Spatial memory in Alzheimer's disease 5XFAD mice is enhanced by XPO1 inhibitor KPT-330.

The proteostatic decline in Alzheimer's disease is well established and improvement in proteostasis could potentially delay cognitive impairment. One emerging entry point to modulate proteostasis is the regulation of nucleo-cytoplasmic partitioning of proteins across the nuclear pore via karyopherins. The nuclear exportin XPO1 is a key regulator of proteostasis by driving the assembly of ribosomes and by modulating the process of autophagy. We recently found that XPO1 inhibitor KPT-330 (Selinexor), an FDA approved drug against multiple myelomas, enhances proteostasis, leading to benefits in models of neurodegenerative diseases in C. elegans and Drosophila . Here, we find that KPT-330 increases autophagy in murine neuronal cells and improves spatial memory performance in a murine model of Alzheimer's disease (5XFAD). Unexpectedly, general amyloid deposition in several brain regions was significantly increased by KPT-330, but specific regions, especially the thalamus, displayed significantly lower deposition, suggesting that XPO1 inhibition has regional-specific effects on proteostasis and amyloid plaque formation. Altogether, we conclude that XPO1 inhibition can improve cognition via spatially-specific reductions in amyloid deposition.

TNFSF13 insufficiency disrupts human colonic epithelial cell-mediated B cell differentiation.

Cytokines mediating epithelial and immune cell interactions modulate mucosal healing- a process that goes awry with chronic inflammation as in inflammatory bowel disease. TNFSF13 is a cytokine important for B cell maturation and function, but roles for epithelial TNFSF13 and putative contribution to inflammatory bowel disease are poorly understood. We evaluated functional consequences of a novel monoallelic TNFSF13 variant using biopsies, tissue-derived colonoids and induced pluripotent stem cell (iPSC)-derived colon organoids. TNFSF13 variant colonoids exhibited a >50% reduction in secreted TNFSF13, increased epithelial proliferation, and reduced apoptosis, which was confirmed in iPSC-derived colon organoids. Single cell RNA-sequencing, flow cytometry, and co-immunoprecipitation identified FAS as the predominant colonic epithelial receptor for TNFSF13. Imaging mass cytometry revealed an increase in epithelial-associated B cells in TNFSF13 variant colon tissue sections. Finally, TNFSF13 variant colonoids co-cultured with memory B cells demonstrated a reduction in the production of IgA+ plasma cells compared to control colonoid co-cultures. Our findings support a role for epithelial TNFSF13 as a regulator of colonic epithelial growth and epithelial crosstalk with B cells.

Biologics for eosinophilic otitis media: a retrospective case study in a multidisciplinary center.

PURPOSE: Eosinophilic otitis media (EOM) is a difficult-to-treat otitis media characterized by eosinophilic accumulation in the middle ear mucosa and effusion. It is refractory to conventional treatments and is strongly associated with asthma and chronic rhinosinusitis with nasal polyps (CRSwNP). The diagnostic criteria for EOM were established by IINO in 2011. With the recognition of type 2 inflammatory diseases, the gold standard of treatment is the systemic and topical administration of corticosteroids. Recently, several retrospective studies have demonstrated the efficacy of biologic treatments in EOM. We aimed to share our experience regarding the response of EOM after the use of biologics. METHODS: This is a retrospective observational analysis including patients with refractory EOM treated with different biologics (benralizumab, omalizumab, mepolizumab, dupilumab) for concomitant severe asthma, urticaria and/or severe uncontrolled CRSwNP from 2011 to 2023. Treatment effectiveness in terms of EOM severity was measured using medical Global Evaluation of Treatment Effectiveness (GETE). RESULTS: We illustrated 4 clinical cases of uncontrolled comorbid EOM and demonstrated the complexity of multidisciplinary medical pathway with good response to biologics. We also observed that response to EOM and CRSwNP does not always follow that of asthma. CONCLUSIONS: The results of our small sample were consistent with those found in the literature and showed control of EOM with biologics. We need a larger multicentric sample and methodology to confirm these results and to compare the efficacy of different biologics.

Using Multi-Layer Perceptron Driven Diagnosis to Compare Biomarkers for Primary Open Angle Glaucoma.

Purpose: To use neural network machine learning (ML) models to identify the most relevant ocular biomarkers for the diagnosis of primary open-angle glaucoma (POAG). Methods: Neural network models, also known as multi-layer perceptrons (MLPs), were trained on a prospectively collected observational dataset comprised of 93 glaucoma patients confirmed by a glaucoma specialist and 113 control subjects. The base model used only intraocular pressure, blood pressure, heart rate, and visual field (VF) parameters to diagnose glaucoma. The following models were given the base parameters in addition to one of the following biomarkers: structural features (optic nerve parameters, retinal nerve fiber layer [RNFL], ganglion cell complex [GCC] and macular thickness), choroidal thickness, and RNFL and GCC thickness only, by optical coherence tomography (OCT); and vascular features by OCT angiography (OCTA). Results: MLPs of three different structures were evaluated with tenfold cross validation. The testing area under the receiver operating characteristic curve (AUC) of the models were compared with independent samples t-tests. The vascular and structural models both had significantly higher accuracies than the base model, with the hemodynamic AUC (0.819) insignificantly outperforming the structural set AUC (0.816). The GCC + RNFL model and the model containing all structural and vascular features were also significantly more accurate than the base model. Conclusions: Neural network models indicate that OCTA optic nerve head vascular biomarkers are equally useful for ML diagnosis of POAG when compared to OCT structural biomarker features alone.

Description of Bacterial RNA Transcripts Detected in Mycobacterium tuberculosis - Infected Cells from Peripheral Human Granulomas using Single Cell RNA Sequencing.

Mycobacterium tuberculosis (Mtb) remains a global human health threat and a significant cause of human morbidity and mortality. We document here the capture of Mtb transcripts in libraries designed to amplify eukaryotic mRNA. These reads are often considered spurious or nuisance and are rarely investigated. Because of early literature suggesting the possible presence of polyadenylated transcripts in Mtb RNA, we included the H37Rv Mtb reference genome when assembling scRNA seq libraries from fine needle aspirate samples from patients presenting at the TB clinic, Port Moresby General Hospital, Papua New Guinea. We used 10X Genomics single-cell RNA sequencing transcriptomics pipeline, which initiates mRNA amplification with poly-T primers on ~30-micron beads designed to capture, in this case, human mRNA associated with individual cells in the clinical samples. Utilizing the 10X Genomics Cell Ranger tool to align sequencing reads, we consistently detected bacterial small and large ribosomal subunit RNA sequences (rrs and rrl, respectively) and other bacterial gene transcripts in the cell culture and patient samples. We interpret Mtb reads associated with the host cell's unique molecular identifier (UMI) and transcriptome to indicate infection of that individual host cell. The Mtb transcripts detected showed frequent sequence variation from the reference genome, with greater than 90% of the rrs or rrl reads from many clinical samples having at least 1 sequence difference compared to the H37Rv reference genome. The data presented includes only bacterial sequences from patients with TB infections that were confirmed by the hospital pathology lab using acid-fast microscopy and/or GeneXpert analysis. The repeated, non-random nature of the sequence variations detected in Mtb rrs and rrl transcripts from multiple patients, suggests that, even though this appears to be a stochastic process, there is possibly some selective pressure that limits the types and locations of sequence variation allowed. The variation does not appear to be entirely artefactual, and it is hypothesized that it could represent an additional mechanism of adaptation to enhance bacterial fitness against host defenses or chemotherapy.

Long-Term Redetachment Rates of Pneumatic Retinopexy versus Pars Plana Vitrectomy in Retinal Detachment: A PIVOT Post Hoc Analysis.

PURPOSE: To assess long-term redetachment rates of the Pneumatic Retinopexy versus Vitrectomy for the Management of Primary Rhegmatogenous Retinal Detachment Outcomes Randomized Trial (PIVOT). DESIGN: Randomized controlled trial. SUBJECTS: PIVOT trial participants. METHODS: This study was performed at St. Michael's Hospital, Unity Health Toronto, Toronto, Canada. PIVOT trial participants who had undergone either pneumatic retinopexy (PnR) or pars plana vitrectomy (PPV) for rhegmatogenous retinal detachment (RRD) repair with a minimum follow-up of 2 years were assessed for long-term redetachment by chart review or telephone interview. The latter was the only accepted method for those with <2 years of follow-up. Patients were only eligible if no reintervention to reattach the retina was performed within the first year of the initial procedure. MAIN OUTCOME MEASURES: Long-term redetachment rates for PnR vs. PPV after RRD repair. RESULTS: Sixty-one participants who underwent PPV and 62 who underwent PnR were analyzed. The long-term redetachment rates were 0% and 1.61% (1/62) in the PPV and PnR groups, respectively (P = 0.32). The mean follow-up duration in years was 5.43 ± 3.60 vs. 5.51 ± 3.03 in the PPV and PnR groups, respectively. CONCLUSIONS: There was no statistically significant difference in long-term redetachment rates for PnR vs. PPV. Both procedures are durable treatment options for RRD over an extended period, rarely requiring additional intervention for redetachment. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

The Clinical Usefulness of a Glaucoma Polygenic Risk Score in 4 Population-Based European Ancestry Cohorts.

PURPOSE: We used a polygenic risk score (PRS) to identify high-risk groups for primary open-angle glaucoma (POAG) within population-based cohorts. DESIGN: Secondary analysis of 4 prospective population-based studies. PARTICIPANTS: We included four European-ancestry cohorts: the United States-based Nurses' Health Study, Nurses' Health Study 2, and the Health Professionals Follow-up Study and the Rotterdam Study (RS) in The Netherlands. The United States cohorts included female nurses and male health professionals ≤ 55 years of age. The RS included residents ≤ 45 years of age living in Rotterdam, The Netherlands. METHODS: Polygenic risk score weights were estimated by applying the lassosum method on imputed genotype and phenotype data from the UK Biobank. This resulted in 144 020 variants, single nucleotide polymorphism and insertions or deletions, with nonzero ßs that we used to calculate a PRS in the target populations. Using multivariable Cox proportional hazard models, we estimated the relationship between the standardized PRS and relative risk for POAG. Additionally, POAG prediction was tested by calculating these models' concordance (Harrell's C statistic). Finally, we assessed the association between PRS tertiles and glaucoma-related traits. MAIN OUTCOME MEASURES: The relative risk for POAG and Harrell's C statistic. RESULTS: Among 1046 patients and 38 809‬ control participants, the relative risk (95% confidence interval) for POAG for participants in the highest PRS quintile was 3.99 (3.08-5.18) times higher in the United States cohorts and 4.89 (2.93-8.17) times higher in the RS, compared with participants with median genetic risk (third quintile). Combining age, sex, intraocular pressure of more than 25 mmHg, and family history resulted in a meta-analyzed concordance of 0.75 (95% CI, 0.73-0.75). Adding the PRS to this model improved the concordance to 0.82 (95% CI, 0.80-0.84). In a meta-analysis of all cohorts, patients in the highest tertile showed a larger cup-to-disc ratio at diagnosis, by 0.10 (95% CI, 0.06 0.14), and a 2.07-fold increased risk of requiring glaucoma surgery (95% CI, 1.19-3.60). CONCLUSIONS: Incorporating a PRS into a POAG predictive model improves identification concordance from 0.75 up to 0.82, supporting its potential for guiding more cost-effective screening strategies. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Transformer-Based Deep Learning Prediction of 10-Degree Humphrey Visual Field Tests From 24-Degree Data.

Purpose: To predict 10-2 Humphrey visual fields (VFs) from 24-2 VFs and associated non-total deviation features using deep learning. Methods: We included 5189 reliable 24-2 and 10-2 VF pairs from 2236 patients, and 28,409 reliable pairs of macular OCT scans and 24-2 VF from 19,527 eyes of 11,560 patients. We developed a transformer-based deep learning model using 52 total deviation values and nine VF test features to predict 68 10-2 total deviation values. The mean absolute error, root mean square error, and the R2 were evaluation metrics. We further evaluated whether the predicted 10-2 VFs can improve the structure-function relationship between macular thinning and paracentral VF loss in glaucoma. Results: The average mean absolute error and R2 for 68 10-2 VF test points were 3.30 ± 0.52 dB and 0.70 ± 0.11, respectively. The accuracy was lower in the inferior temporal region. The model placed greater emphasis on 24-2 VF points near the central fixation point when predicting the 10-2 VFs. The inclusion of nine VF test features improved the mean absolute error and R2 up to 0.17 ± 0.06 dB and 0.01 ± 0.01, respectively. Age was the most important 24-2 VF test parameter for 10-2 VF prediction. The predicted 10-2 VFs achieved an improved structure-function relationship between macular thinning and paracentral VF loss, with the R2 at the central 4, 12, and 16 locations of 24-2 VFs increased by 0.04, 0.05 and 0.05, respectively (P < 0.001). Conclusions: The 10-2 VFs may be predicted from 24-2 data. Translational Relevance: The predicted 10-2 VF has the potential to improve glaucoma diagnosis.

Impact of Demographics on Regional Visual Field Loss and Deterioration in Glaucoma.

Purpose: To elucidate the impact of demographics, including gender, race, ethnicity, and preferred language, on regional visual field (VF) loss and progression in glaucoma. Methods: Multivariable linear mixed regressions were performed to determine the impact of race, ethnicity, and preferred language on regional VF loss with adjustment for age and gender. Regional VF loss was defined by pointwise total deviation values and VF loss patterns quantified by an unsupervised machine learning method termed archetypal analysis. All cross-sectional and longitudinal analyses were performed both without and with adjustment for VF mean deviation, which represented overall VF loss severity. P values were corrected for multiple comparisons. Results: All results mentioned had corrected P values less than 0.05. Asian and Black patients showed worse pointwise VF loss than White patients with superior hemifield more affected. Patients with a preferred language other than English demonstrated worse pointwise VF loss than patients with English as their preferred language. Longitudinal analyses revealed Black patients showed worse VF loss/year compared to White patients. Patients with a preferred language other than English demonstrated worse VF loss/year compared to patients preferring English. Conclusions: Blacks and non-English speakers have more severe VF loss, with superior hemifield being more affected and faster VF worsening. Translational Relevance: This study furthered our understanding of racial, ethnic, and socioeconomic disparities in glaucoma outcomes. Understanding the VF loss burden in different racial, ethnic, and socioeconomic groups may guide more effective glaucoma screening and community outreach efforts. This research could help reduce vision loss and improve quality of life in disproportionately affected populations by guiding public health efforts to promote glaucoma awareness and access to care.

Technology and Methodology in Glaucoma Case Detection.

Even the most powerful handheld screening tool for glaucoma will not find cases cost-effectively because the disease prevalence is low. However, a tier 1 biomarker tool that enhances disease prevalence followed by the use of a screening tool could serve as a future glaucoma screening strategy.

Case report: A case of cutaneous gallstones.

Gallbladder spillage during laparoscopic cholecystectomy procedures is common but rarely leads to patient morbidity due to complications such as abscesses or fistulas. We present the case of a 52-year-old woman post cholecystectomy, who presented to our dermatology clinic with abdominal pain and an epigastric subcutaneous nodule. The nodule was removed, leading to a complete resolution of her pain. On histopathology, it was found to be a cutaneous cholelithiasis.

Diagnostic Capability of OCTA-Derived Macular Biomarkers for Early to Moderate Primary Open Angle Glaucoma.

Background/Objectives: To investigate macular vascular biomarkers for the detection of primary open-angle glaucoma (POAG). Methods: A total of 56 POAG patients and 94 non-glaucomatous controls underwent optical coherence tomography angiography (OCTA) assessment of macular vessel density (VD) in the superficial (SCP), and deep (DCP) capillary plexus, foveal avascular zone (FAZ) area, perimeter, VD, choriocapillaris and outer retina flow area. POAG patients were classified for severity based on the Glaucoma Staging System 2 of Brusini. ANCOVA comparisons adjusted for age, sex, race, hypertension, diabetes, and areas under the receiver operating characteristic curves (AUCs) for POAG/control differentiation were compared using the DeLong method. Results: Global, hemispheric, and quadrant SCP VD was significantly lower in POAG patients in the whole image, parafovea, and perifovea (p < 0.001). No significant differences were found between POAG and controls for DCP VD, FAZ parameters, and the retinal and choriocapillaris flow area (p > 0.05). SCP VD in the whole image and perifovea were significantly lower in POAG patients in stage 2 than stage 0 (p < 0.001). The AUCs of SCP VD in the whole image (0.86) and perifovea (0.84) were significantly higher than the AUCs of all DCP VD (p < 0.05), FAZ parameters (p < 0.001), and retinal (p < 0.001) and choriocapillaris flow areas (p < 0.05). Whole image SCP VD was similar to the AUC of the global retinal nerve fiber layer (RNFL) (AUC = 0.89, p = 0.53) and ganglion cell complex (GCC) thickness (AUC = 0.83, p = 0.42). Conclusions: SCP VD is lower with increasing functional damage in POAG patients. The AUC for SCP VD was similar to RNFL and GCC using clinical diagnosis as the reference standard.

Classifying and quantifying changes in papilloedema using machine learning.

Background: Machine learning (ML) can differentiate papilloedema from normal optic discs using fundus photos. Currently, papilloedema severity is assessed using the descriptive, ordinal Frisén scale. We hypothesise that ML can quantify papilloedema and detect a treatment effect on papilloedema due to idiopathic intracranial hypertension. Methods: We trained a convolutional neural network to assign a Frisén grade to fundus photos taken from the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT). We applied modified subject-based fivefold cross-validation to grade 2979 longitudinal images from 158 participants' study eyes (ie, the eye with the worst mean deviation) in the IIHTT. Compared with the human expert-determined grades, we hypothesise that ML-estimated grades can also demonstrate differential changes over time in the IIHTT study eyes between the treatment (acetazolamide (ACZ) plus diet) and placebo (diet only) groups. Findings: The average ML-determined grade correlated strongly with the reference standard (r=0.76, p<0.001; mean absolute error=0.54). At the presentation, treatment groups had similar expert-determined and ML-determined Frisén grades. The average ML-determined grade for the ACZ group (1.7, 95% CI 1.5 to 1.8) was significantly lower (p=0.0003) than for the placebo group (2.3, 95% CI 2.0 to 2.5) at the 6-month trial outcome. Interpretation: Supervised ML of fundus photos quantified the degree of papilloedema and changes over time reflecting the effects of ACZ. Given the increasing availability of fundus photography, neurologists will be able to use ML to quantify papilloedema on a continuous scale that incorporates the features of the Frisén grade to monitor interventions.

RNA-binding protein PCBP2 regulates pancreatic ß cell function and adaptation to glucose.

Glucose plays a key role in shaping pancreatic ß cell function. Thus, deciphering the mechanisms by which this nutrient stimulates ß cells holds therapeutic promise for combating ß cell failure in type 2 diabetes (T2D). ß Cells respond to hyperglycemia in part by rewiring their mRNA metabolism, yet the mechanisms governing these changes remain poorly understood. Here, we identify a requirement for the RNA-binding protein PCBP2 in maintaining ß cell function basally and during sustained hyperglycemic challenge. PCBP2 was induced in primary mouse islets incubated with elevated glucose and was required to adapt insulin secretion. Transcriptomic analysis of primary Pcbp2-deficient ß cells revealed impacts on basal and glucose-regulated mRNAs encoding core components of the insulin secretory pathway. Accordingly, Pcbp2-deficient ß cells exhibited defects in calcium flux, insulin granule ultrastructure and exocytosis, and the amplification pathway of insulin secretion. Further, PCBP2 was induced by glucose in primary human islets, was downregulated in islets from T2D donors, and impacted genes commonly altered in islets from donors with T2D and linked to single-nucleotide polymorphisms associated with T2D. Thus, these findings establish a paradigm for PCBP2 in governing basal and glucose-adaptive gene programs critical for shaping the functional state of ß cells.

Use of Diagnostic Codes for Primary Open-Angle Glaucoma Polygenic Risk Score Construction in Electronic Health Record-Linked Biobanks.

PURPOSE: Polygenic risk scores (PRSs) likely predict risk and prognosis of glaucoma. We compared the PRS performance for primary open-angle glaucoma (POAG), defined using International Classification of Diseases (ICD) codes vs manual medical record review. DESIGN: Retrospective cohort study. METHODS: We identified POAG cases in the Mount Sinai BioMe and Mass General Brigham (MGB) biobanks using ICD codes. We confirmed POAG based on optical coherence tomograms and visual fields. In a separate 5% sample, the absence of POAG was confirmed with intraocular pressure and cup-disc ratio criteria. We used genotype data and either self-reported glaucoma diagnoses or ICD-10 codes for glaucoma diagnoses from the UK Biobank and the lassosum method to compute a genome-wide POAG PRS. We compared the area under the curve (AUC) for POAG prediction based on ICD codes vs medical records. RESULTS: We reviewed 804 of 996 BioMe and 367 of 1006 MGB ICD-identified cases. In BioMe and MGB, respectively, positive predictive value was 53% and 55%; negative predictive value was 96% and 97%; sensitivity was 97% and 97%; and specificity was 44% and 53%. Adjusted PRS AUCs for POAG using ICD codes vs manual record review in BioMe were not statistically different (P ≥.21) by ancestry: 0.77 vs 0.75 for African, 0.80 vs 0.80 for Hispanic, and 0.81 vs 0.81 for European. Results were similar in MGB (P ≥.18): 0.72 vs 0.80 for African, 0.83 vs 0.86 for Hispanic, and 0.74 vs 0.73 for European. CONCLUSIONS: A POAG PRS performed similarly using either manual review or ICD codes in 2 electronic health record-linked biobanks; manual assessment of glaucoma status might not be necessary for some PRS studies. However, caution should be exercised when using ICD codes for glaucoma diagnosis given their low specificity (44%-53%) for manually confirmed cases of glaucoma.

Single Cell Analysis of Peripheral TB-Associated Granulomatous Lymphadenitis.

We successfully employed a single cell RNA sequencing (scRNA-seq) approach to describe the cells and the communication networks characterizing granulomatous lymph nodes of TB patients. When mapping cells from individual patient samples, clustered based on their transcriptome similarities, we uniformly identify several cell types that known to characterize human and non-human primate granulomas. Whether high or low Mtb burden, we find the T cell cluster to be one of the most abundant. Many cells expressing T cell markers are clearly quantifiable within this CD3 expressing cluster. Other cell clusters that are uniformly detected, but that vary dramatically in abundance amongst the individual patient samples, are the B cell, plasma cell and macrophage/dendrocyte and NK cell clusters. When we combine all our scRNA-seq data from our current 23 patients (in order to add power to cell cluster identification in patient samples with fewer cells), we distinguish T, macrophage, dendrocyte and plasma cell subclusters, each with distinct signaling activities. The sizes of these subclusters also varies dramatically amongst the individual patients. In comparing FNA composition we noted trends in which T cell populations and macrophage/dendrocyte populations were negatively correlated with NK cell populations. In addition, we also discovered that the scRNA-seq pipeline, designed for quantification of human cell mRNA, also detects Mtb RNA transcripts and associates them with their host cell's transcriptome, thus identifying individual infected cells. We hypothesize that the number of detected bacterial transcript reads provides a measure of Mtb burden, as does the number of Mtb-infected cells. The number of infected cells also varies dramatically in abundance amongst the patient samples. CellChat analysis identified predominating signaling pathways amongst the cells comprising the various granulomas, including many interactions between stromal or endothelial cells and the other component cells, such as Collagen, FN1 and Laminin,. In addition, other more selective communications pathways, including MIF, MHC-1, MHC-2, APP, CD 22, CD45, and others, are identified as originating or being received by individual immune cell components.

The Evolving Surgical Paradigm of Scleral Allograft Bio-Tissue Use in Ophthalmic Surgery: Techniques and Clinical Indications for Ab-Externo and Ab-Interno Scleral Reinforcement.

To review the latest surgical advances and evolving clinical use of scleral bio-tissue for reinforcement in the eye and review the published literature on novel surgical applications of scleral allograft bio-tissue. Conventional surgical procedures for scleral reinforcement using homologous scleral allograft have been traditionally ab-externo interventions comprising of anterior or posterior reinforcement of the sclera for clinical indications such as trauma, scleromalacia, glaucoma drainage device coverage, scleral perforation, buckle repair as well as posterior reinforcement for pathologic myopia and staphyloma. There have been a few novel ab-interno uses of scleral bio-tissue for reinforcement in both retina and glaucoma. Over the last decade, there has been an increase in peer-reviewed publications on scleral reinforcement, reflecting more interest in its clinical applications. With favorable biological and biomechanical properties, scleral allograft may be an ideal substrate for an array of new applications and surgical uses.