Individual timing consistency across long-distance songbird migrations.

Migration timing in long-distance migratory birds plays an essential role in individual survival and fitness and is thought to be driven by circannual routines cued by photoperiod with some plasticity to environmental conditions. We examined the individual order of migration timing in purple martins (Progne subis), a neotropical migratory songbird that travels between breeding sites throughout eastern North America and nonbreeding sites in Brazil. Migration timing data were collected for 295 different individual purple martins over 9 years using light-level geolocators deployed at breeding sites across the range. We used linear mixed-effect models to examine the influence of the rank order of individual departure dates in one season on the rank order of four subsequent migration events while controlling for the effects of breeding latitude, sex, and age. Overall, we found evidence for consistent individual timing that can extend across 8 months and 12,000-24,000 km of migration. Individual rank order of migration timing in purple martins was generally conserved across migrations with consistent timings between fall departure dates from, and spring arrival dates to the breeding site the following year (0.28 ± 0.03, 95% CI 0.22-0.34), as well as at a finer scale across fall migration (0.33 ± 0.05, 95% CI 0.23-0.43), over the stationary nonbreeding period (0.39 ± 0.04, 95% CI 0.31-0.47), and across spring migration (0.03 ± 0.001, 95% CI 0.028-0.032). These results demonstrate that purple martins exhibit consistency in individual migration timing throughout the annual cycle that is likely driven by inherent individual circannual schedules. We additionally found that migration distance played a significant role, as the consistency of individual timing lessened over longer distances. Understanding how individual birds time migrations and if individuals are consistent between events can provide insight into how birds respond to shifts in their environment with climate change.

Comparative analysis of LAG3 antibodies shows differential binding patterns by flow cytometry.

BACKGROUND: LAG3 is an immune checkpoint molecule with emerging therapeutic use. Expression of LAG3 is well studied on T cells, but the proportion of LAG3-expressing cells varies greatly by study and its comparative expression between non-T cells is lacking. METHODS/OBJECTIVES: This study uses flow cytometry to compare surface LAG3 expression between T cells, NK cells, B cells, pDCs and monocytes of healthy donors. This study also compares three monoclonal LAG3 antibodies to a commonly used polyclonal LAG3 antibody on ex vivo and PHA-blasts from healthy donors and LAG3+ and LAG3- cell lines. RESULTS: LAG3 was most highly expressed on classical and intermediate monocytes (25 % and 32 %, respectively), while LAG3 expression on B cells, NK cells and iNKT cells was negligible. Notably, the polyclonal antibody stained a higher proportion of all cell types than the monoclonal antibodies, which had similar staining patterns to one another. Further study using LAG3+ and LAG3- cell lines showed greater specificity and similar sensitivity of the monoclonal antibody T47-530 than the polyclonal antibody. CONCLUSION: Monocytes may represent an unappreciated source of LAG3 and target of LAG3 checkpoint inhibitors. Furthermore, the discrepancies between monoclonal and polyclonal LAG3 antibodies warrants consideration when designing future studies and interpreting past studies, and may explain discrepancies in the literature.

Hesperetin but not ellagic acid increases myosin heavy chain expression and cell fusion in C2C12 myoblasts in the presence of oxidative stress.

Introduction: Skeletal muscle regeneration is impaired in elderly. An oxidative stress-induced decrease in differentiation capacity of muscle satellite cells is a key factor in this process. The aim of this study is to investigate whether orange polyphenol hesperetin and pomegranate polyphenol ellagic acid enhance myoblast differentiation in the presence and absence of oxidative stress, and to explore underlying mechanisms. Methods: C2C12 myoblasts were proliferated for 24 h and differentiated for 120 h while exposed to hesperetin (5, 20, 50 µM), ellagic acid (0.05, 0.1 µM) or a combination (20 µM hesperetin, 0.05 µM ellagic acid) with and without oxidative stress-inducing compound menadione (9 µM) during 24 h of proliferation and during the first 5 h of differentiation. The number of proliferating cells was assessed using fluorescent labeling of incorporated 5-ethynyl-2'-deoxyuridine. Myosin heavy chain expression was assessed by fluorescence microscopy and cell fusion index was calculated. Furthermore, protein expression of phosphorylated p38 and myomixer were assessed using Western blot. Results: None of the compounds induced effects on cell proliferation. Without menadione, 50 µM hesperetin increased fusion index by 12.6% compared to control (p < 0.01), while ellagic acid did not affect measured parameters of differentiation. Menadione treatment did not change myosin heavy chain expression and fusion index. In combination with menadione, 20 µM hesperetin increased myosin heavy chain expression by 35% (p < 0.01) and fusion index by 7% (p = 0.04) compared to menadione. Furthermore, the combination of menadione with hesperetin and ellagic acid increased myosin heavy chain expression by 35% compared to menadione (p = 0.02). Hesperetin and ellagic acid did not change p38 phosphorylation and myomixer expression compared to control, while treatment with menadione increased p38 phosphorylation (p < 0.01) after 5 h and decreased myomixer expression (p = 0.04) after 72 h of differentiation. Conclusion and discussion: Hesperetin increased myosin heavy chain expression in the presence of oxidative stress induced by menadione, and increased cell fusion both in the presence and absence of menadione. Ellagic acid did not affect the measured parameters of myoblast differentiation. Therefore, hesperetin should be considered as nutritional prevention or treatment strategy to maintain muscle function in age-related diseases such as sarcopenia. Future research should focus on underlying mechanisms and translation of these results to clinical practice.

Integrating mechanism-based T cell phenotypes into a model of tumor-immune cell interactions.

Interactions between cancer cells and immune cells in the tumor microenvironment influence tumor growth and can contribute to the response to cancer immunotherapies. It is difficult to gain mechanistic insights into the effects of cell-cell interactions in tumors using a purely experimental approach. However, computational modeling enables quantitative investigation of the tumor microenvironment, and agent-based modeling, in particular, provides relevant biological insights into the spatial and temporal evolution of tumors. Here, we develop a novel agent-based model (ABM) to predict the consequences of intercellular interactions. Furthermore, we leverage our prior work that predicts the transitions of CD8+ T cells from a naïve state to a terminally differentiated state using Boolean modeling. Given the details incorporated to predict T cell state, we apply the integrated Boolean-ABM framework to study how the properties of CD8+ T cells influence the composition and spatial organization of tumors and the efficacy of an immune checkpoint blockade. Overall, we present a mechanistic understanding of tumor evolution that can be leveraged to study targeted immunotherapeutic strategies.

Enhancing Postmarketing Surveillance of Medical Products With Large Language Models.

Importance: The Sentinel System is a key component of the US Food and Drug Administration (FDA) postmarketing safety surveillance commitment and uses clinical health care data to conduct analyses to inform drug labeling and safety communications, FDA advisory committee meetings, and other regulatory decisions. However, observational data are frequently deemed insufficient for reliable evaluation of safety concerns owing to limitations in underlying data or methodology. Advances in large language models (LLMs) provide new opportunities to address some of these limitations. However, careful consideration is necessary for how and where LLMs can be effectively deployed for these purposes. Observations: LLMs may provide new avenues to support signal-identification activities to identify novel adverse event signals from narrative text of electronic health records. These algorithms may be used to support epidemiologic investigations examining the causal relationship between exposure to a medical product and an adverse event through development of probabilistic phenotyping of health outcomes of interest and extraction of information related to important confounding factors. LLMs may perform like traditional natural language processing tools by annotating text with controlled vocabularies with additional tailored training activities. LLMs offer opportunities for enhancing information extraction from adverse event reports, medical literature, and other biomedical knowledge sources. There are several challenges that must be considered when leveraging LLMs for postmarket surveillance. Prompt engineering is needed to ensure that LLM-extracted associations are accurate and specific. LLMs require extensive infrastructure to use, which many health care systems lack, and this can impact diversity, equity, and inclusion, and result in obscuring significant adverse event patterns in some populations. LLMs are known to generate nonfactual statements, which could lead to false positive signals and downstream evaluation activities by the FDA and other entities, incurring substantial cost. Conclusions and Relevance: LLMs represent a novel paradigm that may facilitate generation of information to support medical product postmarket surveillance activities that have not been possible. However, additional work is required to ensure LLMs can be used in a fair and equitable manner, minimize false positive findings, and support the necessary rigor of signal detection needed for regulatory activities.

A methodological framework for assessing sea level rise impacts on nitrate loading in coastal agricultural watersheds using SWAT+: A case study of the Tar-Pamlico River basin, North Carolina, USA.

This study addresses the urgent need to understand the impacts of climate change on coastal ecosystems by demonstrating how to use the SWAT+ model to assess the effects of sea level rise (SLR) on agricultural nitrate export in a coastal watershed. Our framework for incorporating SLR in the SWAT+ model includes: (1) reclassifying current land uses to water for areas with elevations below 0.3 m based on SLR projections for mid-century; (2) creating new SLR-influenced land uses, SLR-influenced crop database, and hydrological response units for areas with elevations below 2.4 m; and (3) adjusting SWAT+ parameters for the SLR-influenced areas to simulate the effects of saltwater intrusion on processes such as plant yield and denitrification. We demonstrate this approach in the Tar-Pamlico River basin, a coastal watershed in eastern North Carolina, USA. We calibrated the model for monthly nitrate load at Washington, NC, achieving a Nash-Sutcliffe Efficiency (NSE) of 0.61. Our findings show that SLR substantially alters nitrate delivery to the estuary, with increased nitrate loads observed in all seasons. Higher load increases were noted in winter and spring due to elevated flows, while higher percentage increases occurred in summer and fall, attributed to reduced plant uptake and disrupted nitrogen cycle transformations. Overall, we observed an increase in mean annual nitrate loads from 155,000 kg NO3-N under baseline conditions to 157,000 kg NO3-N under SLR scenarios, confirmed by a statistically significant paired t-test (p = 2.16 × 10-10). This pioneering framework sets the stage for more sophisticated and accurate modeling of SLR impacts in diverse hydrological scenarios, offering a vital tool for hydrological modelers.

Mitochondrial Ca2+-coupled generation of reactive oxygen species, peroxynitrite formation, and endothelial dysfunction in Cantú syndrome.

Cantú syndrome is a multisystem disorder caused by gain-of-function (GOF) mutations in KCNJ8 and ABCC9, the genes encoding the pore-forming inward rectifier Kir6.1 and regulatory sulfonylurea receptor SUR2B subunits, respectively, of vascular ATP-sensitive K+ (KATP) channels. In this study, we investigated changes in the vascular endothelium in mice in which Cantú syndrome-associated Kcnj8 or Abcc9 mutations were knocked in to the endogenous loci. We found that endothelium-dependent dilation was impaired in small mesenteric arteries from Cantú mice. Loss of endothelium-dependent vasodilation led to increased vasoconstriction in response to intraluminal pressure or treatment with the adrenergic receptor agonist phenylephrine. We also found that either KATP GOF or acute activation of KATP channels with pinacidil increased the amplitude and frequency of wave-like Ca2+ events generated in the endothelium in response to the vasodilator agonist carbachol. Increased cytosolic Ca2+ signaling activity in arterial endothelial cells from Cantú mice was associated with elevated mitochondrial [Ca2+] and enhanced reactive oxygen species (ROS) and peroxynitrite levels. Scavenging intracellular or mitochondrial ROS restored endothelium-dependent vasodilation in the arteries of mice with KATP GOF mutations. We conclude that mitochondrial Ca2+ overload and ROS generation, which subsequently leads to nitric oxide consumption and peroxynitrite formation, cause endothelial dysfunction in mice with Cantú syndrome.

An investigation of composition, morphology, mechanical properties, and microdamage accumulation of human type 2 diabetic bone.

This study investigates the biomechanics of type 2 diabetic bone fragility through a multiscale experimental strategy that considers structural, mechanical, and compositional components of ex vivo human trabecular and cortical bone. Human tissue samples were obtained from the femoral heads of patients undergoing total hip replacement. Mechanical testing was carried out on isolated trabecular cores using monotonic and cyclic compression loading and nanoindentation experiments, with bone microdamage analysed using micro-computed tomography (CT) imaging. Bone composition was evaluated using Raman spectroscopy, high-performance liquid chromatography, and fluorometric spectroscopy. It was found that human type 2 diabetic bone had altered mechanical, compositional, and morphological properties compared to non-type 2 diabetic bone. High-resolution micro-CT imaging showed that cores taken from the central trabecular region of the femoral head had higher bone mineral density (BMD), bone volume, trabecular thickness, and reduced trabecular separation. Type 2 diabetic bone also had enhanced macro-mechanical compressive properties under mechanical loading compared to non-diabetic controls, with significantly higher apparent modulus, yield stress, and pre-yield toughness evident, even when properties were normalised against the bone volume. Using nanoindentation, there were no significant differences in the tissue-level mechanical properties of cortical or trabecular bone in type 2 diabetic samples compared to controls. Through compositional analysis, higher levels of furosine were found in type 2 diabetic trabecular bone, and an increase in both furosine and carboxymethyl-lysine (an advanced glycation end-product) was found in cortical bone. Raman spectroscopy showed that type 2 diabetic bone had a higher mineral-to-matrix ratio, carbonate substitution, and reduced crystallinity compared to the controls. Together, this study shows that type 2 diabetes leads to distinct changes in both organic and mineral phases of the bone tissue matrix, but these changes did not coincide with any reduction in the micro- or macro-mechanical properties of the tissue under monotonic or cyclic loading.

Electrophysiology of Human iPSC-derived Vascular Smooth Muscle Cells and Cell-autonomous Consequences of Cantú Syndrome Mutations.

Cantú syndrome (CS), a multisystem disease with a complex cardiovascular phenotype, is caused by gain-of-function (GoF) variants in the Kir6.1/SUR2 subunits of ATP-sensitive potassium (KATP) channels and is characterized by low systemic vascular resistance, as well as tortuous, dilated, vessels, and decreased pulse-wave velocity. Thus, CS vascular dysfunction is multifactorial, with both hypomyotonic and hyperelastic components. To dissect whether such complexities arise cell autonomously within vascular smooth muscle cells (VSMCs) or as secondary responses to the pathophysiological milieu, we assessed electrical properties and gene expression in human induced pluripotent stem cell-derived VSMCs (hiPSC-VSMCs), differentiated from control and CS patient-derived hiPSCs, and in native mouse control and CS VSMCs. Whole-cell voltage clamp of isolated aortic and mesenteric arterial VSMCs isolated from wild-type (WT) and Kir6.1[V65M] (CS) mice revealed no clear differences in voltage-gated K+ (Kv) or Ca2+ currents. Kv and Ca2+ currents were also not different between validated hiPSC-VSMCs differentiated from control and CS patient-derived hiPSCs. While pinacidil-sensitive KATP currents in control hiPSC-VSMCs were similar to those in WT mouse VSMCs, they were considerably larger in CS hiPSC-VSMCs. Under current-clamp conditions, CS hiPSC-VSMCs were also hyperpolarized, consistent with increased basal K conductance and providing an explanation for decreased tone and decreased vascular resistance in CS. Increased compliance was observed in isolated CS mouse aortae and was associated with increased elastin mRNA expression. This was consistent with higher levels of elastin mRNA in CS hiPSC-VSMCs and suggesting that the hyperelastic component of CS vasculopathy is a cell-autonomous consequence of vascular KATP GoF. The results show that hiPSC-VSMCs reiterate expression of the same major ion currents as primary VSMCs, validating the use of these cells to study vascular disease. Results in hiPSC-VSMCs derived from CS patient cells suggest that both the hypomyotonic and hyperelastic components of CS vasculopathy are cell-autonomous phenomena driven by KATP overactivity within VSMCs .

Completeness and readability of GPT-4-generated multilingual discharge instructions in the pediatric emergency department.

Objectives: The aim of this study was to assess the completeness and readability of generative pre-trained transformer-4 (GPT-4)-generated discharge instructions at prespecified reading levels for common pediatric emergency room complaints. Materials and Methods: The outputs for 6 discharge scenarios stratified by reading level (fifth or eighth grade) and language (English, Spanish) were generated fivefold using GPT-4. Specifically, 120 discharge instructions were produced and analyzed (6 scenarios: 60 in English, 60 in Spanish; 60 at a fifth-grade reading level, 60 at an eighth-grade reading level) and compared for completeness and readability (between language, between reading level, and stratified by group and reading level). Completeness was defined as the proportion of literature-derived key points included in discharge instructions. Readability was quantified using Flesch-Kincaid (English) and Fernandez-Huerta (Spanish) readability scores. Results: English-language GPT-generated discharge instructions contained a significantly higher proportion of must-include discharge instructions than those in Spanish (English: mean (standard error of the mean) = 62% (3%), Spanish: 53% (3%), P = .02). In the fifth-grade and eighth-grade level conditions, there was no significant difference between English and Spanish outputs in completeness. Readability did not differ across languages. Discussion: GPT-4 produced readable discharge instructions in English and Spanish while modulating document reading level. Discharge instructions in English tended to have higher completeness than those in Spanish. Conclusion: Future research in prompt engineering and GPT-4 performance, both generally and in multiple languages, is needed to reduce potential for health disparities by language and reading level.

Compound-SNE: Comparative alignment of t-SNEs for multiple single-cell omics data visualisation.

SUMMARY: One of the first steps in single-cell omics data analysis is visualization, which allows researchers to see how well-separated cell-types are from each other. When visualizing multiple datasets at once, data integration/batch correction methods are used to merge the datasets. While needed for downstream analyses, these methods modify features space (e.g. gene expression)/PCA space in order to mix cell-types between batches as well as possible. This obscures sample-specific features and breaks down local embedding structures that can be seen when a sample is embedded alone. Therefore, in order to improve in visual comparisons between large numbers of samples (e.g., multiple patients, omic modalities, different time points), we introduce Compound-SNE, which performs what we term a soft alignment of samples in embedding space. We show that Compound-SNE is able to align cell-types in embedding space across samples, while preserving local embedding structures from when samples are embedded independently. AVAILABILITY AND IMPLEMENTATION: Python code for Compound-SNE is available for download at https://github.com/HaghverdiLab/Compound-SNE. SUPPLEMENTARY INFORMATION: Available online. Provides algorithmic details and additional tests.

A new measure of regulatory focus: Preventing measurement error by promoting best validation practices.

OBJECTIVE AND BACKGROUND: The goals of this project were to improve our understanding of chronic regulatory focus constructs and to provide researchers with a measure that adequately assesses the constructs, can distinguish individual differences effectively across the range of the constructs, and is appropriate for use in diverse populations. METHOD: Employing best practices in construct validation, we developed the International Personality Item Pool Regulatory Focus Scale (IPIP-RFS). Utilizing 14 samples (N = 4867), we established substantive (via expert ratings and regulatory focus literature), structural (via factor analysis, item response theory, and measurement invariance), and external (via convergent, discriminant, and predictive associations) validity. RESULTS: The IPIP-RFS adequately assesses the constructs of chronic promotion focus and prevention focus, can accurately assess individuals along the continua of the constructs, and is suitable for use among populations that vary in gender, race, and age. Individual differences in promotion focus reflect self-regulation and goal pursuit related to cognitive and behavioral exploration and flexibility (i.e., plasticity), whereas individual differences in prevention focus reflect self-regulation and goal pursuit related to motivational and interpersonal steadiness (i.e., stability). CONCLUSIONS: Promotion and prevention focus are important elements of personality with broad implications for functioning and outcomes in health and other important domains.

A novel ABCC9 variant in a Greek family with Cantu syndrome affecting multiple generations highlights the functional role of the SUR2B NBD1.

Cantu syndrome (CS) (OMIM #239850) is an autosomal dominant multiorgan system condition, associated with a characteristic facial phenotype, hypertrichosis, and multiple cardiovascular complications. CS is caused by gain-of-function (GOF) variants in KCNJ8 or ABCC9 that encode pore-forming Kir6.1 and regulatory SUR2 subunits of ATP-sensitive potassium (KATP) channels. A novel heterozygous ABCC9 variant, c.2440G>T; p.Gly814Trp, was identified in three individuals from a four generation Greek family. The membrane potential in cells stably expressing hKir6.1 and hSUR2B with p.Gly814Trp was hyperpolarized compared to cells expressing WT channels, and inside-out patch-clamp assays of KATP channels formed with hSUR2B p.Gly814Trp demonstrated a decreased sensitivity to ATP inhibition, confirming a relatively mild GOF effect of this variant. The specific location of the variant reveals an unrecognized functional role of the first glycine in the signature motif of the nucleotide binding domains in ATP-binding cassette (ABC) protein ion channels.

The antimicrobial effectiveness of chlorhexidine and chlorhexidine-silver sulfadiazine-impregnated central venous catheters against the emerging fungal pathogen Candida auris.

BACKGROUND: Candida auris is an emerging multidrug-resistant fungus associated with catheter-related bloodstream infections. In vitro efficacy of chlorhexidine (CHX) and CHX-silver sulfadiazine-impregnated (CHX-S) antimicrobial central venous catheters (CVCs) against C auris was investigated. METHODS: Minimum inhibitory and bactericidal CHX concentrations were determined against 19 C auris isolates. To assess extraluminal efficacy, segments from CVCs impregnated externally (CHX-S1) and both externally and internally (CHX-S2) were plasma-conditioned for 1- and 6-day, and to assess intraluminal efficacy, CHX-S2 CVCs were preconditioned with saline-lock for 6days, followed by 24-hour C auris inoculation and microbial adherence determination on impregnated and nonimpregnated CVCs. RESULTS: CHX inhibited all C auris isolates with minimum inhibitory and bactericidal concentrations range of 8 to 128 µg/mL. C auris adherence was reduced on CHX-S1 and CHX-S2 extraluminally by 100% on day 1, 86.96% to 100% on day 7, and intraluminally on CHX-S2 by 56.86% to 90.52% on day 7. DISCUSSION: CHX and CHX-S CVC performance against C auris observed in this study is consistent with antimicrobial benefits observed in prior preclinical and randomized controlled clinical studies. CONCLUSIONS: CHX showed strong inhibitory and cidal effects on C auris. CHX-S CVCs proved highly efficacious against this pathogen under in vitro conditions. Additional studies, however, are required to confirm clinical benefit.

Increasing the Dye Payload of Cetuximab-IRDye800CW Enables Photodynamic Therapy.

Cetuximab (Cet)-IRDye800CW, among other antibody-IRDye800CW conjugates, is a potentially effective tool for delineating tumor margins during fluorescence image-guided surgery (IGS). However, residual disease often leads to recurrence. Photodynamic therapy (PDT) following IGS is proposed as an approach to eliminate residual disease but suffers from a lack of molecular specificity for cancer cells. Antibody-targeted PDT offers a potential solution for this specificity problem. In this study, we show, for the first time, that Cet-IRDye800CW is capable of antibody-targeted PDT in vitro when the payload of dye molecules is increased from 2 (clinical version) to 11 per antibody. Cet-IRDye800CW (1:11) produces singlet oxygen, hydroxyl radicals, and peroxynitrite upon activation with 810 nm light. In vitro assays on FaDu head and neck cancer cells confirm that Cet-IRDye800CW (1:11) maintains cancer cell binding specificity and is capable of inducing up to ∼90% phototoxicity in FaDu cancer cells. The phototoxicity of Cet-IRDye800CW conjugates using 810 nm light follows a dye payload-dependent trend. Cet-IRDye800CW (1:11) is also found to be more phototoxic to FaDu cancer cells and less toxic in the dark than the approved chromophore indocyanine green, which can also act as a PDT agent. We propose that antibody-targeted PDT using high-payload Cet-IRDye800CW (1:11) could hold potential for eliminating residual disease postoperatively when using sustained illumination devices, such as fiber optic patches and implantable surgical bed balloon applicators. This approach could also potentially be applicable to a wide variety of resectable cancers that are amenable to IGS-PDT, using their respective approved full-length antibodies as a template for high-payload IRDye800CW conjugation.

Simultaneous bilateral total hip arthroplasty-a survey of Irish orthopaedic surgeons' practice.

BACKGROUND: Bilateral total hip arthroplasty may be performed simultaneously (SIMTHA) or in two staged operations. AIM: To assess attitudes towards and utilization of SIMTHA in Irish orthopaedic practice, and to assess patient and surgeon factors which are associated with the management of bilateral hip arthritis. METHODS: A 16-question electronic survey (Google Forms) was distributed via email to consultant Irish orthopaedic surgeons who perform total hip arthroplasty, followed by a reminder 1 month later. A p value < 0.05 was considered significant. RESULTS: There were 53 responses from arthroplasty surgeons, with 28% reporting they never perform SIMTHA, 26% have performed ≤ 5 SIMTHA, and 46% do ≥ 1 SIMTHA per year. Amongst the 15 surgeons who do not do SIMTHA, 60% reported a preference for staged arthroplasty, 20% felt it was not feasible in their institution, and a third reported a lack of experience with SIMTHA. There was a significant association between not performing SIMTHA and years of consultant experience (p = 0.002). There were no institutional guidelines on eligibility criteria for SIMTHA. The most common time interval for staged bilateral arthroplasty was 6-12 weeks (60%). Overall, 56% of surgeons felt SIMTHA is underutilised in the Irish healthcare system; this was associated with greater SIMTHA volume (p = 0.023). CONCLUSION: Half of the Irish arthroplasty surgeons report SIMTHA is a regular aspect of their practice. Performing SIMTHA is associated with greater arthroplasty volume, more recent consultant appointments, and a perception that the operation is underutilised.

Modulation of TMEM16B channel activity by the calcium-activated chloride channel regulator 4 (CLCA4) in human cells.

The Ca2+-activated Cl- channel regulator CLCA1 potentiates the activity of the Ca2+-activated Cl- channel (CaCC) TMEM16A by directly engaging the channel at the cell surface, inhibiting its reinternalization and increasing Ca2+-dependent Cl- current (ICaCC) density. We now present evidence of functional pairing between two other CLCA and TMEM16 protein family members, namely CLCA4 and the CaCC TMEM16B. Similar to CLCA1, (i) CLCA4 is a self-cleaving metalloprotease, and the N-terminal portion (N-CLCA4) is secreted; (ii) the von Willebrand factor type A (VWA) domain in N-CLCA4 is sufficient to potentiate ICaCC in HEK293T cells; and (iii) this is mediated by the metal ion-dependent adhesion site motif within VWA. The results indicate that, despite the conserved regulatory mechanism and homology between CLCA1 and CLCA4, CLCA4-dependent ICaCC are carried by TMEM16B, rather than TMEM16A. Our findings show specificity in CLCA/TMEM16 interactions and suggest broad physiological and pathophysiological links between these two protein families.

Do joint-preserving hip procedures compromise subsequent total hip arthroplasty? A meta-analysis of complications, functional outcome and survivorship.

BACKGROUND: Joint-preserving hip operations can help relieve pain and delay the need for long-term joint arthroplasty. Previous research has not identified procedures that can compromise outcomes following total hip arthroplasty (THA). This meta-analysis aims to evaluate the effect of joint-preserving hip operations on outcomes following subsequent THA. METHODS: MEDLINE, EMBASE and Scopus databases were searched from the date of inception until February 2024. All studies comparing outcomes following THA in individuals with (PS) and without prior surgery (NPS) of the femur or pelvis were included. Data on operative time, blood loss, intra- and post-operative complications, functional outcomes, and implant survivorship were extracted. RESULTS: 16 studies, comprising 2576 patients were included (PS = 939, NPS = 1637). The PS group was associated with significantly longer operative time [MD: 8.1, 95% CI: 4.6-11.6], significantly greater blood loss [MD: 167.8, 95% CI: 135.6-200.0], and a higher risk of intra-operative peri-prosthetic fracture [RR: 1.9, 95% CI: 1.2-3.0], specifically, with prior femoral osteotomy. There were no differences in terms of risks of dislocation [RR: 1.8, 95% CI: 1.0-3.2], implant loosening [RR: 1.0, 95% CI: 0.7-1.5], or revision surgery [RR: 1.3, 95% CI: 1.0-1.7] between the two groups. The PS group was associated with significantly poorer improvements in functional outcome [MD: -5.6, 95% CI: -7.6-(-3.5)], specifically, with prior acetabular osteotomy. Implant survivorship in the two groups was comparable after one year [HR: 1.9, 95% CI: 0.6-6.2] but significantly inferior in the PS group after five years [HR: 2.5, 95% CI: 1.4-4.7], specifically, with prior femoral osteotomy. CONCLUSION: Joint-preserving hip operations are associated with greater intra-operative challenges and complications. In subsequent joint arthroplasty, prior acetabular procedures affect functional outcomes while prior femoral procedures influence implant survivorship. Hip pain due to the morphological sequelae of pediatric hip pathology can be debilitating at a young age. Surgical decision-making at that time needs to consider the survivorship of a THA implanted at that young age against the consequences of hip preservation surgery on further THA.