Cancer-Causing Effects of Orthopaedic Metal Implants in Total Hip Arthroplasty.

BACKGROUND: Metal implants have been preferentially used in THA due to its biocompatibility, mechanical stability and durability. Yet concerns have emerged regarding their potential to release metallic ions, leading to long-term adverse effects, including carcinogenicity. This study aimed to investigate the risk of cancer development in patients with orthopaedic metal implants in total hip arthroplasty (THA). METHODS: Patients with THA conducted at a local tertiary implant centre from 2001-2008 were linked to the local cancer registry and followed up to the end of 2023. Standardized incidence ratios (SIRs) for cancer incidence and its confidence interval by Poisson distribution were calculated. Survival analysis was depicted using the Kaplan-Meier method, and the log-rank test was used to assess the differences across groups. RESULTS: The study cohort included 388 patients and 53 cancers diagnosed during follow-up, at least 5 years post THA. All-site cancer risks were increased in patients with THA (SIR: 1.97; 95% CI: 1.48-2.46), validated with chi-square analysis (chi-square = 15.2551, N = 100,388, p < 0.01). A statistically significant increase in multiple site-specific cancers including haematological cancers were identified. CONCLUSIONS: Patients with THA were found to have an increased risk for cancer compared to the general population during a mean follow-up of 16 years.

Photoacoustic tomography as a method to estimate the optical fluence distribution in turbid media.

Currently, there are no non-invasive experimental methods available for measuring optical fluence distributions in tissue. We present photoacoustic tomography (PAT) as a method to approximate the relative optical fluence distribution in a homogeneous optically scattering medium. Three-dimensional photoacoustic images were captured with a near-full view PAT scanner in phantoms with known optical absorption and scatter properties. Resultant 3D PAT images were compared to the expected optical fluence distributions from Monte Carlo simulations and diffusion theory using volumetric and shape analysis. Volumetric analysis of PAT images compared well with the optical fluence distributions from simulation. Dice similarity coefficients ranged from 51 to 82%. The reduced scattering coefficient estimated from PAT images compared well to estimates from simulations for values below 0.5 mm-1. Near full-view PAT has been found to be useful for estimating the optical fluence distribution in an optically scattering medium. Further development is needed to extend the measurement range.

The IPASC data format: A consensus data format for photoacoustic imaging.

Photoacoustic imaging (PAI) is an emerging modality that has shown promise for improving patient management in a range of applications. Unfortunately, the current lack of uniformity in PAI data formats compromises inter-user data exchange and comparison, which impedes: technological progress; effective research collaboration; and efforts to deliver multi-centre clinical trials. To overcome this challenge, the International Photoacoustic Standardisation Consortium (IPASC) has established a data format with a defined consensus metadata structure and developed an open-source software application programming interface (API) to enable conversion from proprietary file formats into the IPASC format. The format is based on Hierarchical Data Format 5 (HDF5) and designed to store photoacoustic raw time series data. Internal quality control mechanisms are included to ensure completeness and consistency of the converted data. By unifying the variety of proprietary data and metadata definitions into a consensus format, IPASC hopes to facilitate the exchange and comparison of PAI data.

Satisfactory long-term survival, functional and radiological outcomes of open-wedge high tibial osteotomy for managing knee osteoarthritis: Minimum 10-year follow-up study.

BACKGROUND: This prospective cohort study was designed to evaluate the survivorship and functional outcomes associated with long-term results of medial open-wedge high tibial osteotomy (MOWHTO) for the treatment of medial compartment knee osteoarthritis in the Chinese population. Although MOWHTO is a well-established procedure in the management of medial osteoarthritis of the knee, the long-term outcome in the Chinese population has not been reported in current literature. We hypothesised that MOWHTO would result in long-term preservation of knee function in Chinese, similar to that reported in the Caucasian population. METHODS: A cohort of 22 young adult patients (age < 55 years old) undergoing MOWHTO for the treatment of symptomatic medial compartment knee osteoarthritis between 2002 and 2008 was retrospectively surveyed with a minimum follow-up of 10 years. Kaplan-Meier survival analysis was performed, and the failure modes were investigated. The outcomes on survival (not requiring arthroplasty), clinical outcome (Knee Society Knee Score and Knee Society Function Score) and range of motion (numeric rating scale) at preoperative, 1-year postoperative follow-up and at last follow-up (>10 years) were evaluated. In addition, the mechanical tibiofemoral angle was also measured. The Wilcoxon signed-rank test was used for statistical evaluation of nonparametric data in these related samples. RESULT: A total of 31 knees in these 22 cases were included. The follow-up rate was 100% at 13.4 ± 1.9 years (11-17). Mean age at time of surgery was 45.8 ± 9.5 years (18-53). At 10-year follow-up, four knees converted to require total knee arthroplasty (survival: 87.1%). Preoperative varus alignment with mechanical tibiofemoral angle of -9.26 ± 2.83 was corrected to 2.58 ± 2.46 after surgery and remained 2.01 ± 3.52 at the latest follow-up. Knee Society Knee Score increased significantly from 53.7 ± 11.1 preoperatively to 93.8 ± 6.8 at 1-year follow-up and 91.8 ± 9.7 at latest follow-up. Similarly, the functional score also increased significantly from 67.4 ± 21.0 preoperatively to 86.3 ± 14.5 at 1-year follow-up and 82.1 ± 16.6 at latest follow-up (p < 0.01). Whereas, the range of motion significantly decreased from 122.7 ± 6.6 preoperatively to 116.1 ± 15.5 at the latest follow-up. CONCLUSION: Even in cases of severe medial osteoarthritis and varus malalignment, MOWHTO would be a good treatment option for management in active Chinese population less than 55 years. Although the long-term survival and functional outcome after MOWHTO was proven to be satisfactory in our cohort during the 10-year follow-up, a larger cohort to illustrate the long-term functional outcome is still warranted. TRANSLATIONAL POTENTIAL: The finding in this study indicated MOWHTO is a feasible treatment option for young adult patients with osteoarthritis to achieve long-term satisfactory results.

Optical monitoring of cerebral perfusion and metabolism in adults during cardiac surgery with cardiopulmonary bypass.

During cardiac surgery with cardiopulmonary bypass (CPB), adequate maintenance of cerebral blood flow (CBF) is vital in preventing postoperative neurological injury - i.e. stroke, delirium, cognitive impairment. Reductions in CBF large enough to impact cerebral energy metabolism can lead to tissue damage and subsequent brain injury. Current methods for neuromonitoring during surgery are limited. This study presents the clinical translation of a hybrid optical neuromonitor for continuous intraoperative monitoring of cerebral perfusion and metabolism in ten patients undergoing non-emergent cardiac surgery with non-pulsatile CPB. The optical system combines broadband near-infrared spectroscopy (B-NIRS) to measure changes in the oxidation state of cytochrome c oxidase (oxCCO) - a direct marker of cellular energy metabolism - and diffuse correlation spectroscopy (DCS) to provide an index of cerebral blood flow (CBFi). As the heart was arrested and the CPB-pump started, increases in CBFi (88.5 ± 125.7%) and significant decreases in oxCCO (-0.5 ± 0.2 µM) were observed; no changes were noted during transitions off CPB. Fifteen hypoperfusion events, defined as large and sustained reductions in CPB-pump flow rate, were identified across all patients and resulted in significant decreases in perfusion and metabolism when mean arterial pressure dropped to 30 mmHg or below. The maximum reduction in cerebral blood flow preceded the corresponding metabolic reduction by 18.2 ± 15.0 s. Optical neuromonitoring provides a safe and non-invasive approach for assessing intraoperative perfusion and metabolism and has potential in guiding patient management to prevent adverse clinical outcomes.

Structured-light surface scanning system to evaluate breast morphology in standing and supine positions.

Breast shapes are affected by gravitational loads and deformities. Measurements obtained in the standing position may not correlate well with measurements in the supine position, which is more representative of patient position during breast surgery. A dual color 3D surface imaging system capable of scanning patients in both supine and standing positions was developed to evaluate the effect of changes in body posture on breast morphology. The system was evaluated with  breast phantoms to assess accuracy, then tested on ten subjects in three body postures to assess its effectiveness as a clinical tool. The accuracy of the system was within 0.4 mm on average across the model. For the human study, there was no effect of body posture on breast volumes (p value > 0.05), but we observed an effect of completeness of breast scans on body posture (p value < 0.05). Post-hoc tests showed that the supine position and the standing position with hands at the waist differed significantly (p value < 0.05). This study shows that the system can quantitatively evaluate the effect of subject postures, and thereby has the potential to be used to investigate peri-operative changes in breast morphology.

Perfusion and Metabolic Neuromonitoring during Ventricular Taps in Infants with Post-Hemorrhagic Ventricular Dilatation.

Post-hemorrhagic ventricular dilatation (PHVD) is characterized by a build-up of cerebral spinal fluid (CSF) in the ventricles, which increases intracranial pressure and compresses brain tissue. Clinical interventions (i.e., ventricular taps, VT) work to mitigate these complications through CSF drainage; however, the timing of these procedures remains imprecise. This study presents Neonatal NeuroMonitor (NNeMo), a portable optical device that combines broadband near-infrared spectroscopy (B-NIRS) and diffuse correlation spectroscopy (DCS) to provide simultaneous assessments of cerebral blood flow (CBF), tissue saturation (StO2), and the oxidation state of cytochrome c oxidase (oxCCO). In this study, NNeMo was used to monitor cerebral hemodynamics and metabolism in PHVD patients selected for a VT. Across multiple VTs in four patients, no significant changes were found in any of the three parameters: CBF increased by 14.6 ± 37.6% (p = 0.09), StO2 by 1.9 ± 4.9% (p = 0.2), and oxCCO by 0.4 ± 0.6 µM (p = 0.09). However, removing outliers resulted in significant, but small, increases in CBF (6.0 ± 7.7%) and oxCCO (0.1 ± 0.1 µM). The results of this study demonstrate NNeMo's ability to provide safe, non-invasive measurements of cerebral perfusion and metabolism for neuromonitoring applications in the neonatal intensive care unit.

Assessing Time-Resolved fNIRS for Brain-Computer Interface Applications of Mental Communication.

Brain-computer interfaces (BCIs) are becoming increasingly popular as a tool to improve the quality of life of patients with disabilities. Recently, time-resolved functional near-infrared spectroscopy (TR-fNIRS) based BCIs are gaining traction because of their enhanced depth sensitivity leading to lower signal contamination from the extracerebral layers. This study presents the first account of TR-fNIRS based BCI for "mental communication" on healthy participants. Twenty-one (21) participants were recruited and were repeatedly asked a series of questions where they were instructed to imagine playing tennis for "yes" and to stay relaxed for "no." The change in the mean time-of-flight of photons was used to calculate the change in concentrations of oxy- and deoxyhemoglobin since it provides a good compromise between depth sensitivity and signal-to-noise ratio. Features were extracted from the average oxyhemoglobin signals to classify them as "yes" or "no" responses. Linear-discriminant analysis (LDA) and support vector machine (SVM) classifiers were used to classify the responses using the leave-one-out cross-validation method. The overall accuracies achieved for all participants were 75% and 76%, using LDA and SVM, respectively. The results also reveal that there is no significant difference in accuracy between questions. In addition, physiological parameters [heart rate (HR) and mean arterial pressure (MAP)] were recorded on seven of the 21 participants during motor imagery (MI) and rest to investigate changes in these parameters between conditions. No significant difference in these parameters was found between conditions. These findings suggest that TR-fNIRS could be suitable as a BCI for patients with brain injuries.

Long-term outcomes of imiquimod-treated lentigo maligna.

BACKGROUND: Lentigo maligna (LM) may be disfiguring and can progress to LM melanoma. Surgical excision remains the mainstay of treatment, but may result in disfigurement when used for large facial lesions. Topical imiquimod is a nonsurgical alternative although data on its long-term efficacy remain limited. AIM: To assess long-term outcomes of LM treated with imiquimod cream. METHODS: We collected data retrospectively for 33 patients treated with imiquimod cream for biopsy-proven LM from 2001 to 2016. Patients initially applied imiquimod once daily, 5 days/week for 6 weeks, aiming to produce a brisk local inflammatory response. If there was no response, the dose was increased to twice daily 7 days/week for 6 weeks and if again there was no response, to twice daily for 10 weeks. RESULTS: An inflammatory response developed in 29 (88%) of the 33 patients, and of these, 4 patients stopped treatment earlier than planned because they could not tolerate the inflammatory reaction, while 3 patients reported systemic side effects. There was lesion clearance in 21 (72%) of the 29 patients, and they remained clear after a mean follow-up of 4.1 years. Eight failed to clear; in five the lesion was excised, while the remaining three were managed expectantly. CONCLUSIONS: Our results support the use of imiquimod as an alternative to surgery for the treatment of LM in selected cases. With adequate patient preparation, imiquimod is generally tolerated and can achieve excellent cosmetic results. A clinical response is more likely if there is a brisk inflammatory response, and LM will not resolve if there is no inflammatory response.

Development of a Human Photoacoustic Imaging Reporter Gene Using the Clinical Dye Indocyanine Green.

Purpose: To develop a photoacoustic imaging (PAI) reporter gene that has high translational potential. Previous research has shown that human organic anion-transporting polypeptide 1b3 (OATP1B3) promotes the uptake of the near-infrared fluorescent dye indocyanine green (ICG). In this study, the authors have established OATP1B3 and ICG as a reporter gene-probe pair for in vivo PAI. Materials and Methods: Human breast cancer cells were engineered to express OATP1B3. Control cells (not expressing OATP1B3) or OATP1B3-expressing cells were incubated with or without ICG, placed in a breast-mimicking phantom, and imaged with PAI. Control (n = 6) or OATP1B3-expressing (n = 5) cells were then implanted orthotopically into female mice. Full-spectrum PAI was performed before and 24 hours after ICG administration. One-way analysis of variance was performed, followed by Tukey posthoc multiple comparisons, to assess statistical significance. Results: OATP1B3-expressing cells incubated with ICG exhibited a 2.7-fold increase in contrast-to-noise ratio relative to all other controls in vitro (P < .05). In mice, PAI signals after ICG administration were increased 2.3-fold in OATP1B3 tumors relative to those in controls (P < .05). Conclusion: OATP1B3 operates as an in vivo PAI reporter gene based on its ability to promote the cellular uptake of ICG. Benefits include the human derivation of OATP1B3, combined with the use of wavelengths in the near-infrared region, high extinction coefficient, low quantum yield, and clinical approval of ICG. The authors posit that this system will be useful for localized monitoring of emerging gene- and cell-based therapies in clinical applications.© RSNA, 2019Keywords: Animal Studies, Molecular Imaging, Molecular Imaging-Clinical Translation, Molecular Imaging-Reporter Gene Imaging, Optical ImagingSupplemental material is available for this article.

Smectic viral capsids and the aneurysm instability.

The capsids of certain Archaea-infecting viruses undergo large shape changes, while maintaining their integrity against rupture by osmotic pressure. We propose that these capsids are in a smectic liquid crystalline state, with the capsid proteins assembling along spirals. We show that smectic capsids are intrinsically stabilized against the formation of localized bulges with non-zero Gauss curvature while still allowing for large-scale cooperative shape transformation that involves global changes in the Gauss curvature.

Association of common variants in TCF4 and PTPRG with Fuchs' corneal dystrophy: a systematic review and meta-analysis.

TOPIC: A meta-analysis of TCF4 and PTPRG gene variants in Fuchs' corneal dystrophy (FCD). CLINICAL RELEVANCE: To identify novel genetic markers in patients with FCD in different ethnic populations. METHODS: MEDLINE and EMBASE were searched for eligible genetic studies on TCF4 and PTPRG in FCD. Odds ratios (OR) and 95% confidence intervals (CI) of each single-nucleotide polymorphism (SNP) in allelic, dominant and recessive models were estimated using fixed-effect model if I2<50% in the test for heterogeneity, otherwise the random effects model was used. RESULTS: Thirty-three records were obtained, with 8 being suitable for meta-analysis, which included five SNPs in TCF4 and two in PTPRG. There were 1610 FCD patients and 1565 controls tested for TCF4 rs613872. This SNP was strongly associated with FCD in Caucasians (P = 5.0×10-106), with the risk allele G conferring an OR of 3.95 (95% CI: 3.49-4.46). A further 4 TCF4 SNPs (rs17595731, rs2286812, rs618869 and rs9954153) were also significantly associated with FCD in Caucasians (P<10-8). However, we found no SNP associated with FCD in Chinese. In addition, there was no significant association between FCD and PTPRG. CONCLUSION: TCF4 rs613872 is strongly associated with FCD in Caucasians but not in Chinese, which may suggest ethnic diversity in FCD SNP associations. SNPs in PTPRG were not associated with FCD in Caucasians or Chinese populations. Results of this meta-analysis indicate the need for larger-scale and multi-ethnic genetic studies on FCD to further explore the associated gene variants and their roles on the mechanism and genetic basis of FCD.

Prospective study of formalin-fixed Mohs surgery and haematoxylin and eosin stains with control contralateral biopsies for lentigo maligna: 5-year follow-up results.

BACKGROUND: There is little consensus on the optimum form of surgical management for lentigo maligna (LM). Currently, because malignant melanocytes spread down adnexal structures, full-thickness skin removal is the only surgical option. Interpretation of Mohs histological specimens is difficult because of the presence of abnormal melanocytes in otherwise normal sun-damaged skin. OBJECTIVES: To investigate Slow Mohs for surgical excision of LM, to see whether the use of control contralateral skin biopsies would enable the end point of excision to be more easily interpreted and to investigate factors that influence the subclinical amelanotic extensions of LM. METHODS: The Slow Mohs technique for formalin-fixed tissue was used in 74 patients with LM. Before surgery LMs were classified as well defined, poorly defined, incompletely excised or recurrent. Control biopsies were taken from healthy skin of the contralateral side. Specimens were processed in formalin, stained with haematoxylin and eosin (H&E) and the results read at 24-48 h. The excision margin required for complete excision was measured and patients were followed for a minimum of 5 years to exclude recurrence. RESULTS: On average the final excision margin required was 6·7 mm. Margins were significantly greater for ill-defined, recurrent and incompletely excised LM compared with well-defined LM. The presence of depigmented patches preoperatively did not correlate with the excision margin, but LMs showing nesting required significantly wider excision margins. There were seven (12%) recurrences at a mean 4·4 years after surgery in the group with 5-year follow-up. Recurrence occurred only in recurrent and ill-defined primary LM. CONCLUSIONS: The use of Slow Mohs formalin-fixed tissue and H&E section staining, even with comparator biopsies, does not provide sufficient discrimination to identify residual disease confidently.

Host immune defense peptide LL-37 activates caspase-independent apoptosis and suppresses colon cancer.

Cathelicidins are a family of bacteriocidal polypeptides secreted by macrophages and polymorphonuclear leukocytes (PMN). LL-37, the only human cathelicidin, has been implicated in tumorigenesis, but there has been limited investigation of its expression and function in cancer. Here, we report that LL-37 activates a p53-mediated, caspase-independent apoptotic cascade that contributes to suppression of colon cancer. LL-37 was expressed strongly in normal colon mucosa but downregulated in colon cancer tissues, where in both settings its expression correlated with terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive apoptotic cells. Exposure of colon cancer cells to LL-37 induced phosphatidylserine externalization and DNA fragmentation in a manner independent of caspase activation. Apoptogenic function was mediated by nuclear translocation of the proapoptotic factors, apoptosis-inducing factor (AIF) and endonuclease G (EndoG), through p53-dependent upregulation of Bax and Bak and downregulation of Bcl-2 via a pertussis toxin-sensitive G-protein-coupled receptor (GPCR) pathway. Correspondingly, colonic mucosa of cathelicidin-deficient mice exhibited reduced expression of p53, Bax, and Bak and increased expression of Bcl-2 together with a lower basal level of apoptosis. Cathelicidin-deficient mice exhibited an increased susceptibility to azoxymethane-induced colon tumorigenesis, establishing pathophysiologic relevance in colon cancer. Collectively, our findings show that LL-37 activates a GPCR-p53-Bax/Bak/Bcl-2 signaling cascade that triggers AIF/EndoG-mediated apoptosis in colon cancer cells.

Insight on fractal assessment strategies for tin dioxide thin films.

Tin oxide is a unique material of widespread technological applications, particularly in the field of environmental functional materials. New strategies of fractal assessment for tin dioxide thin films formed at different substrate temperatures are of fundamental importance in the development of microdevices, such as gas sensors for the detection of environmental pollutants. Here, tin dioxide thin films with interesting fractal features were successfully prepared by pulsed laser deposition techniques under different substrate temperatures. Fractal method has been first applied to the evaluation of this material. The measurements of carbon monoxide gas sensitivity confirmed that the gas sensing behavior is sensitively dependent on fractal dimensions, fractal densities, and average sizes of the fractal clusters. The random tunneling junction network mechanism was proposed to provide a rational explanation for this gas sensing behavior. The formation process of tin dioxide nanocrystals and fractal clusters could be reasonably described by a novel model.