Diagnostic accuracy of autofluorescence-Raman spectroscopy for surgical margin assessment during Mohs micrographic surgery of basal cell carcinoma.

BACKGROUND: Autofluorescence (AF) - Raman spectroscopy is a technology that can detect residual basal cell carcinoma (BCC) on the resection margin of fresh surgically excised tissue specimens. The technology does not require tissue fixation, staining, labelling, or sectioning, and provides quantitative diagnosis maps of the surgical margins in 30 minutes. OBJECTIVES: To determine the accuracy of the AF-Raman instrument to detect incomplete excisions of BCC during Mohs micrographic surgery, using histology as reference standard. METHODS: Skin layers from 130 patients undergoing Mohs surgery at the Nottingham University Hospitals NHS Trust (September 2022 to July 2023) were investigated with the AF-Raman instrument. The layers were measured fresh, immediately after excision. The AF-Raman results and the intra-operative assessment by Mohs surgeons were compared to a post-operative consensus-derived reference produced by three dermatopathologists. The sensitivity, specificity, positive predictive value, and negative predictive value were calculated. RESULTS: The AF-Raman analysis was successfully completed for 125 out of the 130 layers. The AF-Raman analysis covered 91% of the specimen surface area on average, with the lowest being 87% for eyelid and the highest being 94% for forehead specimens. The AF-Raman instrument identified positive margins in 24 out of 36 BCC-positive cases, resulting in a 67% sensitivity (95% confidence intervals (CI): 49%-82%) and negative margins in 65 out of 89 BCC-negative cases, resulting in a 73% specificity (95% CI 63%-82%). Only one out of the 12 false negative cases was caused by misclassification by the AF-Raman algorithm. The other 11 false negatives cases were produced because no valid Raman signal was recorded at the location of the residual BCC due to either occlusion by blood or poor contact between tissue and cassette window. The intra-operative diagnosis by Mohs surgeons identified positive margins in 31 out of 36 BCC-positive cases, 86% sensitivity (95% CI: 70%-95%), and negative margins in 79 out of 89 BCC-negative cases, 89% specificity (95% CI: 81%-95%). CONCLUSIONS: This study shows that the AF-Raman instrument has potential for intra-operative microscopic assessment of surgical margins in surgery of BCC. Further improvements are required for tissue processing to ensure complete coverage of the surgical specimens. ClinicalTrials.gov ID NCT03482622.

Feasibility of a novel augmented reality overlay for cervical screw placement in phantom spine models.

Study Design: Feasibility study. Purpose: A phantom model was used to evaluate the accuracy of a novel augmented reality (AR) system for cervical screw placement. Overview of Literature: The use of navigation systems is becoming increasingly common in spine procedures. However, numerous factors limit the feasibility of regular and widespread use of navigation tools during spine surgery. AR is a new technology that has already demonstrated utility as a navigation tool during spine surgery. However, advancements in AR technology are needed to increase its adoption by the medical community. Methods: AR technology that uses a fiducial-less registration system was tested in a preclinical cervical spine phantom model study for accuracy during spinal screw placement. A three-dimensional reconstruction of the spine along with trajectory lines was superimposed onto the phantom model using an AR headset. Participants used the AR system to guide screw placement, and post-instrumentation scans were compared for accuracy assessment. Results: Twelve cervical screws were placed under AR guidance. All screws were placed in an acceptable anatomic position. The average distance error for the insertion point was 2.73±0.55 mm, whereas that for the endpoint was 2.71±0.69 mm. The average trajectory angle error for all insertions was 2.69°±0.59°. Conclusions: This feasibility study describes a novel registration approach that superimposes spinal anatomy and trajectories onto the surgeon's real-world view of the spine. These results demonstrate reasonable accuracy in the preclinical model. The results of this study demonstrate that this technology can assist with accurate screw placement. Further investigation using cadaveric and clinical models is warranted.

Global experience of faricimab in clinical settings - a review.

INTRODUCTION: Faricimab is a bispecific antibody that acts to reduce neoangiogenesis in exudative retinal vascular disorders. It is approved for use in neovascular age-related macular degeneration and diabetic macular edema. We review the published efficacy and safety of faricimab in clinical settings. AREAS COVERED: A comprehensive literature review was conducted. Based on the 14 published real-world studies, 1127 patients (1204 eyes) were treated with faricimab. The majority of studies (14) included pre-treated patients. Most studies (13) showed central macular thickness improvement. However visual acuity improved in only half of the studies analyzed. Four studies demonstrated an extension of the treatment. Only 4 eyes (0.33%) reported intraocular inflammation and 3 eyes (0.24%) reported retinal pigment epithelial tear. EXPERT OPINION: The clinical experience with faricimab to date has the potential to provide a stable visual outcome with reduced treatment burden in cases that are resistant to other approved anti-VEGF agents. There are no major safety concerns based on this data analysis.

Simultaneous Liver and Kidney Transplantation in a Patient With Telomere Biology Disorder: A Case Study.

Organ transplantation is the primary therapy for organ failure caused by telomere biology disorder (TBD). We describe the first documented case of simultaneous liver and kidney transplantation (SLKTx) for TBD, although the diagnosis of TBD was reached only three months following SLKTx. The patient was born prematurely, displayed growth retardation, and developed chronic kidney and liver diseases. His pre-SLKTx autoimmune, metabolic, and viral assessments were negative, and persistent pancytopenia (bone marrow cellularity 70-80%) was attributed to renal disease-associated bone marrow changes. Following SLKTx, he was discharged with stable graft function on tacrolimus and prednisolone. Although mycophenolate mofetil was discontinued on the second postoperative day, his pancytopenia persisted. Despite extensive evaluations, including drug, immune, nutritional, and viral assessments, all results were negative. A bone marrow biopsy conducted three months post-transplant revealed significant hypocellularity (40-50%). Whole genome sequencing revealed a likely pathogenic variant of the TINF2 gene. The patient was subsequently treated with danazol. At the nine-month follow-up post-SLKTx, he exhibited stable graft function and improved cell counts while maintaining triple-drug immunosuppression. Given the lack of uniform diagnostic criteria for TBD, healthcare providers must be vigilant with patients presenting with multi-organ failure and persistent cytopenias. Effective pre-transplant screening for TBD can lead to timely diagnoses, better management, and improved post-transplant outcomes.

Evaluation of programmed cell death ligand 1 expression in a contemporary cohort of penile squamous cell carcinoma and its correlation with clinicopathologic and survival parameters: A study of 134 patients.

OBJECTIVES: Penile squamous cell carcinomas (PCs) are rare malignancies with a dismal prognosis in a metastatic setting; therefore, novel immunotherapeutic modalities are an unmet need. One such modality is the immune checkpoint molecule programmed cell death ligand 1 (PD-L1). We sought to analyze PD-L1 expression and its correlation with various clinicopathologic parameters in a contemporary cohort of 134 patients with PC. METHODS: A cohort of 134 patients with PC was studied for PD-L1 immunohistochemistry. The PD-L1 expression was evaluated using a combined proportion score with a cutoff of 1 or higher to define positivity. The results were correlated with various clinicopathologic parameters. RESULTS: Overall, 77 (57%) patients had positive PD-L1 expression. Significantly high PD-L1 expression was observed in high-grade tumors (P = .006). We found that 37% of human papillomavirus (HPV)-associated subtypes and 73% of other histotype tumors expressed PD-L1, while 63% of HPV-associated tumors and 27% of other histotype tumors did not (odds ratio, 1.35; P = .002 when compared for HPV-associated groups vs all others). Similarly, PD-L1-positive tumors had a 3.61-times higher chance of being node positive than PD-L1-negative tumors (P = .0009). In addition, PD-L1 high-positive tumors had a 5-times higher chance of being p16ink4a negative than PD-L1 low-positive tumors (P = .004). The PD-L1-positive tumors had a lower overall survival and cancer-specific survival than PD-L1-negative tumors. CONCLUSIONS: Overall, PD-L1 expression is associated with high-grade and metastatic tumors. Lower PD-L1 expression is observed more frequently in HPV-associated (warty or basaloid) subtypes than in other, predominantly HPV-independent types. As a result, PD-L1 positivity, including higher expression, portends lower overall and cancer-specific survival. These data provide a rational for further investigating PD-L1-based immunotherapeutics in PC.

A Multicenter Retrospective Cohort Study on Management Protocols and Clinical Outcomes After ABO-incompatible Kidney Transplantation in India.

BACKGROUND: There is no robust evidence-based data for ABO-incompatible kidney transplantation (ABOiKT) from emerging countries. METHODS: Data from 1759 living donor ABOiKT and 33 157 ABO-compatible kidney transplantations (ABOcKT) performed in India between March 5, 2011, and July 2, 2022, were included in this retrospective, multicenter (n = 25) study. The primary outcomes included management protocols, mortality, graft loss, and biopsy-proven acute rejection (BPAR). RESULTS: Protocol included rituximab 100 (232 [13.18%]), 200 (877 [49.85%]), and 500 mg (569 [32.34%]); immunoadsorption (IA) (145 [8.24%]), IVIG (663 [37.69%]), and no induction 200 (11.37%). Mortality, graft loss, and BPAR were reported in 167 (9.49%), 136 (7.73%), and 228 (12.96%) patients, respectively, over a median follow-up of 36.3 mo. In cox proportional hazard model, mortality was higher with IA (hazard ratio [HR]: 2.53 [1.62-3.97]; P < 0.001), BPAR (HR: 1.83 [1.25-2.69]; P = 0.0020), and graft loss (HR: 1.66 [1.05-2.64]; P = 0.0310); improved graft survival was associated with IVIG (HR: 0.44 [0.26-0.72]; P = 0.0010); higher BPAR was reported with conventional tube method (HR: 3.22 [1.9-5.46]; P < 0.0001) and IA use (HR: 2 [1.37-2.92]; P < 0.0001), whereas lower BPAR was reported in the prepandemic era (HR: 0.61 [0.43-0.88]; P = 0.008). Primary outcomes were not associated with rituximab dosing or high preconditioning/presurgery anti-A/anti-B titers. Incidence of overall infection 306 (17.39%), cytomegalovirus 66 (3.75%), and BK virus polyoma virus 20 (1.13%) was low. In unmatched univariate analysis, the outcomes between ABOiKT and ABOcKT were comparable. CONCLUSIONS: Our largest multicenter study on ABOiKT provides insights into various protocols and management strategies with results comparable to those of ABOcKT.

miR397b-LAC2 module regulates cadmium stress response by coordinating root lignification and copper homeostasis in Arabidopsis thaliana.

Non-essential heavy metal cadmium (Cd) is toxic to plants and animals. Cadmium affects plant photosynthesis, respiration, and causes water imbalance and may lead to plant death. Cadmium induces toxicity by interfering with the essential metal copper (Cu) homeostasis, which affects plant nutrition. Though root lignin biosynthesis is positively regulated by Cd stress, the underlying mechanisms promoting lignin accumulation and controlling Cd-induced Cu limitation responses are unclear. Here, we elucidated the role of Cu-responsive microRNA (miR397b) in Arabidopsis thaliana plants for Cd stress by targeting the LACCASE2 (LAC2) gene. This study demonstrated the fundamental mechanism of miR397b-mediated Cd stress response by enhancing the lignin content in root tissues. We developed miR397b over-expressing plants, which showed considerable Cd stress tolerance. Plants with knockdown function of LAC2 also showed significant tolerance to Cd stress. miR397b overexpressing and lac2 mutant plants showed root reduction, higher biomass and chlorophyll content, and significantly lower Reactive Oxygen Species (ROS). This study demonstrated the miR397b-mediated Cd stress response in Arabidopsis by enhancing the lignin content in root tissues. We conclude that modulation in miR397b can be potentially used for improving plants for Cd tolerance and Cu homeostasis.

Midpoint of C7 Lateral Mass Serves as an Accurate Reference Point for the Placement of T1 Pedicle Screws: An Anatomic Study.

BACKGROUND AND OBJECTIVES: Free-hand placement of T1 pedicle screws can often be challenging. A reliable free-hand technique for placement of T1 pedicle screws can overcome some of the difficulties associated with poor fluoroscopy in this region. The purpose of this study was to propose a novel anatomic landmark for accurate identification of the T1 entry point using the midpoint of the C7 lateral mass as a reference point. Our hypothesis is that the midpoint of the C7 lateral mass is within 1-2 mm of the center of the T1 pedicle. METHODS: Using 3-dimensional reconstruction software, the pedicle of T1 and the lateral mass of C7 were isolated to assess the location of the T1 pedicle relative to the C7 lateral mass. Specifically, the distance between the center of the T1 pedicle and the center of the C7 lateral mass was measured on 40 computed tomography scans. Furthermore, a clinical validation of this technique was performed by assessing the postoperative computed tomography scans of 53 patients undergoing cervicothoracic instrumentation. The Gertzbein and Robbins classification system was used to grade the accuracy of T1 pedicle screw placements in all patients using this technique. RESULTS: The average horizontal deviation + SD from centers of the T1 pedicle and the C7 lateral mass was 0.398 mm ± 0.953 mm. The T1 pedicle on average was slightly medial to the center of the C7 lateral mass. A total of 98.1% of T1 pedicle screws placed in vivo using the free-hand technique were of Grade A. CONCLUSION: In this article, we demonstrate that the center of the C7 lateral mass overlays the T1 pedicle and the optimal entry point is immediately below the midpoint of the C7 lateral mass. This approach provides a practical and accurate landmark in posterior cervicothoracic spine procedures that reduce the need for additional radiation exposure or increased operative time with image-guided techniques.

Human Dose and Pharmacokinetic Predictions for Biologics at Boehringer Ingelheim: A Retrospective Analysis.

INTRODUCTION: Accurate predictions of pharmacokinetics and efficacious doses for biologics in humans are critical for selecting appropriate first-in-human starting doses and dose ranges and for estimating clinical material needs and cost of goods. This also impacts clinical feasibility, particularly for subcutaneously administered biologics. METHODS: We performed a comprehensive comparison between predicted and observed clearances and doses in humans for a set of 22 biologic drugs developed at Boehringer Ingelheim (BI) over the last 2 decades. The analysis included biologics across three therapeutic areas comprising a wide variety of modalities: mono- and bispecific monoclonal antibodies (mAbs) and nanobodies and a Fab fragment. RESULTS: Our analysis showed that observed clearances in humans were within twofold of predicted clearances for 17 out of 20 biologics (85%). Six biologics had uncharacteristically high observed human clearances (range 32-280 mL/h) for their respective molecular classes, impacting their clinical developability. For three molecules, molecular characteristics contributed to the high clearance. Clinically selected doses were within twofold of predicted for 58% of projects. With 42% and 25% of projects selecting clinical doses higher than two- or threefold the predicted value, respectively, the importance of better understanding not only the pharmacokinetic (PK) but also the predictivity of pharmacodynamic models is highlighted. CONCLUSIONS: We provide a clinical pharmacology perspective on the commonly accepted twofold range of human clearance predictions as well as the implications of higher than predicted targeted efficacious plasma concentration on clinical development. Finally, an analysis of key success factors for biologics at BI was conducted, which may be relevant for the entire pharmaceutical industry. This is one of the largest retrospective analyses for biologics and provides further evidence that successful predictions of human PK and efficacious dose will be further facilitated by gathering key translational data early in research.

Evaluation of dermatoglyphics patterns as predisposition factor for occurrence of oral submucous fibrosis: A hospital-based case-control study.

Background: One of the key factors in the prevention of the disease is the identification of the risk factors early in life. Based on multifactorial causation of oral submucous fibrosis (OSMF), apart from habit history, the genetical predisposition may be considered as an important risk factor in the occurrence of OSMF disease. The dermatoglyphic pattern may prove a salient genetic marker for the determination of OSMF as both are having similar intrauterine development period. Objectives: To find out and compare the association between dermatoglyphics and OSMF. Materials and Methods: The present study was conducted on total 108 subjects divided in three groups where Group A was subjects with OSMF, Group B was subjects with tobacco related habits but without OSMF, and Group C was healthy controls. Fingerprint patterns of both hands were recorded and classified into whorls, loops and arches. Results: The loop pattern was significantly higher in subjects having OSMF (Group A) as compared Group B and Group C in general as well as for left and right hands. The maximum prominence of loop patterns was noted in the little finger among the subjects with OSMF. Results for subjects with OSMF and without OSMF under five years of having tobacco chewing habits had also clearly demonstrated prominence of loop patterns in the subjects with OSMF. Conclusion: The results of our study show that there is a staunch possibility of genetically determined factors in the form of loop finger prints can be responsible for the occurrence of OSMF.

Perineural low dexamethasone dose as adjuvant in supraclavicular brachial plexus block for arteriovenous fistula creation in end stage renal disease: a randomized controlled trial

Abstract Background and aims: Dexamethasone as adjunct to local anesthetic solution improves the quality of brachial plexus block (BPB). However, evidence for its efficacy at low doses (< 4 mg) is lacking. This study was designed to evaluate the duration of analgesia attained with low dose dexamethasone as adjuvant to local anesthetic for creation of arteriovenous fistula (AVF) under BPB. Methods: Sixty-six patients scheduled for AVF creation were randomly allocated to receive either saline (control) or 2 mg dexamethasone, together with 0.5% ropivacaine and 0.2% lignocaine. The primary outcome was duration of analgesia, defined as time from performing the block to the first analgesic request. The secondary outcomes were time from injection to complete sensory block, time from injection to complete motor block, duration of motor block, postoperative analgesic consumption, and fistula patency at three months. Results: All the blocks were effective. In the group that received dexamethasone, the time to first analgesic request was significantly delayed (432 ± 43.8 minutes vs. 386.4 ± 40.2 minutes; p < 0.01). The onset of sensory and motor blockade occurred faster in dexamethasone group and overall analgesic consumption was also reduced. However, dexamethasone addition did not prolong the duration of motor block. There was no statistically significant difference in the patency of fistulas between the two groups at three months. (p = 0.34). Conclusion: Addition of low-dose perineural dexamethasone to local anesthetic solution significantly prolonged the duration of analgesia. Further trials are warranted to compare the adverse effects between dexamethasone doses of 4 mg and lower.

Development and clinical validation of a novel algorithmic score (GAAD) for detecting HCC in prospective cohort studies.

BACKGROUND: Alpha-fetoprotein (AFP) and des-gamma carboxyprothrombin (DCP), also known as protein induced by vitamin K absence-II (PIVKA-II [DCP]) are biomarkers for HCC with limited diagnostic value when used in isolation. The novel GAAD algorithm is an in vitro diagnostic combining PIVKA-II (DCP) and AFP measurements, age, and gender (biological sex) to generate a semi-quantitative result. We conducted prospective studies to develop, implement, and clinically validate the GAAD algorithm for differentiating HCC (early and all-stage) and benign chronic liver disease (CLD), across disease stages and etiologies. METHODS: Patients aged ≥18 years with HCC or CLD were prospectively enrolled internationally into algorithm development [n = 1084; 309 HCC cases (40.7% early-stage) and 736 controls] and clinical validation studies [n = 877; 366 HCC cases (47.6% early-stage) and 303 controls]. Serum samples were analyzed on a cobas® e 601 analyzer. Performance was assessed using receiver operating characteristic curve analyses to calculate AUC. RESULTS: For algorithm development, AUC for differentiation between early-stage HCC and CLD was 90.7%, 84.4%, and 77.2% for GAAD, AFP, and PIVKA-II, respectively. The sensitivity of GAAD for the detection of early-stage HCC was 71.8% with 90.0% specificity. Similar results were shown in the clinical validation study; AUC for differentiation between early-stage HCC and CLD was 91.4% with 70.1% sensitivity and 93.7% specificity. GAAD also showed strong specificity, with a lower rate of false positives regardless of disease stage, etiology, or region. CONCLUSIONS: The GAAD algorithm significantly improves early-stage HCC detection for patients with CLD undergoing HCC surveillance. Further phase III and IV studies are warranted to assess the utility of incorporating the algorithm into clinical practice.