Detection of antibodies against structural proteins of foot-and-mouth disease virus in bovines of western Uttar Pradesh, India.

Foot-and-mouth disease (FMD) is considered as one of the most important contagious viral diseases affecting cloven-footed animals. For effective control of FMD, immunization along with herd immunity is essential in the field conditions. To assure and track the coverage and effectiveness of the vaccination program, the serological studies are very much required after the vaccination program. The present study was aimed to investigate the prevalence of antibodies against structural proteins of FMD virus (FMDV) serotypes of O, A and Asia-1 in seven districts of western Uttar Pradesh, India, and assure the efficacy of vaccination under National Animal Disease Control Program. A total of 308 sera samples were collected from apparent healthy vaccinated cattle and buffaloes from seven districts including Amroha, Baghpat, Bareilly, Bulandsahar, Gautam Budh Nagar, Meerut and Muzaffarnagar of western Uttar Pradesh, India. Determination of antibodies against structural proteins of FMDV was carried out using solid-phase blocking enzyme-linked immunosorbent assay. The protective level of the FMDV serotypes O, A and Asia-1 included in the inactivated trivalent vaccine was 66.55, 48.05 and 47.08% in bovines, respectively. To provide the higher level of protection against the circulating FMDV, the present study recommended the thorough investigation of the immunogenic interaction between the vaccine strains and the field strains. Further investigations should also be conducted with larger sample size and across diverse geographical regions to gain a more comprehensive understanding of herd immunity.

The Effect of Interlayer Delay on the Heat Accumulation, Microstructures, and Properties in Laser Hot Wire Directed Energy Deposition of Ti-6Al-4V Single-Wall.

Laser hot wire directed energy deposition (LHW-DED) is a layer-by-layer additive manufacturing technique that permits the fabrication of large-scale Ti-6Al-4V (Ti64) components with a high deposition rate and has gained traction in the aerospace sector in recent years. However, one of the major challenges in LHW-DED Ti64 is heat accumulation, which affects the part quality, microstructure, and properties of as-built specimens. These issues require a comprehensive understanding of the layerwise heat-accumulation-driven process-structure-property relationship in as-deposited samples. In this study, a systematic investigation was performed by fabricating three Ti-6Al-4V single-wall specimens with distinct interlayer delays, i.e., 0, 120, and 300 s. The real-time acquisition of high-fidelity thermal data and high-resolution melt pool images were utilized to demonstrate a direct correlation between layerwise heat accumulation and melt pool dimensions. The results revealed that the maximum heat buildup temperature of the topmost layer decreased from 660 °C to 263 °C with an increase to a 300 s interlayer delay, allowing for better control of the melt pool dimensions, which then resulted in improved part accuracy. Furthermore, the investigation of the location-specific composition, microstructure, and mechanical properties demonstrated that heat buildup resulted in the coarsening of microstructures and, consequently, the reduction of micro-hardness with increasing height. Extending the delay by 120 s resulted in a 5% improvement in the mechanical properties, including an increase in the yield strength from 817 MPa to 859 MPa and the ultimate tensile strength from 914 MPa to 959 MPa. Cooling rates estimated at 900 °C using a one-dimensional thermal model based on a numerical method allowed us to establish the process-structure-property relationship for the wall specimens. The study provides deeper insight into the effect of heat buildup in LHW-DED and serves as a guide for tailoring the properties of as-deposited specimens by regulating interlayer delay.

Imageable Radioembolization Microspheres for Treatment of Unresectable Hepatocellular Carcinoma: Interim Results from a First-in-Human Trial.

PURPOSE: To Describe 6-Month safety, efficacy and multimodal imageability after imageable glass Yttrium-90 radioembolization for unresectable Hepatocellular Carcinoma (HCC) in a First-in Human Trial METHODS: Eye90 microspheres® (Eye90), an FDA Breakthrough Designated Device, are glass radiopaque Y-90 microspheres visible on CT and SPECT/CT. Six subjects with unresectable HCC underwent selective (≤ 2 segments) Eye90 treatment in a prospective open-label pilot trial. Key inclusion criteria included liver only HCC, ECOG ≤ 1, total lesion length ≤ 9 cm and Child-Pugh A. Prospective partition dosimetry was utilized. Safety, biochemistry, toxicity, adverse events (AE), multimodal imageability on CT and SPECT/CT and 3 and 6-month MRI local modified RECIST (mRECIST) response was evaluated. RESULTS: 6 subjects with HCC (7 lesions) were treated with Eye90 and followed to 180 days. Administration success was 100%. Eye90 CT radiopacity distribution correlated with SPECT/CT. Target lesion complete response was observed in 3 of 6 subjects (50%) and partial response in 2 (33.3%). Two subjects could not be assessed at 180 days. At 180 days, target lesion complete response was maintained in 3 subjects (50%) and partial response in 1 (16.7%). All subjects reported AEs, and 5 reported AEs related to treatment. There were no treatment related serious AEs. CONCLUSIONS: Eye90 was safe and effective in six subjects with unresectable HCC up to 6 months. Eye90 was imageable via CT and SPECT/CT with correlation between CT radiopacity and SPECT/CT radioactivity distribution. Eye90 provided previously unavailable CT based tumor targeting information.

Contrast-enhanced photon-counting micro-CT of tumor xenograft models.

Objective. Photon-counting micro-computed tomography (micro-CT) is a major advance in small animal preclinical imaging. Small molecule- and nanoparticle-based contrast agents have been widely used to enable the differentiation of liver tumors from surrounding tissues using photon-counting micro-CT. However, there is a notable gap in the application of these market-available agents to the imaging of breast and ovarian tumors using photon-counting micro-CT. Herein, we have used photon-counting micro-CT to determine the effectiveness of these contrast agents in differentiating ovarian and breast tumor xenografts in live, intact mice.Approach. Nude mice carrying different types of breast and ovarian tumor xenografts (AU565, MDA-MB-231 and SKOV-3 human cancer cells) were injected with ISOVUE-370 (a small molecule-based agent) or Exitron Nano 12000 (a nanoparticle-based agent) and subjected to photon-counting micro-CT. To improve tumor visualization using photon-counting micro-CT, we developed a novel color visualization method, which changes color tones to highlight contrast media distribution, offering a robust alternative to traditional material decomposition methods with less computational demand.Main results. Ourin vivoexperiments confirm the effectiveness of this color visualization approach, showing distinct enhancement characteristics for each contrast agent. Qualitative and quantitative analyses suggest that Exitron Nano 12000 provides superior vasculature enhancement and better quantitative consistency across scans, while ISOVUE-370 delivers a more comprehensive tumor enhancement but with significant variance between scans due to its short blood half-time. Further, a paired t-test on mean and standard deviation values within tumor volumes showed significant differences between the AU565 and SKOV-3 tumor models with the nanoparticle-based contrast agent (p-values < 0.02), attributable to their distinct vascularity, as confirmed by immunohistochemical analysis.Significance. These findings underscore the utility of photon-counting micro-CT in non-invasively assessing the morphology and anatomy of different tumor xenografts, which is crucial for tumor characterization and longitudinal monitoring of tumor progression and response to treatments.

Tunable Q-factor wavelet transform based identification of diabetic patients using ECG signals.

Diabetes is a chronic health condition that is characterized by increased levels of glucose (sugar) in the blood. It can have harmful effects on different parts of the body, such as the retina of the eyes, skin, nervous system, kidneys, and heart. Diabetes affects the structure of electrocardiogram (ECG) impulses by causing cardiovascular autonomic dysfunction. Multi-resolution analysis of the input ECG signal is utilized in this paper to develop a machine learning-based system for the automated detection of diabetic patients. In the first step, the input ECG signal is decomposed into sub-bands utilizing the tunable Q-factor wavelet transform (TQWT) technique. In the second step, four entropy-based characteristics are evaluated from each SB and elected using the K-W test method. To develop an automatic diabetes detection system, selected features are given as input with 10-fold validation to a SVM classifier using various kernel functions. The 3rd sub-band of TQWT with the Coarse Gaussian kernel function kernel of the SVM classifier yields a classification accuracy of 91.5%. In the same dataset, the comparative analysis demonstrates that the proposed method outperforms other existing methods.

Thrombopoietin mimetic stimulates bone marrow vascular and stromal niches to mitigate acute radiation syndrome.

BACKGROUND: Acute radiation syndrome (ARS) manifests after exposure to high doses of radiation in the instances of radiologic accidents or incidents. Facilitating regeneration of the bone marrow (BM), namely the hematopoietic stem and progenitor cells (HSPCs), is key in mitigating ARS and multi-organ failure. JNJ-26366821, a PEGylated thrombopoietin mimetic (TPOm) peptide, has been shown as an effective medical countermeasure (MCM) to treat hematopoietic-ARS (H-ARS) in mice. However, the activity of TPOm on regulating BM vascular and stromal niches to support HSPC regeneration has yet to be elucidated. METHODS: C57BL/6J mice (9-14 weeks old) received sublethal or lethal total body irradiation (TBI), a model for H-ARS, by 137Cs or X-rays. At 24 h post-irradiation, mice were subcutaneously injected with a single dose of TPOm (0.3 mg/kg or 1.0 mg/kg) or PBS (vehicle). At homeostasis and on days 4, 7, 10, 14, 18, and 21 post-TBI with and without TPOm treatment, BM was harvested for histology, BM flow cytometry of HSPCs, endothelial (EC) and mesenchymal stromal cells (MSC), and whole-mount confocal microscopy. For survival, irradiated mice were monitored and weighed for 30 days. Lastly, BM triple negative cells (TNC; CD45-, TER-119-, CD31-) were sorted for single-cell RNA-sequencing to examine transcriptomics after TBI with or without TPOm treatment. RESULTS: At homeostasis, TPOm expanded the number of circulating platelets and HSPCs, ECs, and MSCs in the BM. Following sublethal TBI, TPOm improved BM architecture and promoted recovery of HSPCs, ECs, and MSCs. Furthermore, TPOm elevated VEGF-C levels in normal and irradiated mice. Following lethal irradiation, mice improved body weight recovery and 30-day survival when treated with TPOm after 137Cs and X-ray exposure. Additionally, TPOm reduced vascular dilation and permeability. Finally, single-cell RNA-seq analysis indicated that TPOm increased the expression of collagens in MSCs to enhance their interaction with other progenitors in BM and upregulated the regeneration pathway in MSCs. CONCLUSIONS: TPOm interacts with BM vascular and stromal niches to locally support hematopoietic reconstitution and systemically improve survival in mice after TBI. Therefore, this work warrants the development of TPOm as a potent radiation MCM for the treatment of ARS.

Transabdominal motor evoked potential neuromonitoring of lumbosacral spine surgery.

BACKGROUND CONTEXT: Transcranial Motor Evoked Potentials (TcMEPs) can improve intraoperative detection of femoral plexus and nerve root injury during lumbosacral spine surgery. However, even under ideal conditions, TcMEPs are not completely free of false-positive alerts due to the immobilizing effect of general anesthetics, especially in the proximal musculature. The application of transcutaneous stimulation to activate ventral nerve roots directly at the level of the conus medularis (bypassing the brain and spinal cord) has emerged as a method to potentially monitor the motor component of the femoral plexus and lumbosacral nerves free from the blunting effects of general anesthesia. PURPOSE: To evaluate the reliability and efficacy of transabdominal motor evoked potentials (TaMEPs) compared to TcMEPs during lumbosacral spine procedures. DESIGN: We present the findings of a single-center 12-month retrospective experience of all lumbosacral spine surgeries utilizing multimodality intraoperative neuromonitoring (IONM) consisting of TcMEPs, TaMEPs, somatosensory evoked potentials (SSEPs), electromyography (EMG), and electroencephalography. PATIENT SAMPLE: Two hundred and twenty patients having one, or a combination of lumbosacral spine procedures, including anterior lumbar interbody fusion (ALIF), lateral lumbar interbody fusion (LLIF), posterior spinal fusion (PSF), and/or transforaminal lumbar interbody fusion (TLIF). OUTCOME MEASURES: Intraoperative neuromonitoring data was correlated to immediate post-operative neurologic examinations and chart review. METHODS: Baseline reliability, false positive rate, true positive rate, false negative rate, area under the curve at baseline and at alerts, and detection of pre-operative deficits of TcMEPs and TaMEPs were compared and analyzed for statistical significance. The relationship between transcutaneous stimulation voltage level and patient BMI was also examined. RESULTS: TaMEPs were significantly more reliable than TcMEPs in all muscles except abductor hallucis. Of the 27 false positive alerts, 24 were TcMEPs alone, and 3 were TaMEPs alone. Of the 19 true positives, none were detected by TcMEPs alone, 3 were detected by TaMEPs alone (TcMEPs were not present), and the remaining 16 true positives involved TaMEPs and TcMEPs. TaMEPs had a significantly larger area under the curve (AUC) at baseline than TcMEPs in all muscles except abductor hallucis. The percent decrease in TcMEP and TaMEP AUC during LLIF alerts was not significantly different. Both TcMEPs and TaMEPs reflected three pre-existing motor deficits. Patient BMI and TaMEP stimulation intensity were found to be moderately positively correlated. CONCLUSIONS: These findings demonstrate the high reliability and predictability of TaMEPs and the potential added value when TaMEPs are incorporated into multimodality IONM during lumbosacral spine surgery.

Thrombopoietin mimetic stimulates bone marrow vascular and stromal niches to mitigate acute radiation syndrome.

Background: Acute radiation syndrome (ARS) manifests after exposure to high doses of radiation in the instances of radiologic accidents or incidents. Facilitating the regeneration of the bone marrow (BM), namely the hematopoietic stem and progenitor cells (HSPCs), is a key in mitigating ARS and multi-organ failure. JNJ-26366821, a PEGylated thrombopoietin mimetic (TPOm) peptide, has been shown as an effective medical countermeasure (MCM) to treat hematopoietic-ARS (H-ARS) in mice. However, the activity of TPOm on regulating BM vascular and stromal niches to support HSPC regeneration has not yet been elucidated. Methods: C57BL/6J mice (9-14 weeks old) received sublethal or lethal total body irradiation (TBI), a model for H-ARS, by 137Cs or X-rays. At 24 hours post-irradiation, mice were subcutaneously injected with a single dose of TPOm (0.3 mg/kg or 1.0 mg/kg) or PBS (vehicle). At homeostasis and on days 4, 7, 10, 14, 18, and 21 post-TBI with and without TPOm treatment, BM was harvested for histology, BM flow cytometry of HSPCs, endothelial (EC) and mesenchymal stromal cells (MSC), and whole-mount confocal microscopy. For survival, irradiated mice were monitored and weighed for 30 days. Lastly, BM triple negative cells (TNC; CD45-, TER-119-, CD31-) were sorted for single-cell RNA-sequencing to examine transcriptomics after TBI with or without TPOm treatment. Results: At homeostasis, TPOm expanded the number of circulating platelets and HSPCs, ECs, and MSCs in the BM. Following sublethal TBI, TPOm improved BM architecture and promoted recovery of HSPCs, ECs, and MSCs. Furthermore, TPOm elevated VEGF-C levels in normal and irradiated mice. Following lethal irradiation, mice improved body weight recovery and 30-day survival when treated with TPOm after 137Cs and X-ray exposure. Additionally, TPOm reduced vascular dilation and permeability. Finally, single-cell RNA-seq analysis indicated that TPOm increased the expression of collagens in MSCs to enhance their interaction with other progenitors in BM and upregulated the regeneration pathway in MSCs. Conclusions: TPOm interacts with BM vascular and stromal niches to locally support hematopoietic reconstitution and systemically improve survival in mice after TBI. Therefore, this work warrants the development of TPOm as a potent radiation MCM for the treatment of ARS.

Transcription elongation defects link oncogenic SF3B1 mutations to targetable alterations in chromatin landscape.

Transcription and splicing of pre-messenger RNA are closely coordinated, but how this functional coupling is disrupted in human diseases remains unexplored. Using isogenic cell lines, patient samples, and a mutant mouse model, we investigated how cancer-associated mutations in SF3B1 alter transcription. We found that these mutations reduce the elongation rate of RNA polymerase II (RNAPII) along gene bodies and its density at promoters. The elongation defect results from disrupted pre-spliceosome assembly due to impaired protein-protein interactions of mutant SF3B1. The decreased promoter-proximal RNAPII density reduces both chromatin accessibility and H3K4me3 marks at promoters. Through an unbiased screen, we identified epigenetic factors in the Sin3/HDAC/H3K4me pathway, which, when modulated, reverse both transcription and chromatin changes. Our findings reveal how splicing factor mutant states behave functionally as epigenetic disorders through impaired transcription-related changes to the chromatin landscape. We also present a rationale for targeting the Sin3/HDAC complex as a therapeutic strategy.

Immunotherapy-resistant acute lymphoblastic leukemia cells exhibit reduced CD19 and CD22 expression and BTK pathway dependency.

While therapies targeting CD19 by antibodies, chimeric antigen receptor T cells (CAR-T), and T cell engagers have improved the response rates in B cell malignancies, the emergence of resistant cell populations with low CD19 expression can lead to relapsed disease. We developed an in vitro model of adaptive resistance facilitated by chronic exposure of leukemia cells to a CD19 immunotoxin. Single-cell RNA-Seq (scRNA-Seq) showed an increase in transcriptionally distinct CD19lo populations among resistant cells. Mass cytometry demonstrated that CD22 was also decreased in these CD19lo-resistant cells. An assay for transposase-accessible chromatin with sequencing (ATAC-Seq) showed decreased chromatin accessibility at promoters of both CD19 and CD22 in the resistant cell populations. Combined loss of both CD19 and CD22 antigens was validated in samples from pediatric and young adult patients with B cell acute lymphoblastic leukemia (B-ALL) that relapsed after CD19 CAR-T-targeted therapy. Functionally, resistant cells were characterized by slower growth and lower basal levels of MEK activation. CD19lo resistant cells exhibited preserved B cell receptor signaling and were more sensitive to both Bruton's tyrosine kinase (BTK) and MEK inhibition. These data demonstrate that resistance to CD19 immunotherapies can result in decreased expression of both CD19 and CD22 and can result in dependency on BTK pathways.

Broad de-regulated U2AF1 splicing is prognostic and augments leukemic transformation via protein arginine methyltransferase activation.

The role of splicing dysregulation in cancer is underscored by splicing factor mutations; however, its impact in the absence of such rare mutations is poorly understood. To reveal complex patient subtypes and putative regulators of pathogenic splicing in Acute Myeloid Leukemia (AML), we developed a new approach called OncoSplice. Among diverse new subtypes, OncoSplice identified a biphasic poor prognosis signature that partially phenocopies U2AF1-mutant splicing, impacting thousands of genes in over 40% of adult and pediatric AML cases. U2AF1-like splicing co-opted a healthy circadian splicing program, was stable over time and induced a leukemia stem cell (LSC) program. Pharmacological inhibition of the implicated U2AF1-like splicing regulator, PRMT5, rescued leukemia mis-splicing and inhibited leukemic cell growth. Genetic deletion of IRAK4, a common target of U2AF1-like and PRMT5 treated cells, blocked leukemia development in xenograft models and induced differentiation. These analyses reveal a new prognostic alternative-splicing mechanism in malignancy, independent of splicing-factor mutations.

Improving Unrelated Donor Equity: Assessing Mismatched Donor Opportunities with Real-World Data in a Minority-Predominant Cohort.

Recent advances in graft-versus-host disease (GVHD) prophylaxis including post-transplant cyclophosphamide (PTCy) and abatacept have significantly improved outcomes following HLA-mismatched allogenic hematopoietic stem cell transplantation (allo-HSCT) and have tremendous potential for reducing racial disparities in donor availability. A recent small study employing bone marrow as the source of stem cells showed similar outcomes after 5/8 versus 7/8 matches and is currently being tested in a larger study using peripheral blood stem cells. In this study, we examine real-world alternative donor HSCT options for a minority-predominant cohort in the Bronx, NY, focusing on the availability of lesser-matched (5/8 to 7/8) donors. Records of patients who underwent HLA typing at Montefiore Medical Center (2019 to 2022) were reviewed. The National Marrow Donor Program registry was queried to evaluate the availability of donors with at least 99% likelihood of HLA match at various levels (5/8, 6/8, 7/8, 8/8). Two hundred forty-one patients were included, 70% were non-White. Although the availability of ≥7/8 donors was less common in non-White patients, 100% of patients from each group had at least one or more 5/8 and 6/8 HLA-matched donors and more than 80% of these patients had >100 potential 5/8 and 6/8 HLA-matched donors. There was no statistical difference by race or ethnicity in the mean number of donors at 5/8 and 6/8 HLA-match levels. We demonstrate through real-world data that patients from diverse ethnic and racial backgrounds have access to 5/8 and 6/8 HLA-matched donors for allo-HSCT, potentially eliminating disparities in donor availability and allowing prioritization of other donor selection characteristics such as donor age, sex, ABO, and B leader matching. Further work is needed to study whether the use of mismatched donors offers a more potent graft-versus malignancy effect and optimal GVHD prophylaxis.

Mosaic loss of Y chromosome is associated with aging and epithelial injury in chronic kidney disease.

BACKGROUND: Mosaic loss of Y chromosome (LOY) is the most common chromosomal alteration in aging men. Here, we use single-cell RNA and ATAC sequencing to show that LOY is present in the kidney and increases with age and chronic kidney disease. RESULTS: The likelihood of a cell having LOY varies depending on its location in the nephron. Cortical epithelial cell types have a greater proportion of LOY than medullary or glomerular cell types, which may reflect their proliferative history. Proximal tubule cells are the most abundant cell type in the cortex and are susceptible to hypoxic injury. A subset of these cells acquires a pro-inflammatory transcription and chromatin accessibility profile associated with expression of HAVCR1, VCAM1, and PROM1. These injured epithelial cells have the greatest proportion of LOY and their presence predicts future kidney function decline. Moreover, proximal tubule cells with LOY are more likely to harbor additional large chromosomal gains and express pro-survival pathways. Spatial transcriptomics localizes injured proximal tubule cells to a pro-fibrotic microenvironment where they adopt a secretory phenotype and likely communicate with infiltrating immune cells. CONCLUSIONS: We hypothesize that LOY is an indicator of increased DNA damage and potential marker of cellular senescence that can be applied to single-cell datasets in other tissues.

Contrast-enhanced photon-counting micro-CT of tumor xenograft models.

Photon-counting micro computed tomography (micro-CT) offers new potential in preclinical imaging, particularly in distinguishing materials. It becomes especially helpful when combined with contrast agents, enabling the differentiation of tumors from surrounding tissues. There are mainly two types of contrast agents in the market for micro-CT: small molecule-based and nanoparticle-based. However, despite their widespread use in liver tumor studies, there is a notable gap in research on the application of these commercially available agents for photon-counting micro-CT in breast and ovarian tumors. Herein, we explored the effectiveness of these agents in differentiating tumor xenografts from various origins (AU565, MDA-MB-231, and SKOV-3) in nude mice, using photon-counting micro-CT. Specifically, ISOVUE-370 (a small molecule-based agent) and Exitrone Nano 12000 (a nanoparticle-based agent) were investigated in this context. To improve tumor visualization, we proposed a novel color visualization method for photon-counting micro-CT, which changes color tones to highlight contrast media distribution, offering a robust alternative to traditional material decomposition methods with less computational demand. Our in vivo experiments confirm its effectiveness, showing distinct enhancement characteristics for each contrast agent. Qualitative and quantitative analyses suggested that Exitrone Nano 12000 provides superior vasculature enhancement and better quantitative consistency across scans, while ISOVUE-370 gives more comprehensive tumor enhancement but with a significant variance between scans due to its short blood half-time. This variability leads to high sensitivity to timing and individual differences among mice. Further, a paired t-test on mean and standard deviation values within tumor volumes showed significant differences between the AU565 and SKOV-3 tumor models with the nanoparticle-based (p-values < 0.02), attributable to their distinct vascularity, as confirmed by immunohistochemistry. These findings underscore the utility of photon-counting micro-CT in non-invasively assessing the morphology and anatomy of different tumor xenografts, which is crucial for tumor characterization and longitudinal monitoring of tumor development and response to treatments.

Validation of a Midfacial Scale and Its Use in a Randomized, Evaluator-Blinded Study of CPM-HA-V.

BACKGROUND: Age-related loss of midfacial contour is frequently corrected using dermal fillers. A validated photonumeric scale is beneficial when evaluating post-treatment aesthetic improvement. OBJECTIVE: To present scale-development activities for the Merz Cheek Fullness Assessment Scale (MCFAS) and report pilot-study results of a hyaluronic-acid filler (Belotero Volume with Lidocaine; CPM-HA-V) to treat midfacial volume loss. METHODS: A 5-point photonumeric scale was developed to objectively assess midface volume loss. Rater reliability was evaluated using live assessments. The clinical relevance of a 1-point difference in severity grade was evaluated using photographic comparisons. Pilot-study participants, with moderate-to-severe volume loss on the MCFAS, were randomized 2:1 to treatment or untreated control. Effectiveness was evaluated using the MCFAS, and adverse events were recorded. RESULTS: The MCFAS demonstrated substantial intra- and interrater agreement among physicians (weighted kappa > 0.6). The mean absolute difference (95% confidence interval) in scale ratings was 1.12 (1.00, 1.24) for photographic pairs differing by one grade and was 0.55 (0.48, 0.63) for pairs of the same grade, suggesting a 1-point difference is clinically relevant. In the pilot study, significant  (P < 0.0001) differences were observed in MCFAS response rates between treatment and control. No safety concerns were identified. CONCLUSION: The MCFAS is a validated, reliable, and clinically relevant photonumeric scale for rating midfacial volume loss in males and females of various ages and skin types. In a pilot study, CPM-HA-V was found to be safe and tolerable, and the MCFAS was able to detect clinically meaningful post-treatment changes. J Drugs Dermatol. 2024;23(1):     doi:10.36849/JDD.7981.

Fluorescence Lifetime Imaging for Quantification of Targeted Drug Delivery in Varying Tumor Microenvironments.

Rationale: Trastuzumab (TZM) is a monoclonal antibody that targets the human epidermal growth factor receptor (HER2) and is clinically used for the treatment of HER2-positive breast tumors. However, the tumor microenvironment can limit the access of TZM to the HER2 targets across the whole tumor and thereby compromise TZM's therapeutic efficacy. An imaging methodology that can non-invasively quantify the binding of TZM-HER2, which is required for therapeutic action, and distribution within tumors with varying tumor microenvironments is much needed. Methods: We performed near-infrared (NIR) fluorescence lifetime (FLI) Forster Resonance Energy Transfer (FRET) to measure TZM-HER2 binding, using in vitro microscopy and in vivo widefield macroscopy, in HER2 overexpressing breast and ovarian cancer cells and tumor xenografts, respectively. Immunohistochemistry was used to validate in vivo imaging results. Results: NIR FLI FRET in vitro microscopy data show variations in intracellular distribution of bound TZM in HER2-positive breast AU565 and AU565 tumor-passaged XTM cell lines in comparison to SKOV-3 ovarian cancer cells. Macroscopy FLI (MFLI) FRET in vivo imaging data show that SKOV-3 tumors display reduced TZM binding compared to AU565 and XTM tumors, as validated by ex vivo immunohistochemistry. Moreover, AU565/XTM and SKOV-3 tumor xenografts display different amounts and distributions of TME components, such as collagen and vascularity. Therefore, these results suggest that SKOV-3 tumors are refractory to TZM delivery due to their disrupted vasculature and increased collagen content. Conclusion: Our study demonstrates that FLI is a powerful analytical tool to monitor the delivery of antibody drug tumor both in cell cultures and in vivo live systems. Especially, MFLI FRET is a unique imaging modality that can directly quantify target engagement with potential to elucidate the role of the TME in drug delivery efficacy in intact live tumor xenografts.

NAC and Zuotin/Hsp70 chaperone systems coexist at the ribosome tunnel exit in vivo.

The area surrounding the tunnel exit of the 60S ribosomal subunit is a hub for proteins involved in maturation and folding of emerging nascent polypeptide chains. How different factors vie for positioning at the tunnel exit in the complex cellular environment is not well understood. We used in vivo site-specific cross-linking to approach this question, focusing on two abundant factors-the nascent chain-associated complex (NAC) and the Hsp70 chaperone system that includes the J-domain protein co-chaperone Zuotin. We found that NAC and Zuotin can cross-link to each other at the ribosome, even when translation initiation is inhibited. Positions yielding NAC-Zuotin cross-links indicate that when both are present the central globular domain of NAC is modestly shifted from the mutually exclusive position observed in cryogenic electron microscopy analysis. Cross-linking results also suggest that, even in NAC's presence, Hsp70 can situate in a manner conducive for productive nascent chain interaction-with the peptide binding site at the tunnel exit and the J-domain of Zuotin appropriately positioned to drive stabilization of nascent chain binding. Overall, our results are consistent with the idea that, in vivo, the NAC and Hsp70 systems can productively position on the ribosome simultaneously.

Dorsal root ganglion stimulator-A targeted therapy for post-herpetic neuralgia: The Middle East Experience.

BACKGROUND: Post herpetic neuralgia (PHN) is a chronic neuropathic pain syndrome which presents after an episode of herpes zoster caused by the reactivation of varicella zoster virus. Conservative treatment starts with pharmacological measures using Anti-epileptics and Antidepressants. Some patients also respond well to epidural steroid injections too, but the effect is usually short lasting. Dorsal Root Ganglion Stimulator (DRG-S) has recently been suggested as a new treatment modality for PHN due to its selective targeting of the pathophysiologic focus. CASE SERIES: We are reporting three cases, who were suffering from neuropathic pain after an episode of herpes zoster. Pain and pain related suffering scores were high, even with multiple antiepileptics and opioid medications. They underwent DRG-S implant and appreciated more than 50% reduction of their pain score, meaningful reduction in the dose of medications along with significant improvement of their general well being measured using Generalized Anxiety Disorder Questionnaire (GAD-7), pain disability index (PDI), and 9 Question Patient Health Questionnaire (PHQ-9). To our knowledge this is the first report on DRG stimulator from the Middle East Region. CONCLUSION: DRG-S has potential to be a preferable treatment option in patients with refractory PHN and acts as a specific targeted therapy in the treatment of these patients.

Radiological Patterns of Lung Injury on HRCT in COVID-19 Patients: An Experience From Tertiary Care Centre in India.

INTRODUCTION: During the outbreak of the COVID-19 pandemic, radiological examinations became crucial in assessing the severity and progression of lung injuries in COVID-19 patients. AIM: This study was done to identify radiological patterns of lung injuries in COVID-19 patients, assess lobar involvement, and perform CT severity scoring on symptomatic patients on a baseline scan. METHODS AND MATERIAL: All the RT-PCR-positive patients were retrospectively enrolled in the study from August 16, 2020 to October 12, 2020. The final heart-resolution computed tomographic (HRCT) thorax data of a total of 119 COVID-19 patients was analyzed using simple statistical methods. A p-value of less than 0.05 (p < 0.05) was considered statistically significant. RESULTS: A total of 119 HRCT thorax scans of symptomatic indoor RT-PCR-positive patients were reviewed. Over 50% of the patients were under 50 (n = 66; 25 = 5; 25-50 = 61). Males > females: 3.25:1 (M = 91; F = 28). Peripheral involvement dominated (n = 90). Both lungs were affected equally, but the right lower lobe was more involved (n = 103) than the left (n = 98). Inpatient care was needed for 64.70% of CT severity score (CTSS) 10 COVID-19 patients (n = 77). Most positive CT scans (n = 115) revealed ground glass opacities (n = 112; 97.39%). Vascular dilatation or vasculitis (n = 65; 56.62%) and organizing pneumonia-like changes (n = 61; 53.04%) were also common. Vascular enlargement (56.53 percent, n = 65) and reverse halo (52.17%, n = 60) were the most common CT signs. CONCLUSION:  The most common chest CT finding in COVID-19 was ground-glass opacity in peripheral distribution with extensive lung involvement. These ground glass opacities may coalesce into consolidations. Vascular dilatation, organizing pneumonia, interlobular septal thickening, and crazy paving were other important imaging characteristics.