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.

Effect of Treatment of Residual Disease After Immunotherapy-Based Combinations on Complete Response Rate of Patients With Metastatic Renal Cell Carcinomas.

INTRODUCTION: Immune checkpoint inhibitor (ICI)-based combinations have revolutionized the management of first-line metastatic renal cell carcinoma (mRCC) by improving patient survival. Large phase 3 randomized trials assessing ICI-based combinations have reported complete response (CR) rates of 10% to 18% in the first-line setting. However, there is a scarcity of data about the effect of treatment of residual disease regarding CR rates improvement. MATERIALS AND METHODS: We included retrospectively all consecutive mRCC patients treated in first-line setting at the Institut de Cancérologie Strasbourg Europe with an ICI-based combination involving ICI or TKI, either alone or with added local treatment of residual disease. Patients were characterized according to IMDC risk. Radiologic response was defined according to RECIST v1.1. RESULTS: We enrolled 80 mRCC patients treated with ICI-based combinations between May 2015 and May 2022. The median age was 63 years. Regarding IMDC risk, there were 12 favourable (15%), 50 intermediate (63%), and 18 poor-risk (22%) patients. Forty-seven patients (59%) received ICI + ICI, 24 (30%) received ICI + TKI, and 9 (11%) received another ICI-based therapy. In total, 8 achieved CR (10%), 36 patients (45%) achieved partial response, 23 (29%) achieved stable disease and 12 achieved progressive disease (15%) as the best response with systemic therapy alone. By adding local treatment of residual disease, 11 additional patients (14%) achieved radiological NED. Residual disease resected sites included kidney (n = 6), lymph nodes (n = 5), lung metastases (n = 2) and liver metastases (n = 1). CONCLUSIONS: The resection of residual disease after first-line ICI-based therapy is associated with improved CR rate (CR + NED) in patients with mRCC. These results need to be validated in prospective trial. PATIENT SUMMARY: In recent years, the advent of immunotherapy has radically changed the management of patients with metastatic kidney cancer. Approximately 10% to 18% of these patients using immune checkpoint inhibitor (ICI)-based combinations no longer have detectable disease on CT scans (complete response). There are currently few data on the use of treatment of residual disease to increase the number of patients in complete response. In this retrospective study, the complete response rate with ICI-based treatment was 10%. When local treatment was added, the number of patients with a complete response increased to 24%. This strategy could increase the number of patients with a prolonged complete response in the future.

Strand-resolved mutagenicity of DNA damage and repair.

DNA base damage is a major source of oncogenic mutations1. Such damage can produce strand-phased mutation patterns and multiallelic variation through the process of lesion segregation2. Here we exploited these properties to reveal how strand-asymmetric processes, such as replication and transcription, shape DNA damage and repair. Despite distinct mechanisms of leading and lagging strand replication3,4, we observe identical fidelity and damage tolerance for both strands. For small alkylation adducts of DNA, our results support a model in which the same translesion polymerase is recruited on-the-fly to both replication strands, starkly contrasting the strand asymmetric tolerance of bulky UV-induced adducts5. The accumulation of multiple distinct mutations at the site of persistent lesions provides the means to quantify the relative efficiency of repair processes genome wide and at single-base resolution. At multiple scales, we show DNA damage-induced mutations are largely shaped by the influence of DNA accessibility on repair efficiency, rather than gradients of DNA damage. Finally, we reveal specific genomic conditions that can actively drive oncogenic mutagenesis by corrupting the fidelity of nucleotide excision repair. These results provide insight into how strand-asymmetric mechanisms underlie the formation, tolerance and repair of DNA damage, thereby shaping cancer genome evolution.

Larger Tumor Size and Elevated Serum Chromogranin A Levels Predict Metastatic Disease on DOTATATE Imaging in Patients with Gastroenteropancreatic Neuroendocrine Tumors.

PURPOSE: DOTATATE PET/CT (DOTATATE) is superior to conventional imaging in detecting metastasis for gastroenteropancreatic neuroendocrine tumors (GEP-NETs). However, limited availability, high-cost, and additive radiation exposure necessitate guidelines for its use. This study seeks to investigate the relationship between clinical characteristics and metastasis on DOTATATE. METHODS: This was a retrospective analysis of 815 patients who underwent DOTATATE at UCLA from 2014 to 2022. After applying inclusion and exclusion criteria, the study cohort consisted of 163 patients with pathologically diagnosed GEP-NETs, who either underwent primary tumor resection within 1-year prior, or had not undergone resection at the time of DOTATATE imaging. The presence of metastasis was determined using DOTATATE. Fisher's exact test, chi-squared test, and Mann-Whitney test were conducted to compare intergroup difference. Multivariate analysis was performed to identify clinical characteristics associated with metastasis on DOTATATE. RESULTS: Of patients with GEP-NETs, 40.5% (n = 66) were diagnosed with metastases by using DOTATATE. Those with metastatic disease were more likely to exhibit a larger primary tumor size (median 3.4 vs. 1.2, cm, P < 0.001), elevated serum chromogranin A level (CgA, median 208 vs. 97, mg/ml, P = 0.005), and higher tumor grade (P < 0.001). Primary tumor size ≥2 cm and serum CgA level ≥150 ng/mL for metastatic disease had a sensitivity and specificity of 64% and 89%, and 72% and 59%, respectively. Multivariate analysis demonstrated that primary tumor size (≥2/<2, cm, odds ratio [OR] 47.90, P < 0.001), tumor functionality (functional/nonfunctional, adjusted OR 10.17 P = 0.008), serum CgA level (≥150/<150, ng/ml, OR 6.25, P = 0.005), and tumor grade G2 (G2/G1, OR 9.6, P < 0.001) were independently associated with metastases on DOTATATE. CONCLUSIONS: Among patients with GEP-NETs, primary tumor size ≥2 cm, serum CgA level ≥150 ng/mL, and tumor grade G2 are associated with an increased risk of metastases on DOTATATE, and these predictors may be helpful to identify patients where DOTATATE is indicated for complete staging.

Exploring the Ocular Surface Microbiome and Tear Proteome in Glaucoma.

Although glaucoma is a leading cause of irreversible blindness worldwide, its pathogenesis is incompletely understood, and intraocular pressure (IOP) is the only modifiable risk factor to target the disease. Several associations between the gut microbiome and glaucoma, including the IOP, have been suggested. There is growing evidence that interactions between microbes on the ocular surface, termed the ocular surface microbiome (OSM), and tear proteins, collectively called the tear proteome, may also play a role in ocular diseases such as glaucoma. This study aimed to find characteristic features of the OSM and tear proteins in patients with glaucoma. The whole-metagenome shotgun sequencing of 32 conjunctival swabs identified Actinobacteria, Firmicutes, and Proteobacteria as the dominant phyla in the cohort. The species Corynebacterium mastitidis was only found in healthy controls, and their conjunctival microbiomes may be enriched in genes of the phospholipase pathway compared to glaucoma patients. Despite these minor differences in the OSM, patients showed an enrichment of many tear proteins associated with the immune system compared to controls. In contrast to the OSM, this emphasizes the role of the proteome, with a potential involvement of immunological processes in glaucoma. These findings may contribute to the design of new therapeutic approaches targeting glaucoma and other associated diseases.

The Role of Chromatic Aberration in Vision.

The study of biological optics would be complicated enough if light only came in a single wavelength. However, altering the wavelength (or distribution of wavelengths) of light has multiple effects on optics, including on diffraction, scattering (of various sorts), transmission through and reflection by various media, fluorescence, and waveguiding properties, among others. In this review, we consider just one wavelength-dependent optical effect: longitudinal chromatic aberration (LCA). All vertebrate eyes that have been tested have significant LCA, with shorter (bluer) wavelengths of light focusing closer to the front of the eye than longer (redder) wavelengths. We consider the role of LCA in the visual system in terms of both how it could degrade visual acuity and how biological systems make use of it.

Multiple Vertebral Compression Fractures Secondary to Pregnancy-induced Osteoporosis: A Case Report.

Introduction: Although rare in incidence, pregnancy-induced osteoporosis (PIO)-associated OVCFs represent a significant cause of morbidity for the young, peri-partum female population. Case Report: We present the case of a 27-year-old nulliparous lady who suffered seven osteoporosis vertebral compression fractures (OVCFs) with associated sagittal imbalance, the challenges posed to the attending physician or surgeon in treating this rare condition, as well as an in-depth discussion of previous literature reported on pregnancy-induced osteoporosis (PLIO) to date. Although rare in incidence, PLIO-associated OVCFs represent a significant cause of morbidity for the young, peripartum female. Conclusion: This case demonstrates how multiple PLIO-associated OVCFs may be managed successfully, with careful consideration of sagittal imbalance, using a combination of medical and non-operative orthopedic therapies at medium-term follow-up.

Analysis of optical coherence tomography biomarker probability detection in central serous chorioretinopathy by using an artificial intelligence-based biomarker detector.

AIM: To adopt a novel artificial intelligence (AI) optical coherence tomography (OCT)-based program to identify the presence of biomarkers associated with central serous chorioretinopathy (CSC) and whether these can differentiate between acute and chronic central serous chorioretinopathy (aCSC and cCSC). METHODS: Multicenter, observational study with a retrospective design enrolling treatment-naïve patients with aCSC and cCSC. The diagnosis of aCSC and cCSC was established with multimodal imaging and for the current study subsequent follow-up visits were also considered. Baseline OCTs were analyzed by an AI-based platform (Discovery® OCT Fluid and Biomarker Detector, RetinAI AG, Switzerland). This software allows to detect several different biomarkers in each single OCT scan, including subretinal fluid (SRF), intraretinal fluid (IRF), hyperreflective foci (HF) and flat irregular pigment epithelium detachment (FIPED). The presence of SRF was considered as a necessary inclusion criterion for performing biomarker analysis and OCT slabs without SRF presence were excluded from the analysis. RESULTS: Overall, 160 eyes of 144 patients with CSC were enrolled, out of which 100 (62.5%) eyes were diagnosed with cCSC and 60 eyes (34.5%) with aCSC. In the OCT slabs showing presence of SRF the presence of biomarkers was found to be clinically relevant (> 50%) for HF and FIPED in aCSC and cCSC. HF had an average percentage of 81% (± 20) in the cCSC group and 81% (± 15) in the aCSC group (p = 0.4295) and FIPED had a mean percentage of 88% (± 18) in cCSC vs. 89% (± 15) in the aCSC (p = 0.3197). CONCLUSION: We demonstrate that HF and FIPED are OCT biomarkers positively associated with CSC when present at baseline. While both HF and FIPED biomarkers could aid in CSC diagnosis, they could not distinguish between aCSC and cCSC at the first visit. AI-assisted biomarker detection shows promise for reducing invasive imaging needs, but further validation through longitudinal studies is needed.

Short-term revision rate of Rigicon Testi10TM testicular prosthesis in adolescents and adults: a retrospective chart review.

Testicular prosthesis implantation is a valuable solution for the physical, cosmetic, and psychological challenges associated with testicular loss which may affect males of any age. We evaluated the safety and reliability of the new Rigicon Testi10TM testicular prosthesis in adults and adolescents by performing an IRB-approved retrospective study of data drawn from Patient Information Forms (PIFs). A total of 427 patients (382 adults and 45 adolescents) had at least one testicular prosthesis implanted. Only one adult patient required revision surgery due to rupture of the Rigicon Testi10 TM saline-filled prosthesis. A 40-year-old patient was found to have a leaking prosthesis approximately one week postoperatively, which was suspected to be due to inadvertently punctured by the surgeon during the sterile saline filling process. There were no post-implantation revisions required for adolescent patients. According to our results, Kaplan-Meier calculation of survival from removal or revision was 99.8% for all patients at 54 months (99.7% for adults and 100% for adolescents). The complication rates among patients in this study are lower than those reported in previous published studies. Our study underscores the generally safe nature of testicular prosthesis implantation, as well as the very rare incidence of revision surgery for this new device.

The use of radiomic analysis of magnetic resonance imaging findings in predicting features of early osteoarthritis of the knee-a systematic review and meta-analysis.

The primary aim of this study was to systematically review current literature evaluating the use of radiomics in establishing the role of magnetic resonance imaging (MRI) findings in native knees in predicting features of osteoarthritis (OA). A systematic review was performed with respect to PRISMA guidelines in search of studies reporting radiomic analysis of magnetic resonance imaging (MRI) to analyse patients with native knee OA. Sensitivity and specificity of radiomic analyses were included for meta-analysis. Following our initial literature search of 1271 studies, only 5 studies met our inclusion criteria. This included 1730 patients (71.5% females) with a mean age of 55.4 ± 15.6 years (range 24-66). The mean RQS of included studies was 16.6 (11-21). Meta-analysis demonstrated the pooled sensitivity and specificity for MRI in predicting features of OA in patients with native knees were 0.74 (95% CI 0.71, 0.78) and 0.85 (95% CI 0.83, 0.87), respectively. The results of this systematic review suggest that the high sensitivities and specificity of MRI-based radiomics may represent potential biomarker in the early identification and classification of native knee OA. Such analysis may inform surgeons to facilitate earlier non-operative management of knee OA in the select pre-symptomatic patients, prior to clinical or radiological evidence of degenerative change.

A mitochondrial carrier transports glycolytic intermediates to link cytosolic and mitochondrial glycolysis in the human gut parasite Blastocystis.

Stramenopiles form a clade of diverse eukaryotic organisms, including multicellular algae, the fish and plant pathogenic oomycetes, such as the potato blight Phytophthora, and the human intestinal protozoan Blastocystis. In most eukaryotes, glycolysis is a strictly cytosolic metabolic pathway that converts glucose to pyruvate, resulting in the production of NADH and ATP (Adenosine triphosphate). In contrast, stramenopiles have a branched glycolysis in which the enzymes of the pay-off phase are located in both the cytosol and the mitochondrial matrix. Here, we identify a mitochondrial carrier in Blastocystis that can transport glycolytic intermediates, such as dihydroxyacetone phosphate and glyceraldehyde-3-phosphate, across the mitochondrial inner membrane, linking the cytosolic and mitochondrial branches of glycolysis. Comparative analyses with the phylogenetically related human mitochondrial oxoglutarate carrier (SLC25A11) and dicarboxylate carrier (SLC25A10) show that the glycolytic intermediate carrier has lost its ability to transport the canonical substrates malate and oxoglutarate. Blastocystis lacks several key components of oxidative phosphorylation required for the generation of mitochondrial ATP, such as complexes III and IV, ATP synthase, and ADP/ATP carriers. The presence of the glycolytic pay-off phase in the mitochondrial matrix generates ATP, which powers energy-requiring processes, such as macromolecular synthesis, as well as NADH, used by mitochondrial complex I to generate a proton motive force to drive the import of proteins and molecules. Given its unique substrate specificity and central role in carbon and energy metabolism, the carrier for glycolytic intermediates identified here represents a specific drug and pesticide target against stramenopile pathogens, which are of great economic importance.

All living organisms breakdown food molecules to generate energy for processes, such as growing, reproducing and movement. The series of chemical reactions that breakdown sugars into smaller molecules ­ known as glycolysis ­ is so important that it occurs in all life forms, from bacteria to humans. In higher organisms, such as fungi and animals, these reactions take place in the cytosol, the space surrounding the cell's various compartments. A transport protein then shuttles the end-product of glycolysis ­ pyruvate ­ into specialised compartments, known as the mitochondria, where most energy is produced. However, recently it was discovered that a group of living organisms, called the stramenopiles, have a branched glycolysis in which the enzymes involved in the second half of this process are located in both the cytosol and mitochondrial matrix. But it was not known how the intermediate molecules produced after the first half of glycolysis enter the mitochondria. To answer this question, Pyrihová et al. searched for transport protein(s) that could link the two halves of the glycolysis pathway. Computational analyses, comparing the genetic sequences of many transport proteins from several different species, revealed a new group found only in stramenopiles. Pyrihová et al. then used microscopy to visualise these new transport proteins ­ called GIC-1 and GIC-2 ­ in the parasite Blastocystis, which infects the human gut, and observed that they localise to mitochondria. Further biochemical experiments showed that GIC-1 and GIC-2 can physically bind these intermediate molecules, but only GIC-2 can transport them across membranes. Taken together, these observations suggest that GIC-2 links the two halves of glycolysis in Blastocystis. Further analyses could reveal corresponding transport proteins in other stramenopiles, many of which have devastating effects on agriculture, such as Phytophthora, which causes potato blight, or Saprolegnia, which causes skin infections in farmed salmon. Since human cells do not have equivalent transporters, they could be new drug targets not only for Blastocystis, but for these harmful pathogens as well.

Long-term Safety in Epstein-Barr Virus-Seropositive Kidney-only Transplant Recipients Treated With Belatacept in Clinical Practice: Final Study Results From the ENLiST Registry.

Background: Belatacept, a selective T-cell costimulation blocker, was associated with improved survival and renal function but also with a risk of posttransplant lymphoproliferative disorder (PTLD) in adult kidney transplant recipients in phase 3 trials. This registry examined long-term safety in Epstein-Barr virus (EBV)-seropositive kidney transplant recipients treated with belatacept. Methods: This US-based, prospective, voluntary, multicenter registry (Evaluating Nulojix Long-Term Safety in Transplant [ENLiST]) included adult EBV-seropositive kidney-only transplant recipients treated de novo (within 14 d of transplantation) with belatacept. Primary objectives were to estimate incidence rates of confirmed PTLD, central nervous system (CNS) PTLD, and progressive multifocal encephalopathy (PML). The minimum follow-up was 2 y. Results: Of 985 enrolled transplant recipients, 933 EBV-seropositive patients received belatacept, with 523 (56.1%) receiving concomitant tacrolimus at transplant (for up to 12 mo). By study end, 3 cases of non-CNS PTLD (incidence rate, 0.08/100 person-years), 1 case of CNS PTLD (0.03/100 person-years), and no cases of PML had been reported. Two patients with non-CNS PTLD received concomitant belatacept and tacrolimus and 1 received belatacept and lymphocyte-depleting therapy. Incidence rates were comparable between patients who received concomitant belatacept and tacrolimus and those who did not receive tacrolimus (0.09/100 person-years and 0.07/100 person-years, respectively; P = 0.96). Two of 4 patients with PTLD died, and 2 were alive at the end of the study. Cumulatively, 131 graft losses or deaths were reported by study end. Conclusions: Our results from the ENLiST registry, a large, prospective real-world study, showed that the incidence rates of PTLD and CNS PTLD in belatacept-treated EBV-seropositive transplant recipients were consistent with findings from previous phase 3 trials.

Variability in Methodology of Erectile Dysfunction Regenerative Therapy Trials on ClinicalTrials.gov.

OBJECTIVE: To evaluate the variability in the criteria of erectile dysfunction (ED) regenerative therapy trials registered on ClinicalTrials.gov. METHODS: Interventional trials on ClinicalTrials.gov with the keywords "erectile dysfunction" and variations of "shockwave," "platelet rich plasma," "stem cell," "regenerative," and "restorative" were examined. Inclusion/exclusion criteria and primary/secondary outcomes were compared between extracorporeal shockwave therapy (ESWT), platelet rich plasma and stem cell injections (PRP/SC), and other regenerative therapies (ORT) groups. RESULTS: Of the 92 trials analyzed, International Index of Erectile Function (IIEF) score was the most common primary outcome (72%), with a higher prevalence in ESWT trials than PRP/SC or ORT trials (89% vs 44% and 58%, P <.001). Safety/tolerability was a primary outcome for 44% of PRP/SC trials and 25% of ORT trials but no ESWT trials (P <.001). ESWT trials more frequently had sexual/romantic relationship-based inclusion criteria and cancer treatment-related exclusion criteria than PRP/SC and ORT trials. CONCLUSION: There is substantial variability in the inclusion/exclusion criteria and outcome measures among ED regenerative therapy trials. ESWT trials most frequently utilized IIEF and had the strictest inclusion/exclusion criteria, suggesting more rigorous and functional outcome-based studies. Conversely, PRP/SC and ORT trials, but not ESWT trials, had safety/tolerability as a primary outcome, likely due to the experimental nature of these therapies. The variability in inclusion/exclusion criteria and outcome measures limits comparison of the various ED regenerative therapies.

Clinical networking results in continuous improvement of the outcome of patients with acute promyelocytic leukemia.

The introduction of all-trans retinoic acid (ATRA) combined with anthracyclines has significantly improved the outcomes for patients with acute promyelocytic leukemia (APL), and this strategy remains the standard of care in countries where arsenic trioxide is not affordable. However, data from national registries and real-world databases indicate that low- and middle-income countries (LMIC) still face disappointing results, mainly due to high induction mortality and suboptimal management of complications. The American Society of Hematology established the International Consortium on Acute Leukemias (ICAL) to address this challenge through international clinical networking. Here, we present the findings from the ICAPL study involving 806 patients with APL recruited in Brazil, Chile, Paraguay, Peru, and Uruguay. The induction mortality rate has decreased to 14.6% compared to the pre-ICAL rate of 32%. Multivariable logistic regression analysis revealed as factors associated with induction death: age ≥ 40 years, ECOG = 3, high-risk status based on the PETHEMA/GIMEMA classification, albumin level ≤ 3.5 g/dL, bcr3 PML/RARA isoform, the interval between presenting symptoms to diagnosis exceeding 48 hours, and the occurrence of central nervous system and pulmonary bleeding. With a median follow-up of 53 months, the estimated 4-year overall survival (OS) rate is 81%, the 4-year disease-free survival (DFS) rate is 80%, and the 4-year cumulative incidence of relapse (CIR) rate is 15%. These results parallel those observed in studies conducted in high-income countries, highlighting the long-term effectiveness of developing clinical networks to improve clinical care and infrastructure in LMIC.

Predicting Preterm Birth Using Proteomics.

The complexity of preterm birth (PTB), both spontaneous and medically indicated, and its various etiologies and associated risk factors pose a significant challenge for developing tools to accurately predict risk. This review focuses on the discovery of proteomics signatures that might be useful for predicting spontaneous PTB or preeclampsia, which often results in PTB. We describe methods for proteomics analyses, proteomics biomarker candidates that have so far been identified, obstacles for discovering biomarkers that are sufficiently accurate for clinical use, and the derivation of composite signatures including clinical parameters to increase predictive power.

Corrigendum: Comparison of indocyanine green angiography and swept-source wide-field optical coherence tomography angiography in posterior uveitis.

[This corrects the article DOI: 10.3389/fmed.2022.853315.].