115 controls, respectively. We further meta-analysed these two sets of results. We performed two-sample Mendelian randomization (MR) to test the causal effect of low-density lipoprotein (LDL) cholesterol on the risk of GCA.

Results

The MHC class II region showed significant associations in UKBB, FinnGen and the meta-analysis. The VLDLR region was associated with GCA risk in the meta-analysis. The T allele of rs7044155 increased the expression of VLDLR, decreased the LDL cholesterol level and decreased the disease risk. The subsequent MR results indicated that a 1 s.d. increase in LDL cholesterol was associated with an increased risk of GCA (odds ratio 1.21, 95% CI 1.01–1.45; P = 0.04).

Conclusions

Our study identified associations between GCA risk and the MHC class II and VLDLR regions. Moreover, LDL cholesterol was suggested to have a causal effect on the risk of developing GCA.
Susceptibility to mycobacterial infection in VEXAS syndrome
Authors: Riescher Stanislas , Lecomte Raphael , Danic Gwenvael , Graveleau Julie , Le Bris Yannick , Hello Muriel , Guillouzouic Aurélie , Guardiolle Vianney , Garnier Alice , Grossi Olivier , Gaborit Benjamin , Néel Antoine
Published: February 2024

Objectives

VEXAS is a recently described acquired auto-inflammatory and haematological syndrome caused by somatic mutations in UBA1. To date, VEXAS is not a recognized cause of acquired immunodeficiency.

Methods

Two of our ten VEXAS patients developed a disseminated Mycobacterium avium infection. To shed light on this observation, we retrospectively studied all patients with disseminated non-tuberculous mycobacterial infections (NTMi) seen at our institution over 13 years. Inclusion criteria were a positive blood/bone marrow culture, or two positive cultures from distinct sites, or one positive culture with two involved sites.

Results

Patient 1 presented with fever, rash, orbital cellulitis and lung infiltrates. Patient 2 presented with fever and purpura. In both cases, Mycobacterium avium was identified on bone marrow culture. Twenty cases of disseminated NTMi were reviewed. Among 11 HIV-negative patients, three had chronic immune-mediated disease; three had untreated myeloid neoplasm; two had VEXAS; one had undergone kidney transplantation; one had GATA-2 deficiency; and one had no identified aetiology. None had lymphoid neoplasia or had undergone bone marrow transplantation. HIV-negative cases had higher CD4 counts than HIV-positive patients (median CD4: 515/mm3  vs 38/mm3, P < 0.001). Monocytopenia was present in seven cases. At 2 years, six patients had died, including both VEXAS patients.

Conclusion

VEXAS patients have an intrinsic susceptibility to disseminated NTMi, which may result from monocytic dysfunction. NTMi can mimic VEXAS flare. Clinicians should maintain a high suspicion for opportunistic infections before escalating immunosuppressive therapy. Further studies are needed to confirm and better decipher the herein reported observations.
Effect of gender and age on bDMARD efficacy for axial spondyloarthritis patients: a meta-analysis of randomized controlled trials
Authors: Xie Yan , Liu Yang , Wu Qiuhong
Published: February 2024

Objective

To study the therapeutic variations of biologic and targeted synthetic DMARDs (b/tsDMARDs) between genders and across age stages in axial SpA (axSpA) patients through meta-analysis.

Methods

Randomized controlled trials published by PubMed, Scopus and Embase before 10 August 2023, testing the efficacy of b/tsDMARDs in axSpA, were searched and systematically reviewed. The Assessment of Spondyloarthritis International Society ≥40% improvement (ASAS40) was used as the primary outcome of treatment response.

Results

Only one study meet the inclusion criteria related to tsDMARDs, which was excluded from further analysis. Nine studies of bDMARDs, with 4127 patients, were included for the final analysis. When compared with placebo, both males [odds ratio (OR) 3.14 (95% CI 2.66, 3.70)] and females [OR 2.32 (95% CI 1.82, 2.82)] and younger [OR 4.00 (95% CI 2.50, 6.40)] and older [OR 2.21 (95% CI 1.15, 4.22)] patients presented significantly better responses to bDMARDs. Also, the efficacies were more evident in males [OR 1.89 (95% CI 1.56, 2.30)] and younger [OR 2.07 (95% CI 1.42, 3.02)] patients. Subgroup analysis revealed that the gender difference in efficacy was more obvious in non-radiographic axSpA (nr-axSpA) patients (Pheterogeneity = 0.03, I2 = 78.1%). Moreover, males with radiographic axSpA (r-axSpA) and nr-axSpA shared similar responses to bDMARDs (Pheterogeneity = 0.87, I2 = 0%), while females with r-axSpA showed greater response than those with nr-axSpA (Pheterogeneity = 0.005, I2 = 87.4%).

Conclusions

The bDMARDs were efficacious in all axSpA patients regardless of gender or age. However, the treatment responses were more evident in male and younger patients. Also, females with r-axSpA had greater responses than those with nr-axSpA, whereas no relevant difference was observed in males, indicating that the gender difference on efficacy was greater in nr-axSpA patients.
Dynamic analysis of an aircraft towing slip-out system considering vertical wheel constraints
Authors: Lu Xin , Sun Yuning , Tang Jie , Zhang Wei
Published: February 2024

To analyse the vertical dynamic characteristics of the aircraft towing system under different constraints on the nose landing gear wheels of the aircraft during the towing slip-out mode, a dynamic model of the towing system considering the constraints between the clamping mechanism and the aircraft nose landing gear wheels was established based on the general towing system dynamic model. On this basis, an analysis was conducted to determine whether considering the aircraft wheel constraints affects the vertical vibration acceleration of the towing vehicle and the nose landing gear in low-speed (10 km/h) and high-speed (40 km/h) operating conditions. With the consideration of constraints at both ends of the aircraft wheels, the vertical acceleration of the towing vehicle's centre of mass increased by 153% and 172% at low speed and high speed, respectively, compared to not considering the aircraft wheel constraints. Additionally, with the consideration of constraints at both ends of the aircraft wheels, the vertical acceleration of the nose landing gear's centre of mass decreased to 20% and 57% at low speed and high speed, respectively, compared to not considering the aircraft wheel constraints. An analysis of the vertical vibration acceleration of the towing vehicle under different wheel constraint conditions found that the Root Mean Square (RMS) value of the vertical vibration acceleration of the towing vehicle's centre of mass was minimized when the clamping angles of the clamping mechanism to the nose landing gear wheels were 63° and 64°, respectively. Under this clamping angle, the influence of the clamping forces at both ends of the clamping mechanism on the vertical vibration acceleration of the towing vehicle was minimal. The research results provide valuable reference for the direct constraints between the clamping mechanism and the nose landing gear wheels in the aircraft towing slip-out system.
Auditory Neural Responses and Communicative Functioning in Children With Microcephaly Related to Congenital Zika Syndrome
Authors: Key Alexandra P. , Powell Sarah L. , Cavalcante Juliana , Frizzo Ana , Mandra Patricia , Tavares Adriana , Menezes Pedro , Hood Linda J.
Published: February 2024

Objectives:

Children with microcephaly exhibit neurodevelopmental delays and compromised communicative functioning, yielding challenges for clinical assessment and informed intervention. This study characterized auditory neural function and communication abilities in children with microcephaly due to congenital Zika syndrome (CZS).

Design:

Click-evoked auditory brainstem responses (ABR) at fast and slow stimulation rates and natural speech-evoked cortical auditory evoked potentials (CAEP) were recorded in 25 Brazilian children with microcephaly related to CZS (M age: 5.93 ± 0.62 years) and a comparison group of 25 healthy children (M age: 5.59 ± 0.80 years) matched on age, sex, ethnicity, and socioeconomic status. Communication abilities in daily life were evaluated using caregiver reports on Vineland Adaptive Behavior Scales-3.

Results:

Caregivers of children with microcephaly reported significantly lower than typical adaptive functioning in the communication and socialization domains. ABR wave I latency did not differ significantly between the groups, suggesting comparable peripheral auditory function. ABR wave V absolute latency and waves I-V interwave latency were significantly shorter in the microcephaly group for both ears and rates. CAEP analyses identified reduced N2 amplitudes in children with microcephaly as well as limited evidence of speech sound differentiation, evidenced mainly by the N2 response latency. Conversely, in the comparison group, speech sound differences were observed for both the P1 and N2 latencies. Exploratory analyses in the microcephaly group indicated that more adaptive communication was associated with greater speech sound differences in the P1 and N2 amplitudes. The trimester of virus exposure did not have an effect on the ABRs or CAEPs.

Conclusions:

Microcephaly related to CZS is associated with alterations in subcortical and cortical auditory neural function. Reduced ABR latencies differ from previous reports, possibly due to the older age of this cohort and careful assessment of peripheral auditory function. Cortical speech sound detection and differentiation are present but reduced in children with microcephaly. Associations between communication performance in daily life and CAEPs highlight the value of auditory evoked potentials in assessing clinical populations with significant neurodevelopmental disabilities.
Minimally Invasive Anterior Closing–wedge Osteotomy for Posterior Tibial Slope Correction: A Pilot Study
Authors: Baker Hayden P. , Lee Cody S. , Serotte Jordan , Poff Charles , Athiviraham Aravind , Hynes Kelly , Strelzow Jason A.
Published: February 2024

Introduction:

The purpose of this study was to investigate the feasibility of performing a new minimally invasive technique for anterior closing–wedge high tibial osteotomy. Our hypothesis was that we would be able to successfully perform the minimally invasive osteotomy with consistent correction of the posterior tibial slope.

Materials and Methods:

Five lower limbs from cadaveric unidentified donors were obtained. Fluoroscopic imaging of the knee was obtained to determine the baseline tibial slope. A standard anterior closing–wedge osteotomy was planned to obtain the desired correction. The anterior bony segment was resected from the proximal tibia utilizing the Shannon burr under fluoroscopic guidance through a 2 cm medial incision. Fixation was completed with 2 staples positioned medial and lateral to the tibial tubercle.

Results:

The average posterior tibial slope of the 5 specimens was 8 degrees (SD: 2.3, range: 6 to 12). The average final posterior tibial was 1.8 degrees (SD: 2.1, range: −1 to 5). The average slope correction was 6.2 degrees (SD: 0.7, range: 5 to 7). Posterior tibial cortical fracture did not occur in any of the cases.

Conclusions:

Our novel minimally invasive anterior closing–wedge high tibial osteotomy technique resulted in a reproducible correction of posterior tibial slope in a cadaveric model. This is the first study to describe a minimally invasive technique for anterior closing–wedge high tibial osteotomy. Larger cadaveric studies including multiple surgeons across institutions are warranted to validate the described technique between providers.

Level of Evidence:

Level IV—Controlled laboratory study
Early Mobilization Using a Mobile Patient Lift in the ICU: A Randomized Controlled Trial
Authors: Suzuki Ginga , Kanayama Hiromi , Arai Yoshiaki , Iwanami Yuji , Kobori Toshimitsu , Masuyama Yuka , Yamamoto Saki , Serizawa Hibiki , Nakamichi Yoshimi , Watanabe Masayuki , Honda Mitsuru , Okuni Ikuko
Published: February 2024

Objectives:

To ascertain whether a mobile patient lift facilitates early mobilization in ventilated ICU patients.

Design:

A single-center, open-label, randomized controlled trial.

Setting:

An academic ICU in Tokyo.

Patients:

Eighty patients were admitted to ICU and expected ventilation for at least 48 hours.

Interventions:

In the intervention group, in addition to the rehabilitation protocol received by the control group, patients were assisted in sitting, standing, transfers, and walking using the mobile patient lift.

Measurements and Main Results:

The intervention group predominantly stood faster than the control group (1.0 vs. 3.0 d, p < 0.01). The Intervention group also had significantly higher Functional Status Score-ICU scores at ICU discharge. However, the Medical Research Council score and Barthel index at discharge, length of ICU stay, and number of ventilator-free days did not differ between the two groups.

Conclusions:

The use of mobile patient lifts facilitates the earlier standing of patients on ventilators. This may contribute to patients improved physical function in the ICU.

Trial Registration:

The study protocol was registered with the University Hospital Medical Information Network (UMIN) under the registration number UMIN000044965. Registered July 30, 2021.
Effects of CTLA-4 Single Nucleotide Polymorphisms on Toxicity of Ipilimumab-Containing Regimens in Patients With Advanced Stage Melanoma
Authors: de Joode Karlijn , Mora Alfonso Rojas , van Schaik Ron H.N. , Zippelius Alfred , van der Veldt Astrid , Gerard Camille Léa , Läubli Heinz , Michielin Olivier , von Moos Roger , Joerger Markus , Levesque Mitchell P. , Aeppli Stefanie , Mangana Johanna , Mangas Cristina , Trost Nadine , Meyer Stefan , Parvex Sandra Leoni , Mathijssen Ron , Metaxas Yannis
Published: February 2024

Single nucleotide polymorphisms (SNPs) in the cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) gene, an inhibitor of T-cell priming, are associated with auto and alloimmunity. Studies implied a role for these SNPs as surrogate markers for immunotherapy-outcome in patients with melanoma. However, no predictive SNPs are defined to date. We analyzed different CTLA-4 SNPs in a large multicenter cohort of patients with ipilimumab-treated melanoma and investigated possible correlations with treatment-related outcomes. Archival blood and/or tumor tissue samples were collected from 361 patients with advanced-stage ipilimumab-treated (±nivolumab) in 6 Swiss and Dutch hospitals. Matrix-assisted laser desorption/ionization–time of flight mass spectrometry based DNA genotyping was performed for 10 different CTLA-4 SNPs: 49A>G, CT60G>A, Jo27T>C, Jo30G>A, Jo31G>T, −658C>T, −1722T>C, −1661A>G, 318C>T, and C>T rs1863800. Associations between different allele genotypes and occurrence of grade ≥3 adverse events (AEs) and survival were tested using univariable logistic regressions or Cox proportional hazard models. 262/361 (73%) patients could be analyzed; 65% of those were males, the median age was 58 years, 39% showed a partial or complete response, and 65% had ≥1 AEs. A TT-genotype of −1722T>C SNP was significantly associated with a lower incidence of grade ≥3 AEs (P = 0.049), whereas the GG-genotype of CT60G>A correlated with a higher incidence of grade ≥3 AEs (P = 0.026). The TT-genotype of Jo27T>C SNP (P = 0.056) and GG-genotype of Jo31G>T (P = 0.046) were associated with overall survival. CTLA-4 SNPs might predict treatment-related outcomes in patients with melanoma receiving ipilimumab. Confirmatory studies are needed to fully exploit those findings as predictive biomarkers for ipilimumab AEs.
The Keystone Perforator Island Flap: Review of Utility and Versatile Clinical Applications
Authors: Pawlak Natalie , De La Cruz Ku Gabriel , Chatterjee Abhishek , Persing Sarah , Homsy Christopher
Published: February 2024

Background:

The keystone perforator island flap (KPIF) was described almost a decade ago. However, this flap has only recently been recognized for its advantages in various clinical applications in plastic surgery. A better understanding of the versatility of KPIFs can help promote the widespread adoption of this technique for complex wounds in various anatomical regions.

Methods:

A retrospective chart review was conducted of patients undergoing KPIFs from December 2018 to March 2022 at the authors’ home institution. The indications, surgical approaches, patient characteristics, and outcomes were extracted for review and analysis.

Results:

A total of 12 patients (ages 13–86 years) underwent reconstruction with KPIFs for oncologic and nononcologic defects. By anatomic region, three cases involved the upper back, six involved the lumbosacral region, one involved the perineum, and two involved the midfoot. Half of the patients (n = 6) had failed previous attempts at wound closure. The mean defect size was 13.8 × 10.0 cm for the upper back lesions, 13.7 × 4.8 for the lumbosacral defects, and 3.5 × 2.0 for the metatarsal wounds. Median follow-up time for all patients was 7.5 months (IQR: 4–10.5). On follow-up, there was 100% flap survival.

Conclusion:

KPIFs are a simple, safe, and suitable option for reconstructive closure of defects in many anatomical areas, including wounds complicated by previous failed closure attempts, with low complication risk profile.