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Background: Pancreatic adenocarcinoma has a predisposition to invade the neural tissue surrounding the superior mesenteric artery (SMA). Before the advent of neoadjuvant chemotherapy (NAC), any invasion of this tissue was often considered as unresectable disease. Currently, patients who respond favourably to NAC have potentially resectable disease. There is debate over the exact technique of removing this shell of tumour tissue surrounding the SMA, and whether it is comparable to arterial resection and reconstruction., Methods: We describe a technique of en bloc arterial divestment in which an endovascular stapler combined with sharp dissection is used to divide the shell of periadventitial SMA tissue., Conclusions: In patients with locally advanced disease, the technique of arterial divestment can be safely performed where the tumour is not invading below the external elastic lamina. This allows complete tumour resection without incurring the higher morbidity and mortality associated with SMA resection., (© 2024 Wiley Periodicals LLC.)

In vitro nasal models can potentially facilitate development and approval of nasal drug products. This study aims to evaluate the potential for using regional deposition measurements from in vitro nasal models to evaluate nasal spray performance across several products. To accomplish this, the posterior regions of six anatomically realistic nasal airway models of adult and pediatric subjects, representing Low (L), Mean (M) and High (H) posterior drug deposition (PD) for each of the two age groups, were segmented with high anatomical precision into five regions of interest. These models were previously developed with the goal of quantifying the range of intersubject variability of PD following administration of inhaled corticosteroids. The in vitro regional drug deposition values were measured for the reference listed drug (RLD) product for triamcinolone acetonide and two corresponding generic (test) nasal spray products, as well as an RLD product for fluticasone furoate nasal spray. In general, the pediatric models mostly demonstrated higher PD compared to the adult models. The majority (>85 %) of PD was confined to the front and the inferior meatus regions. Subsequent population bioequivalence (PBE) analyses of the regional nasal deposition suggested that the anatomical differences among subjects may impact the nasal spray performance across different nasal products., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Laleh Golshahi reports financial support was provided by Department of Health and Human Services, U.S. Food and Drug Administration. Laleh Golshahi has patent issued to Virginia Commonwealth University. Corresponding Author’s current institution (VCU) is actively in licensing conversations regarding nasal casts with various pharmaceutical product development companies. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: Intraductal papillary mucinous neoplasms (IPMNs) are diverse premalignant tumors of the pancreas. They progress stepwise from adenoma to carcinoma and offer an opportunity for intervention prior to malignant transformation into pancreatic ductal adenocarcinoma (PDAC). The current study aimed to identify differentially expressed genes (DEGs) in invasive PDAC-associated IPMN vs. noninvasive IPMN to understand the potential molecular changes involved in malignant transformation of IPMN into PDAC., Materials and Methods: Archived tissue and data from 12 patients with histologically proven invasive PDAC arising from IPMN specimens were assessed. Gene expression analysis was performed on RNA extracted from macro-dissected tissue specimens using the NanoString nCounter PanCancer Progression assay. Statistical and pathway analysis was performed using SPSS v28 and Ingenuity Pathway Analysis, respectively., Results: A total of 159 genes had significantly (p < 0.05, q < 0.05) different expression in PDAC arising from IPMN compared with that from IPMN alone (91 overexpressed and 68 underexpressed). Interestingly, 14 of top 10 over- and underexpressed genes were predicted to translate secretory proteins, with SignalP scores approaching 1. A number of differential canonical pathways (e.g., LXR/RXR activation pathway, glycolysis I gluconeogenesis I, and hepatic fibrosis) and potential upstream regulators (e.g., TGFB1, THBS2, etc.) were also identified., Conclusion: A differential gene expression profile between PDAC arising from IPMN and IPMN alone was identified. Pathway analysis identified potential mechanisms involved in malignant transformation of IPMN to PDAC., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: To evaluate the anatomic and visual outcomes and safety profile of initial Indian eyes with neovascular age-related macular degeneration (nAMD) treated with intravitreal injection (IVI) of brolucizumab., Methods: This retrospective multicentric, real-world study enrolled consecutive eyes with nAMD that were treated with IVI brolucizumab after it was launched in India in October 2020. Data collected for each eye included best-corrected visual acuity (BCVA), central subfield thickness (CSFT), subretinal fluid (SRF), and intraretinal fluid (IRF) status at 6, 12, and 24 months follow-up. Also recorded were the lens status, treatment protocol, number of injections received before enrollment (in switch-over cases), total number of injections, and adverse effects noticed during the study period. Primary outcomes were change in BCVA, CSFT at follow-up visits, and incidence of intraocular inflammation (IOI). Secondary outcomes were profile of macular neovascularization, treatment protocols, mean number of injections, and maximum injection-free interval observed in eyes treated by pro-re-nata (PRN) protocol., Results: In total, 331 eyes received a mean of 3.55 ± 1.83 injections. Most frequent treatment protocol was PRN (53%). BCVA data was available for 100%, 96%, and 74% eyes at 6, 12, and 24 months follow-up. BCVA and CSFT improved significantly (P < 0.001) at all follow-ups. Two hundred and seventy-six (83.38%) out of 331 eyes received more than one injection; out of these, 241 (87.3%) eyes that were treated by PRN protocol could achieve mean "maximum injection-free interval" of 19.43 ± 8.82 weeks. IOI and retinal vasculitis were reported in 2.11% (7/331) and 0.60% (2/331) eyes, respectively. None of the eyes with IOI or vasculitis lost any vision at the final follow-up., Conclusion: This study demonstrated favorable visual and anatomic outcomes and safety profile for eyes with nAMD treated by IVI brolucizumab. Mean maximum injection-free interval in eyes treated with PRN was 19 weeks., (Copyright © 2024 Indian Journal of Ophthalmology.)

Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Angina Bullosa Hemorrhagica is characterized with rapid appearance of soft, blood-filled blisters on the mucosa of oral cavity and oropharynx. It is a benign condition, and is not associated with any systemic hematological disorder. No etiological factors have been identified and there are no established guidelines for its management. The current case report describes the sudden appearance of large, bluish, soft lesion on the soft palate which was managed with incision and drainage, and healed completely over the next three weeks., (© Association of Otolaryngologists of India 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Female hormone-dependent cancers depend on estrogen for their growth. Numerous studies have explored the antitumor effect of dietary isoflavones on female hormone-dependent cancers. Still, few clinical evidence supports the use of isoflavones in female hormone-dependent cancer patients. This study was performed to examine the impact of dietary isoflavones on tumor growth of female hormone-dependent cancers and accelerate the transformation of research from bench to bedside. We searched PubMed Medline, Web of Science, and Google Scholar for relevant articles related to the effect of dietary isoflavone on tumor growth of experimental animal models of female hormone-dependent cancers from 1998 to 2024. The effects of dietary isoflavones on tumor growth were analyzed between the control and treatment groups using comprehensive meta-analysis software (CMA). We included 30 studies describing tumor growth focused on female hormone-dependent cancer types, including breast, ovarian, and uterine cancers. Overall, a pooled analysis revealed that dietary isoflavones reduced tumor volume (Hedge's g = -1.151, 95% CI = -1.717 to -0.585, p = 0.000) and tumor weight (Hedge's g = -2.584, 95% CI = -3.618 to -1.549, p = 0.000). On the other hand, dietary isoflavones increased tumor area (Hedge's g = 1.136, 95% CI = 0.752 to 1.520, p = 0.000). Dietary isoflavones have potential benefits and risks in female hormone-dependent cancers. Therefore, caution should be exercised when considering the intake of dietary isoflavones in female hormone-dependent cancer patients, particularly in the form of supplements., (© 2024 John Wiley & Sons Ltd.)

Background: Blood transfusion is a cornerstone of modern healthcare, pivotal in saving countless lives annually. However, inadequate knowledge among healthcare providers can lead to serious complications. Despite the availability of assessment tools like the Biomedical Excellence for Safer Transfusion (BEST) test, there is a need for indigenous-validated questionnaires to address knowledge gaps effectively. This study aimed to evaluate bedside transfusion medicine knowledge among clinical residents using a validated questionnaire, focusing on knowledge gaps., Study Design and Methods: A cross-sectional study was conducted at a tertiary care referral center in Northern India. The questionnaire, developed based on national and international transfusion guidelines, was validated by an expert panel, and administered to 245 clinical residents. The questionnaire covered six domains related to transfusion medicine: blood component storage, blood bank procedures, transfusion-transmitted infections, administration of blood components, transfusion reactions, and transfusion practices., Results: The study revealed varying levels of knowledge across specialties and residency years. Overall, residents scored 61 % in transfusion medicine knowledge, with Pediatrics residents demonstrating the highest scores. The incremental increase in knowledge from first to third-year residents underscores the value of continuous, experience-based learning throughout the residency period., Discussion: Study highlights significant knowledge gaps in bedside transfusion practices among clinical residents, emphasizing the need for structured educational interventions. Tailored programs, integrated into undergraduate and postgraduate curricula, are essential to improve transfusion safety and patient outcomes. Addressing these gaps can lead to better bedside transfusion practices, reducing risks and improving the quality of patient care., Competing Interests: Declaration of Competing Interest There are no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Context: Intermittent fasting, a new-age dietary concept derived from an age-old tradition, involves repetitive cycles of fasting/calorie restriction and eating., Objective: We aim to take a deep dive into the biological responses to intermittent fasting, delineate the disease-modifying and cognitive effects of intermittent fasting, and also shed light on the possible side effects., Methods: Numerous in vitro and in vivo studies were reviewed, followed by an in-depth analysis, and compilation of their implications in health and disease., Results: Intermittent fasting improves the body's stress tolerance, which is further amplified with exercise. It impacts various pathological conditions like cancer, obesity, diabetes, cardiovascular disease, and neurodegenerative diseases., Conclusion: During dietary restriction, the human body experiences a metabolic switch due to the depletion of liver glycogen, which promotes a shift towards utilising fatty acids and ketones in the system, thereby significantly impacting adiposity, ageing and the immune response to various diseases.

Competing Interests: Disclosures Dr Chan has received research support from DBV Technologies; has been a member of advisory boards for Pfizer, Miravo, Medexus, Leo Pharma, Kaleo, DBV, AllerGenis, Sanofi Genzyme, Bausch Health, Avir Pharma, AstraZeneca, and ALK; and was co-lead of the Canadian Society of Allergy and Clinical Immunology oral immunotherapy guidelines. Dr Pratap-Singh holds the BC Ministry of Agriculture Endowed Professorship in Food and Beverage Innovation. Drs Williams, Guo and Soller have no conflicts to disclosure.

The mechanosensory hair cell of the vertebrate inner ear responds to the mechanical deflections that result from hearing or change in the acceleration due to gravity, to allow us to perceive and interpret sounds, maintain balance and spatial orientation. In mammals, ototoxic compounds, disease, and acoustic trauma can result in damage and extrusion of hair cells, without replacement, resulting in hearing loss. In contrast, non-mammalian vertebrates can regenerate sensory hair cells. Upon damage, hair cells are extruded and an associated cell type, the supporting cell is transformed into a hair cell. The mechanisms that can trigger regeneration are not known. Using mosaic deletion of the hair cell master gene, Atoh1, in the embryonic avian inner ear, we find that despite hair cells depletion at E9, by E12, hair cell number is restored in sensory epithelium. Our study suggests a homeostatic mechanism can restores hair cell number in the basilar papilla, that is activated when juxtracrine signalling is disrupted. Restoration of hair cell numbers during development may mirror regenerative processes, and our work provides insights into the mechanisms that trigger regeneration., (Copyright © 2024 Elsevier Inc. All rights reserved.)

This study aimed to optimize mesalamine (MES)-nanoparticles (NPs) using Box Behnken Design and investigate its in vivo antioxidant potential in colon drug targeting. The formulation was prepared using oil/water (O/W) emulsion solvent evaporation technique for time dependent colonic delivery. The optimal formulation with the following parameters composition was selected: polymer concentration (% w/w) (A) = 0.63, surfactant concentration (% w/w) (B) = 0.71, sonication duration (min) (C) = 6. The outcomes showed that ethyl cellulose (EC) NP containing MES has particles size of 142 ± 2.8 nm, zeta potential (ZP) of -24.8 ± 2.3 mV, % EE of 87.9 ± 1.6%, and PDI of 0.226 ± 0.15. Scanning electron microscopy revealed NPs has a uniform and spherical shape. The in-vitro release data disclosed that the EC NPs containing MES showed bursts release of 52% ± 1.6% in simulated stomach media within 2 h, followed by a steady release of 93% ± 2.9% in simulated intestinal fluid that lasted for 48 h. The MES release from NP best match with the Korsmeyer-Peppas model ( R 2 = 0.962) and it followed Fickian diffusion case I release mechanism. The formulation stability over six-months at 25 °C ± 2 °C with 65% ± 5% relative humidity, and 40 °C ± 2 °C with 75% ± 5% relative humidity showed no significant changes in colour, EE, particle sizes and ZP. As per in vivo results, MES-NP effectively increased glutathione, SOD level and reduces the LPO level as compared to other treatment groups. The findings hold promise that the developed formulation can suitably give in ulcerative colitis., (Creative Commons Attribution license.)

Objective: The objective of this study is to evaluate the diagnostic performance of urine cytology using The Paris System (TPS 2.0) in comparison with TPS 1.0, and the Four-Tier Reporting System (FTRS) of our institute for identifying high-grade urothelial carcinoma (HGUC)., Methodology: A total of 789 urine cytology specimens from 240 patients including 12 UTUC cases with available histological and clinical details were included. Two hundred twenty-two cases were newly diagnosed, whereas 18 were recurrent tumours. Histopathological evaluation categorised the cases as non-neoplastic (33%, 13.7%), low-grade urothelial neoplasms (LGUNs) (94%, 39.2%), high-grade urothelial carcinoma (HGUCs) (110%, 45.8%) and other malignancies (3%, 1.3%)., Results: TPS 2.0 categorised the cases as 14 (5.7%) non-diagnostic or ND/U, 99 (41.5%) NHGUC, 37 (15.4%) AUC, 24 (10%) SHGUC and 66 (27.5%) HGUC. TPS 1.0 had 14 (5.7%) ND/U, 72 (30%) NHGUC, 61 (24.5%) AUC, 3 (1.3%) LGUC, 24 (10%) SHGUC and 66 (27.5%) HGUC. FTRS classified them as 19 (7.5%) ND/UNS, 44 (18.3%) NEG, 88 (36.7%) INC and 89 (37.1%) POS. The ROHM for TPS 2.0 was 71.4% for ND/U, 12.1% for NHGUC, 29.7% for AUC, 79.2% for SHGUC and 89.4% for HGUC. TPS 1.0 showed a similar ROHM for ND/U, SHGUC and HGUC, whereas had 13.8% for NHGUC and 19.7% for AUCs. FTRS, had 78.9% for UNS, 6.8% for NEG, 35.2% for INC and 73.1% for POS. TPS demonstrated a sensitivity of 70.91% and specificity of 90.77% for identifying HGUC, whereas FTRS showed 59.09% sensitivity and 81.54% specificity. Also, TPS was found to be 75% accurate with 62.5% sensitivity and 100% specificity for UTCC cases separately., Conclusion: TPS 2.0 exhibits diagnostic accuracy with better performance in comparison to FTRS, making it a more reliable system for clinical practice. Our findings endorse the utility of TPS 2.0 in improving the accuracy of urine cytology in predicting histological diagnosis of HGUC., (© 2024 John Wiley & Sons Ltd.)

Objective: Hearing outcomes following Gamma Knife radiosurgery (GKRS) for vestibular schwannoma (VS) are multifactorial and poorly characterized in prior literature. In this study the authors evaluated hearing outcomes chronologically to identify prognostic factors of serviceable hearing preservation (HP) rates following GKRS for VS., Methods: Six medical databases were queried according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Eligible studies reported VS treated with single-fraction GKRS and included the HP rate following GKRS. HP was defined as a postoperative Gardner-Robertson score ≤ 2 among patients with preoperative serviceable hearing. A meta-analysis with random-effects modeling was performed for variables of interest., Results: Data from 42 articles with a total of 6582 patients were analyzed; the average age of patients was 54 years and the average follow-up time was 68 months. The pooled proportion of preoperative serviceable hearing was 76%, and the pooled HP rate was 60% at the last follow-up visit. At < 5 years after GKRS, age was significantly correlated with HP on both continuous and categorical analyses (p = 0.001 and p = 0.011, respectively). Between 5 and < 10 years of follow-up, HP was associated with a radiation dose of 12.5 Gy, but not with age or tumor volume. At ≥ 10 years after radiosurgery, a significant negative correlation was seen between marginal radiation dose and HP on both continuous and categorical analyses (p = 0.001 and p = 0.021, respectively)., Conclusions: This meta-analysis identifies age and radiation dose as independent prognostic factors for HP. Age-related hearing deterioration appears to be concentrated in the first 5 years after GKRS, whereas radiation dose was associated with HP at last follow-up, between 5 and < 10 years, and at ≥ 10 years after radiosurgery. This meta-analysis offers an objective overview of the literature and a framework for clinical decision-making, with applications for treatment planning and patient counseling.

The objectives of this study were to expand and implement a Computational Fluid Dynamics (CFD)-Dissolution, Absorption and Clearance (DAC)-Pharmacokinetics (PK) multi-physics modeling framework for simulating the transport of suspension-based nasal corticosteroid sprays. The mean CFD-predicted peak plasma concentration (C max ) and area under the curve (AUC) of the plasma concentration-time profile, based on three representative nasal airway models (capturing low, medium and high posterior spray deposition), were within one standard deviation of available in vivo PK data for a representative corticosteroid drug (triamcinolone acetonide). The relative differences in mean C max between predictions and in vivo data for low dose (110 µg) and high dose (220 µg) cases were 27.8% and 10.1%, respectively. The models confirmed the dose-dependent dissolution-limited behavior of nasally delivered triamcinolone acetonide observed in available in vivo data. The total uptake from the nasal cavity decreased from 68.3% to 51.3% for the medium deposition model as dose was increased from 110 to 220 µg due to concentration-limited dissolution. The modeling framework is envisioned to facilitate faster development and testing of generic locally acting suspension nasal spray products due to its ability to predict the impact of differences in spray characteristics and patient use parameters on systemic PK., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Hepatitis E is a hepatotropic virus and the most common cause of acute viral hepatitis among adults in India. It has four genotypes, and genotype 1 is mostly associated with sporadic cases. It typically causes self-limiting acute hepatitis following a prodromal course. However, a subset of patients presents with cholestatic features mimicking primary cholestatic liver diseases like primary biliary cholangitis or primary sclerosing cholangitis. Liver injury ranges from asymptomatic rise of liver enzymes to fulminant liver failure. The hepatitis E virus (HEV) has also been implicated in various extrahepatic manifestations such as acute pancreatitis, Guillain-Barré syndrome (GBS), radiculopathy, autoimmune hemolysis, and Bell's palsy. We present an interesting case of acute viral hepatitis E presenting with cholestatic jaundice and extrahepatic manifestations., Competing Interests: Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Malakar et al.)

Background: Neoadjuvant chemotherapy (NAC) can provide improved survival outcomes in pancreatic ductal adenocarcinoma (PDAC) patients who respond to treatment, but currently available biomarkers cannot reliably predict NAC response. This study aimed to determine the potential of a previously identified diagnostic and prognostic biomarker panel (i.e. Ca-125, S100A2, S100A4, Mesothelin and Ca19-9) for the monitoring of NAC-response in PDAC patients., Methods: This single-centre, retrospective study, utilised serum from NAC treated PDAC patients to determine the levels of biomarkers by Enzyme-Linked Immunosorbent Assay (ELISA). The percentage of the tumour bed occupied by viable carcinoma (PVC) was used to divide patients into good (PVC < 50%) and poor (PVC ≥ 50%) NAC-responders. Statistical analysis was performed to measure the ability of individual biomarkers and a biomarker panel in NAC treatment response and patient survival., Results: Serum specimens from a total of 108 PDAC patients were assessed. Ca-125, Ca19-9 and S100A2 showed a significant positive correlation with PVC. Ca-125 demonstrated a superior ability to monitor NAC treatment response (Area under receiver operating curve (AUC): .6954) compared to the more widely used clinical biomarker, Ca19-9 (AUC: .6291). A panel of Ca-125 and Ca19-9 showed good ability to monitor NAC response in PDAC patients (AUC: .7349). Patients with high levels of both Ca-125 and Ca19-9 were shown to have the poorest overall survival (median overall survival: 17 vs. 30 months)., Conclusion: A serum biomarker panel of Ca-125 and Ca19-9 could be used for effective clinical management of PDAC patients undergoing NAC treatment., (© 2024 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

Aims: Venous thromboembolism (VTE) is a potential complication of foot and ankle surgery. There is a lack of agreement on contributing risk factors and chemical prophylaxis requirements. The primary outcome of this study was to analyze the 90-day incidence of symptomatic VTE and VTE-related mortality in patients undergoing foot and ankle surgery and Achilles tendon (TA) rupture. Secondary aims were to assess the variation in the provision of chemical prophylaxis and risk factors for VTE., Methods: This was a multicentre, prospective national collaborative audit with data collection over nine months for all patients undergoing foot and ankle surgery in an operating theatre or TA rupture treatment, within participating UK hospitals. The association between VTE and thromboprophylaxis was assessed with a univariable logistic regression model. A multivariable logistic regression model was used to identify key predictors for the risk of VTE., Results: A total of 13,569 patients were included from 68 sites. Overall, 11,363 patients were available for analysis: 44.79% were elective (n = 5,090), 42.16% were trauma excluding TA ruptures (n = 4,791), 3.50% were acute diabetic procedures (n = 398), 2.44% were TA ruptures undergoing surgery (n = 277), and 7.10% were TA ruptures treated nonoperatively (n = 807). In total, 11 chemical anticoagulants were recorded, with the most common agent being low-molecular-weight heparin (n = 6,303; 56.79%). A total of 32.71% received no chemical prophylaxis. There were 99 cases of VTE (incidence 0.87% (95% CI 0.71 to 1.06)). VTE-related mortality was 0.03% (95% CI 0.005 to 0.080). Univariable analysis showed that increased age and American Society of Anesthesiologists (ASA) grade had higher odds of VTE, as did having previous cancer, stroke, or history of VTE. On multivariable analysis, the strongest predictors for VTE were the type of foot and ankle procedure and ASA grade., Conclusion: The 90-day incidence of symptomatic VTE and mortality related to VTE is low in foot and ankle surgery and TA management. There was notable variability in the chemical prophylaxis used. The significant risk factors associated with 90-day symptomatic VTE were TA rupture and high ASA grade., Competing Interests: J. Mangwani reports support from the Leicester Hospitals Charity, related to this study. J. Mangwani reports payment or honoraria for lectures, presentations, educational events from Orthosolutions, and royalties from Meshworks, unrelated to this study. K. Malhotra reports payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing or educational events from NewClip Technics, unrelated to this study. L. W. Mason reports royalties or licenses, consulting fees, and patents planned, issued or pending from Orthosolutions, unrelated to this study., (© 2024 The British Editorial Society of Bone & Joint Surgery.)

Although metastatic disease is the leading cause of cancer-related deaths, its tumor microenvironment remains poorly characterized due to technical and biospecimen limitations. In this study, we assembled a multi-modal spatial and cellular map of 67 tumor biopsies from 60 patients with metastatic breast cancer across diverse clinicopathological features and nine anatomic sites with detailed clinical annotations. We combined single-cell or single-nucleus RNA sequencing for all biopsies with a panel of four spatial expression assays (Slide-seq, MERFISH, ExSeq and CODEX) and H&E staining of consecutive serial sections from up to 15 of these biopsies. We leveraged the coupled measurements to provide reference points for the utility and integration of different experimental techniques and used them to assess variability in cell type composition and expression as well as emerging spatial expression characteristics across clinicopathological and methodological diversity. Finally, we assessed spatial expression and co-localization features of macrophage populations, characterized three distinct spatial phenotypes of epithelial-to-mesenchymal transition and identified expression programs associated with local T cell infiltration versus exclusion, showcasing the potential of clinically relevant discovery in such maps., Competing Interests: Competing interests A. Regev, J.K. and D.L.A. are co-inventors on patent application number 17/156,392, filed by the Broad Institute, for inventions relating to work in this manuscript. A. Regev is a co-founder and equity holder of Celsius Therapeutics, an equity holder in Immunitas and, until 31 July 2020, a scientific advisory board (SAB) member of Thermo Fisher Scientific, Syros Pharmaceuticals, Neogene Therapeutics and Asimov. From 1 August 2020, A. Regev is an employee of Genentech and has equity in Roche. A. Rotem is an employee of AstraZeneca since September 2020 and has equity in AstraZeneca. E.S.B. co-founded a company that is exploring commercial applications of expansion microscopy. G.N. holds equity in and consults for Akoya Biosciences. J.G.T.Z. owns stocks in the biotechnology exchange-traded funds CNCR, IDNA, IBB and XBI, owns stock in Novo Nordisk and owns stock in Adaptive Biotechnologies, 2seventy bio and bluebird bio. J.J-V. is a contractor at Genentech since 2021. M.S. is a contractor at Genentech since November 2020. O.R.-R. is a co-inventor on patent applications filed by the Broad Institute for inventions related to single-cell genomics. She has given numerous lectures on the subject of single-cell genomics to a wide variety of audiences and, in some cases, has received remuneration to cover time and costs. O.R.-R. is an employee of Genentech since 19 October 2020 and has equity in Roche. S.J.R. is a member of the SAB of Immunitas Therapeutics and receives research funding from Bristol Myers Squibb and Kite/Gilead. X.Z. is a co-founder of and consultant for Vizgen. The other authors declare no competing interests., (© 2024. The Author(s).)

Mood disorders, including depression, remain a significant global health concern, necessitating continuous efforts to develop novel and more effective antidepressant therapies. Although there have been significant advancements in comprehending the biology of Major Depressive Disorder (MDD), a considerable number of people suffering from depression do not exhibit positive responses to the pharmacologic treatments now available. This study specifically examines emerging targets and potential future approaches for pharmaceutical interventions in the treatment of MDD. The discussion revolves around novel therapeutic agents and their effectiveness in treating depression. The focus is on the specific pathophysiological pathways targeted by these agents and the amount of evidence supporting their use. While conventional antidepressants are anticipated to continue being the primary treatment for MDD in the foreseeable future, there is currently extensive research being conducted on numerous new compounds to determine their effectiveness in treating MDD. Many of these compounds have shown encouraging results. This review highlighted the recent advances in the synthesis of antidepressant derivatives and explores their pharmacologic insights for the treatment of mood disorders., Competing Interests: Conflict of interestAuthors are required to disclose financial or non-financial interests that are directly or indirectly related to the work submitted for publication. The authors declare no conflicts of interest., (© King Abdulaziz City for Science and Technology 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Background: Minimally invasive surgical necrosectomy plays an important role in the management of infected pancreatic necrosis, with a goal of removing debris and debriding necrotic tissue. Pulse lavage is designed to simultaneously hydrostatically debride and remove the infected necrotic tissue with suction. It is also able to remove significant amounts of debris without traumatic manipulation of the necrotic tissue which may be adherent to surrounding tissue and can result in injury., Methods and Results: The surgical technique of utilising a waterjet pulse lavage device during the minimally invasive necrosectomy is detailed. Sixteen patients being managed via a step-up approach underwent endoscopic necrosectomy via a radiologically placed drain tract. All sixteen patients were successfully managed endoscopically without conversion to open necrosectomy, and survived their admission. There were no complications associated with the use of the waterjet pulse lavage., Conclusion: Waterjet pulse lavage is a useful adjunct in minimally invasive necrosectomy, which reduces the length of the necrosectomy procedure, and facilitates removal of necrotic tissue while minimising the risk of traumatising healthy tissue., (© 2024. The Author(s).)

Objectives: There is a paucity of data regarding the use of neoadjuvant therapy in pancreatic body or tail ductal adenocarcinomas. Given the differing tumor biology and aggressive nature of pancreatic body or tail adenocarcinomas, patients presenting with these tumors may benefit from upfront resection., Methods: A retrospective cohort study was performed analyzing patients who underwent distal pancreatectomy for pancreatic ductal adenocarcinoma between January 2013 and June 2022. Patients who underwent upfront resection were compared with those who underwent neoadjuvant therapy., Results: Forty-one patients underwent upfront distal pancreatectomy, whereas 40 patients underwent neoadjuvant therapy before curative intent resection. Neoadjuvant therapy did not improve overall survival (37 vs 34 months, P = 0.962) or disease-free survival (13 vs 15 months, P = 0.414), as compared with upfront resection. There was no significant difference in the rate or R 0 resection or postoperative outcomes., Conclusion: No significant improvement in survival was demonstrated for patients undergoing neoadjuvant therapy for pancreatic ductal adenocarcinoma of the pancreatic body or tail when compared with upfront resection. Considering the potential for disease progression given the more aggressive tumor biology of pancreatic body and tail adenocarcinomas, appropriate surgical candidates should be offered upfront resection to provide the best chance of survival and cure., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Intraductal oncocytic papillary neoplasms (IOPNs) of the pancreas are now considered a separate entity to intraductal papillary mucinous neoplasms (IPMN). Invasive IOPNs are extremely rare, and their recurrence patterns, response to adjuvant chemotherapy and long-term survival outcomes are unknown., Methods: Consecutive patients undergoing pancreatic resection (2010-2020) for invasive IOPNs or adenocarcinoma arising from IPMN (A-IPMN) from 18 academic pancreatic centers worldwide were included. Outcomes of invasive IOPNs were compared with A-IPMN invasive subtypes (ductal and colloid A-IPMN)., Results: 415 patients were included: 20 invasive IOPN, 331 ductal A-IPMN and 64 colloid A-IPMN. After a median follow-up of 6-years, 45% and 60% of invasive IOPNs had developed recurrence and died, respectively. There was no significant difference in recurrence or overall survival between invasive IOPN and ductal A-IPMN. Overall survival of invasive IOPNs was inferior to colloid A-IPMNs (median time of survival 24.4 months vs. 86.7, months, p = 0.013), but the difference in recurrence only showed borderline significance (median time to recurrence, 22.5 months vs. 78.5 months, p = 0.132). Adjuvant chemotherapy, after accounting for high-risk features, did not reduce rates of recurrence in invasive IOPN (p = 0.443), ductal carcinoma (p = 0.192) or colloid carcinoma (p = 0.574)., Conclusions: Invasive IOPNs should be considered an aggressive cancer with a recurrence rate and prognosis consistent with ductal type A-IPMN., (Copyright © 2024 International Hepato-Pancreato-Biliary Association Inc. All rights reserved.)

Avian influenza poses a significant global health threat, with the potential for widespread pandemics and devastating consequences. Hemagglutinin (HA), a critical surface glycoprotein of influenza viruses, plays a pivotal role in viral entry and serves as a primary target for subunit vaccine development. In this study, we successfully cloned, expressed, and purified hemagglutinin from the circulating strain of H5N1 influenza virus using a robust molecular biology approach. The cloning process involved insertion of the synthetic HA gene into the pET21b vector, confirmed through double digestion and sequencing. SDS-PAGE analysis confirmed the presence of the expected 60 kDa protein band post-induction. Following expression, the protein was subjected to purification via Ni-NTA affinity chromatography, yielding pure protein fractions. Native PAGE analysis confirmed the protein's oligomeric forms, essential for optimal antigenicity. Western blot analysis further validated protein identity using anti-His and anti-HA antibodies. MALDI-TOF analysis confirmed the protein's sequence integrity, while hemagglutination assay demonstrated its biological activity in binding to N-acetyl neuraminic acid. These findings underscore the potential of recombinant hemagglutinin as a valuable antigen for diagnosis and biochemical assays as well as for vaccine development against avian influenza. In conclusion, this study represents a critical guide for bacterial production of H5N1 HA, which can be a cost-effective and simpler strategy compared to mammalian protein expression. Further research into optimizing vaccine candidates and production methods will be essential in combating the ongoing threat of avian influenza pandemics., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Bacteroides species are successful colonizers of the human colon and can utilize a wide variety of complex polysaccharides and oligosaccharides that are indigestible by the host. To do this, they use enzymes encoded in polysaccharide utilization loci (PULs). While recent work has uncovered the PULs required for the use of some polysaccharides, how Bacteroides utilize smaller oligosaccharides is less well studied. Raffinose family oligosaccharides (RFOs) are abundant in plants, especially legumes, and consist of variable units of galactose linked by α-1,6 bonds to a sucrose (glucose α-1-β-2 fructose) moiety. Previous work showed that an α-galactosidase, BT1871, is required for RFO utilization in Bacteroides thetaiotaomicron . Here, we identify two different types of mutations that increase BT1871 mRNA levels and improve B. thetaiotaomicron growth on RFOs. First, a novel spontaneous duplication of BT1872 and BT1871 places these genes under the control of a ribosomal promoter, driving high BT1871 transcription. Second, nonsense mutations in a gene encoding the PUL24 anti-sigma factor likewise increase BT1871 transcription. We then show that hydrolases from PUL22 work together with BT1871 to break down the sucrose moiety of RFOs and determine that the master regulator of carbohydrate utilization (BT4338) plays a role in RFO utilization in B. thetaiotaomicron . Examining the genomes of other Bacteroides species, we found homologs of BT1871 in a subset and showed that representative strains of species with a BT1871 homolog grew better on melibiose than species that lack a BT1871 homolog. Altogether, our findings shed light on how an important gut commensal utilizes an abundant dietary oligosaccharide., Importance: The gut microbiome is important in health and disease. The diverse and densely populated environment of the gut makes competition for resources fierce. Hence, it is important to study the strategies employed by microbes for resource usage. Raffinose family oligosaccharides are abundant in plants and are a major source of nutrition for the microbiota in the colon since they remain undigested by the host. Here, we study how the model commensal organism, Bacteroides thetaiotaomicron utilizes raffinose family oligosaccharides. This work highlights how an important member of the microbiota uses an abundant dietary resource., Competing Interests: The authors declare no conflict of interest.

Whole genome sequencing (WGS) has become a gold standard for diagnosing genomic variation. Peripheral blood is a common sample source for the extraction of nucleic acids for Next-Generation Sequencing (NGS) applications. Here, we present an integrated and fully automated device design that uses new concepts of fluid mechanics, heat-mass transfer, and thermodynamics of enzymatic reactions to extract nucleic acids from the blood and perform DNA library preparation from a pre-filled plate. We demonstrate that the presented device effectively extracts dsDNA with an average of 25.03 µg/mL and 25.91 µg/mL yield from citrate-stabilized human peripheral blood stored in Fresh (4 °C) and Frozen (-20 °C) conditions, respectively. Furthermore, our method automatically extracts nucleic acids and creates a high-quality sequence-ready DNA library from blood stabilized with citrate and EDTA for 8 samples simultaneously in a single run with a total operation time of ~ 7 h. Our results show the required coverage and depth of the genome, highlighting an essential application of this device in processing blood samples for genome sequencing., (© 2024. The Author(s).)

Background/objectives: Integrated care models, like combined rheumatology/dermatology clinics (RDCs), facilitate efficient coordination between specialists and provide comprehensive care. Given the limited literature on pediatric RDC logistics, outcomes, benefits and, challenges, we comprehensively characterized our patient cohort at the UCSF Benioff Children's Hospital RDC and surveyed pediatric dermatologists participating in RDCs., Methods: We retrospectively reviewed 71 patients new to the UCSF Pediatric RDC between September 2017 and September 2023. A survey was distributed in 2024 to 17 dermatologists in North America, each representing a unique pediatric RDC., Results: 69% of patients (49/71) were female. Seventeen (24%) presented without a known diagnosis; the first RDC visit established a diagnosis for 7 of them (41%). Of patients with a previously established diagnosis, initial RDC evaluation confirmed it in 52 (96%) and revised it for 2 (4%). The most encountered diagnoses were linear morphea (33%), lupus (23%), and psoriasis (13%). New systemic therapy was prescribed for 23% of patients, and additional work-up was recommended via skin biopsy (8%) and imaging (28%). Survey results revealed all pediatric RDCs include trainees, but only 59% (10/17) receive administrative support. All agreed that RDCs are valuable for patient care and most (15/17, 88%) felt that the RDC was a valuable use of their time., Conclusions: Pediatric RDCs are valuable for consensus diagnosis, streamlined evaluation, and management of complex patients. Though clinical and administrative support for RDCs is generally poor, RDCs are valuable to patients, a good use of time for clinicians, and offer educational opportunities for team members., (© 2024 Wiley Periodicals LLC.)

Purpose: To compare the rate of re-detachment in patients with rhegmatogenous retinal detachment and Grade-C PVR following vitreoretinal surgery, with and without serial intravitreal injections of methotrexate., Methods: It was a randomized control trial. Patients aged more than 18 years undergoing pars plana vitrectomy for rhegmatogenous retinal detachment with PVR grade C or more were included in the study. Patients treated with intravitreal injection of methotrexate were grouped as cases and those not injected served as controls. The cases received 3 intravitreal injections of methotrexate at monthly intervals. Patients were evaluated on Day 1, 1st month, 2nd month, 3rd month and 6th month in terms of BCVA, rate of re-attachment and grade of PVR., Results: The case group had 23 patients and the control group had 20 patients. 2 patients in the case group were lost to follow-up after the first follow-up, so they were excluded. So 21 patients in case group and 20 patients in control group were followed up. Six months after surgery, 15 'cases' had completely attached retina whereas 6 patients had partial detachment with macula on. There was no patient amongst the cases with macula-off retinal re-detachment. Out of 20 patients in the control group, 9 had a complete retinal attachment, 4 had partial detachment with macula-on and 7 had partial detachment with macula-off. There was statistically significant difference in macula off retinal detachment rates (p-value- 0.003)., Conclusion: Serial intravitreal methotrexate injections reduce the incidence of re-detachment in patients undergoing PPV for RRD with PVR-C. Further investigation into this promising therapeutic approach is warranted., Key Messages: What is known Methotrexate is an anti-inflammatory agent which is safe for intravitreal use There are case series retrospective and prospective studies suggesting potential benefit of intravitreal methotrexate in preventing re-detachment due to PVR What is new First randomized control trial studying the efficacy of intravitreal methotrexate in preventing re-detachment due to PVR Our study showed statistically significant difference in macula off retinal detachment between the 2 groups at 6 months of follow up., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The lack of culturally-sensitive tool masks the epidemiology of weight-bias and internalized-stigma. This study aimed to translate, adapt, and validate the Modified Weight-Bias Internalization Scale (WBIS-M) into Hindi., Methods: The translation and adaptation process followed the World Health Organization guidelines. Three psychiatrists translated the original WBIS-M into Hindi. The bilingual panel comprised four psychiatrists, two laparoscopic bariatric surgeons, a professor of English, and an individual with severe obesity (with an International English Language Testing System (IELTS) score of Band 8.5) who was familiar with Western culture. The panel identified and resolved inadequate expressions of translations or discrepancies. An independent translator, whose mother tongue was English, back-translated it into the English language. Focused group discussions with individuals with severe obesity were conducted. The final H-WBIS-M was administered to undergraduates ( n = 120) after seven days. Test-retest reliability was assessed. The original WBIS-M, Eating Disorder Diagnostic Screen, and Fat Phobia Scale-Short Form were administered to 120 undergraduates and 55 individuals with severe obesity ( n = 175)]. Reliability and validity of H-WBIS-M were analyzed., Results: Kaiser-Meyer-Olkin measure of sampling adequacy was 0.788, and Bartlett's test of sphericity was χ 2 = 1381.892, p = 0.000. The exploratory factor analysis extracted three components. Spearman-Brown coefficient for H-WBIS-M was 0.875. The internal consistency was α = 0.875 ( p = 0.000), intraclass correlation coefficient was 0.857 (95% confidence interval [CI] = 0.812-0.893) ( p = 0.000), and Pearson correlation ranged from 0.869 to 0.989 ( p = 0.000). Cross-language concordance revealed a significant intraclass correlation coefficient (0.877-0.986) ( p = 0.000) and Pearson correlation ranging from 0.781 to 0.972 ( p = 0.000)., Conclusions: The H-WBIS-M demonstrated good psychometric properties based on standard testing procedures., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article., (© 2024 The Author(s).)

Background: The clinico-oncological outcomes of precursor epithelial subtypes of adenocarcinoma arising from intraductal papillary mucinous neoplasms (A-IPMN) are limited to small cohort studies. Differences in recurrence patterns and response to adjuvant chemotherapy between A-IPMN subtypes are unknown., Methods: Clincopathological features, recurrence patterns and long-term outcomes of patients undergoing pancreatic resection (2010-2020) for A-IPMN were reported from 18 academic pancreatic centres worldwide. Precursor epithelial subtype groups were compared using uni- and multivariate analysis., Results: In total, 297 patients were included (median age, 70 years; male, 78.9%), including 54 (18.2%) gastric, 111 (37.3%) pancreatobiliary, 80 (26.9%) intestinal and 52 (17.5%) mixed subtypes. Gastric, pancreaticobiliary and mixed subtypes had comparable clinicopathological features, yet the outcomes were significantly less favourable than the intestinal subtype. The median time to recurrence in gastric, pancreatobiliary, intestinal and mixed subtypes were 32, 30, 61 and 33 months. Gastric and pancreatobiliary subtypes had worse overall recurrence (p = 0.048 and p = 0.049, respectively) compared with the intestinal subtype but gastric and pancreatobiliary subtypes had comparable outcomes. Adjuvant chemotherapy was associated with improved survival in the pancreatobiliary subtype (p = 0.049) but not gastric (p = 0.992), intestinal (p = 0.852) or mixed subtypes (p = 0.723). In multivariate survival analysis, adjuvant chemotherapy was associated with a lower likelihood of death in pancreatobiliary subtype, albeit with borderline significance [hazard ratio (HR) 0.56; 95% confidence interval (CI) 0.31-1.01; p = 0.058]., Conclusions: Gastric, pancreatobiliary and mixed subtypes have comparable recurrence and survival outcomes, which are inferior to the more indolent intestinal subtype. Pancreatobiliary subtype may respond to adjuvant chemotherapy and further research is warranted to determine the most appropriate adjuvant chemotherapy regimens for each subtype., (© 2024. The Author(s).)

Purpose of Review: We aim to provide an updated perspective on the recent advancements in gene therapy for polycystic kidney disease (PKD), a genetic disorder with significant morbidity. Given the rapid evolution of gene therapy technologies and their potential for treating inherited diseases, this review explores the therapeutic prospects and challenges in applying these technologies to PKD., Recent Findings: Significant progress has been made in understanding the genetic underpinnings of PKD, making it a prime candidate for gene therapy. Re-expression of the PKD genes, treatment with the C-terminal tail of polycystin 1 protein and antagomir therapy against miR-17 have shown promise in reducing cyst formation and preserving kidney function. The rapid development of gene-editing tools, antisense oligonucleotide-based strategies, programmable RNA, and advanced gene delivery systems has opened new possibilities for PKD treatment. However, challenges such as off-target effects, delivery efficiency, and long-term safety remain significant barriers to clinical application., Summary: Current research highlights the transformative potential of gene therapy for PKD. Ongoing studies are crucial to overcoming existing challenges and translating these findings into clinical practice. We highlight the need for multidisciplinary efforts to optimize gene-editing technologies and ensure their safety and efficacy in treating PKD., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Identifying the boundary between the tooth and the resin-based composite (RBC) is difficult when replacing restorations. Ultraviolet (UV) light has been reported to assist the viewer by causing the RBC to fluoresce. Using a laboratory-grade fiberoptic spectrometer, 46 RBCs were exposed to UV light from the Woodpecker O-Star curing light. The opalescence and fluorescence were measured relative to a human tooth that contained just dentin and a tooth that contained both enamel and dentin. After these quantitative measurements, 10 RBCs with large differences in light emittance were compared qualitatively to assess their brightness when exposed to UV light compared to the dentin specimen and the specimen containing both enamel and dentin. It was found that, when exposed to UV light, some of the RBCs were less bright compared to the two samples of teeth used for comparison, but most were brighter; some were up to six times brighter. The filler appears to affect the opalescence peaks, while the resin appears to affect the fluorescence peaks. It was concluded that because RBCs emit very different levels of opalescence and fluorescence, UV light from the Woodpecker O-Star cannot be relied upon to detect all brands of RBC on the tooth. The opalescence and fluorescence can also be used to detect changes in the formulation of the RBC.

The present study aimed to identify nutrients (UPLC-PDA-ESI-MS/MS, HPLC-RI method) and biological activities (antioxidant activity to reduce Fe 3+ and ABTS ·+ , pancreatic lipase inhibitory effect, α-amylase, and α-glucosidase, anti-bacterial) of 14 highbush blueberries (Vaccinium corymbosum L.) cultivars (Northern type) as well as a principal component analysis (PCA) to assess the variation of these properties in the context of biodiversity. Most of the cultivars in this research have been first presented in this paper. Phytochemical profiling of the tested highbush blueberry fruit revealed 75 bioactive compounds, including 5 macroelements, 7 microelements, 7 monophosphate nucleotides, 15 anthocyanins, 1 phenolic acid, 14 flavonols, 11 essential amino acids, 8 non-essential amino acids, 2 sugars, 7 organic acids. The PCA showed that the profile and contents of the analyzed compounds as well as their anti-bacterial, antioxidant, anti-diabetic, and anti-obesity potentials depended significantly on the tested cultivars. Thus, the study provides comprehensive data on cultivar-specific biodiversity and correlations that can be used to design novel extracts rich in polyphenolic, amino acids, and/or minerals extracts from the selected cultivars of highbush blueberry as natural and alternative sources to fulfill the growing industry demand for supplements, pharmaceuticals, and nutraceutical products., (© 2024. The Author(s).)

Treatment-resistant depression (TRD) occurs in almost 50% of the depressed patients. Central kappa opioid receptor (KOR) agonism has been demonstrated to induce depression and anxiety, while KOR antagonism alleviates depression-like symptoms in rodent models and TRD in clinical studies. Previously, we have shown that sustained KOR activation leads to a TRD-like phenotype in mice, and modulation of brain-derived neurotrophic factor (BDNF) expression in the prefrontal cortex (PFC) appears to be one of the molecular determinants of the antidepressant response. In the present study, we observed that sustained KOR activation by a selective agonist, U50488, selectively reduced the levels of Bdnf transcripts II , IV , and Bdnf CDS (protein-coding Exon IX) in the PFC and cultured primary cortical neurons, which was blocked by selective KOR antagonist, norbinaltorphimine . Considering the crucial role of epigenetic pathways in BDNF expression, we further investigated the role of various epigenetic markers in KOR-induced BDNF downregulation in mice. We observed that treatment with U50488 resulted in selective and specific downregulation of acetylation at the ninth lysine residue of the histone H3 protein (H3K9ac) and upregulation of histone deacetylase 5 (HDAC5) expression in the PFC. Further, using anti-H3K9ac and anti-HDAC5 antibodies in the chromatin immune precipitation assay, we detected decreased enrichment of H3K9ac and increased HDAC5 binding at Bdnf II and IV transcripts after U50488 treatment, which were blocked by a selective KOR antagonist, norbinaltorphimine . Further mechanistic studies using HDAC5 selective inhibitor, LMK235, in primary cortical neurons and adeno-associated viral shRNA-mediated HDAC5-knockdown in the PFC of mice demonstrated an essential role of HDAC5 in KOR-mediated reduction of Bdnf expression in the PFC and in depression-like symptoms in mice. These results suggest that KOR engages multiple pathways to induce depression-like symptoms in mice and provide novel insights into the mechanisms by which activation of KOR regulates major depressive disorders.

Increasing accumulation of nanoplastics across ecosystems poses a significant threat to both terrestrial and aquatic life. Surface-enhanced Raman scattering (SERS) is an emerging technique used for nanoplastics detection. However, the identification and classification of nanoplastics using SERS faces challenges regarding sensitivity and accuracy as nanoplastics are sparsely dispersed in the environment. Metal-phenolic networks (MPNs) have the potential to rapidly concentrate and separate various types and sizes of nanoplastics. SERS combined with machine learning may improve prediction accuracy. Herein, we report the integration of MPNs-mediated separation with machine learning-aided SERS methods for the accurate classification and high-precision quantification of nanoplastics, which is tailored to include the complete region of characteristic peaks across diverse nanoplastics in contrast to the traditional manual analysis of SERS spectra on a singular characteristic peak. Our customized machine learning system (e.g., outlier detection, classification, quantification) allows for the identification of detectable nanoplastics (accuracy 81.84%), accurate classification (accuracy > 97%), and sensitive quantification of various types of nanoplastics (polystyrene (PS), poly(methyl methacrylate) (PMMA), polyethylene (PE), and poly(lactic acid) (PLA)) down to ultralow concentrations (0.1 ppm) as well as accurate classification (accuracy > 92%) of nanoplastic mixtures at a subppm level. The effectiveness of this approach is substantiated by its ability to discern between different nanoplastic mixtures and detect nanoplastic samples in natural water systems.

Purpose: The purpose of this study was to analyze the incidence of retinopathy of prematurity (ROP), treatment requiring ROP (TROP), course, and systemic risk factors in extreme preterm or extreme low-birth-weight babies., Methods: A retrospective analysis of neonatal intensive care unit-based ROP screening from January to December 2021 in a tier-2 city in Kerala, India, was done. Inclusion criteria were gestational age (GA) ≤28 weeks or birth weight ≤1000 g. ROP screening and treatment were done according to the International Classification of ROP guidelines. Treatment was indicated in babies with type 1 ROP or aggressive ROP. Details of ROP screening, treatment, and neonatal risk factors were collected from the records. The results were statistically analyzed, and P < 0.05 was considered statistically significant., Results: The study included 54 babies with a mean GA of 27.47 ± 1.76 weeks and a mean BW of 847.43 ± 189.22 g. ROP was detected at an average postmenstrual age of 33.8 ± 1.7 weeks. The incidence of any ROP and TROP was 87% and 19.14%, respectively. All babies with TROP were managed with laser or intravitreal antivascular endothelial growth factor injection or both. ROP resolved spontaneously in 60%, but those with Zone 2 disease had delayed regression. Inotropic support and anemia were found to increase the risk for ROP., Conclusion: The incidence and outcome of any ROP and TROP in this study are comparable to the rates reported globally, and this reflects the improvement in neonatal care. The use of inotropes and anemia may increase the risk for ROP and needs to be managed judiciously., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Middle East African Journal of Ophthalmology.)

Prostate cancer (PC) is the fifth leading cause of cancer-related deaths among men worldwide. Prostate-specific membrane antigen (PSMA), a molecular target of PC, is clinically used for the treatment and diagnosis of PC using radioligand approaches. However, no PSMA-based chemotherapies have yet been approved by the FDA. Here, we present a novel therapeutic approach using PSMA-targeted 2-deoxyglucose-dendrimer (PSMA-2DG-D) for targeted delivery of a potent tyrosine kinase inhibitor, cabozantinib (Cabo), selectively to PC cells. PSMA-2DG-D demonstrates intracellular localization in PSMA (+) PC cells through PSMA-mediated internalization. This PSMA-specific targeting translates to enhanced efficacy of Cabo compared to the free drug when conjugated to PSMA-2DG-D. Furthermore, systemically administered fluorescently labeled PSMA-2DG-D-Cy5 specifically targets PSMA (+) tumors with minimal off-target accumulation in the PC3-PIP tumor xenograft mouse model. This demonstrates that the PSMA-2DG-D platform is a promising new delivery system for potent chemotherapeutics, where systemic side effects are a significant concern.

Purpose: Spinal stereotactic body radiation therapy (SBRT) has become the standard of care in management of patients with limited sites of metastatic disease, radioresistant histologies, painful vertebral metastases with long life expectancy and cases of reirradiation. Our case-based guidelines aim to assist radiation oncologists in the appropriate utilization of SBRT for common, yet challenging, cases of spinal metastases., Methods and Materials: Cases were selected to include scenarios of large volume sacral disease with nerve entrapment, medically inoperable disease abutting the thecal sac, and local failure after prior SBRT. Relevant literature was reviewed, and areas requiring further investigation were discussed to offer a framework for evidence-based clinical practice., Results: Spinal SBRT can be effectively delivered in challenging cases following multidisciplinary discussion by using a methodical approach to patient selection, appropriate dose selection, and adherence to evidence-based dose constraints., Conclusions: The Radiosurgery Society's case-based practice review offers guidance to practicing physicians treating technically challenging SBRT candidate patients with spinal metastases., Competing Interests: Disclosures Anubhav G. Amin reports receiving consulting fees and payment for lectures from Globus. Samuel Chao reports payment for travel, honoraria, and research support from Blue Earth Diagnostics; and honoraria from GE Healthcare and Varian Medical Systems. Matthew Foote reports research grant from Elekta; consulting fees and honoraria from Varian and Elekta; and leadership role with Stereotactic Interest Group of Australasia. Matthias Guckenberger reports grants from ViewRay, Siemens Healthineers, and Astra Zeneca; consulting fees and honoraria from Astra Zeneca; and leadership role with ESTRO. Daniel Koffler reports internal departmental support for attending meetings; patent for Chimeric Immunomagnetic Nanosensors for cancer stem cell imaging; and leadership role in ESTRO workshop group in spatially fractionated RT. Simon Lo reports grant funding from Kuni Foundation, Hutchinson Center, and Elekta; has travel support from the Japanese Society for Radiation Oncology (JASTRO); and serves as member of the Board of Directors and National Medical Director of the Distinction in Practice in Stereotatic Radiotherapy Program for the Radiosurgery Society and Alternate Councilor for the American College of Radiology. Kristin J. Redmond reported receiving research support from Accuray, Canon, and Icotec; participating on a data and safety monitoring board for BioMimetix; has travel support from Icotec and Brainlab; honorarium from Accuray; and patent pending with Canon. Daniel Lubelski reports consulting fees from Carbofix, Mindset Medical, and Dillon Technologies. Arjun Sahgal has received research grants from Elekta AB, Varian, Seagen, and Brainlab; is an advisor/consultant with Varian, Elekta (Gamma Knife Icon), and Brainlab; has received honoraria for past educational seminars from AstraZeneca, Elekta AB, Varian, Brainlab, Cerapedics, Seagen, and Carbo FIX; is a vice president of the International Stereotactic Radiosurgery Society; is a cochair of the AO Spine Knowledge Forum Tumor, belongs to the Elekta MR-Linac Research Consortium; is a Clinical Steering Committee member; and chairs the Elekta Oligometastases Group and the Elekta Gamma Knife Icon Group. Shankar Siva received salary support from Cancer Council Victoria via the Colebatch Fellowship; grants or contracts from Varian, Bayer Pharmaceuticals, and Merck Sharp & Dohme; payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing, or educational events from AstraZeneca, Varian, Roche Pharmaceuticals, and Telix Pharmaceuticals; a leadership or fiduciary role on the American Society of Radiation Oncology Science Council and the Advanced Radiotherapy Techniques committee of the International Association for the Study of Lung Cancer; and is on the board of directors of the Radiosurgery Society, within the past 36 months. Balamurugan Vellayappan reports honoraria from Elekta and support for travel from Brainlab. The other authors declare no conflicts of interest. Artificial Intelligence was not utilized in this effort., (Copyright © 2024 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Background: Pure tone audiometry (PTA) is considered the standard method of hearing assessment. However, technical and logistical challenges preclude its usage for hearing screening at primary healthcare facilities. Free field hearing (FFH) tests such as conversation voice (CV) and whispered voice (WV) tests have been used for hearing assessment. However, their correlation to PTA and accuracy in detection of hearing loss are doubtful. This study aims to determine if FFH tests can be used for estimation of hearing thresholds., Methods: A retrospective analytical study was conducted at the otorhinolaryngology department. Spearman's correlation coefficient ( ρ ) was determined between FFH recognition distance and average air conduction PTA thresholds. A statistical regression model was developed to estimate hearing thresholds from the FFH recognition distance. The FFH tests were studied for their accuracy in detection of hearing loss., Results: The audiometric records of 437 persons (874 ears) were analysed. The CV and WV tests were found to have a high correlation ( ρ  = -0.757 and -0.758, respectively) with average PTA thresholds in persons with hearing loss. The WV test was found to have a 94.7% sensitivity, 90.8% specificity, 97.6% positive predictive value, 80.9% negative predictive value, and 93.9% accuracy in detection of hearing loss., Conclusion: FFH tests such as WV test can be used to estimate the hearing thresholds and screen for hearing loss when audiometric tests are not logistically feasible, such as at primary-level healthcare facilities, remote locations, and in schools. However, such tests should not be regarded as a substitute to PTA., Competing Interests: All authors have none to declare., (© 2023 Director General, Armed Forces Medical Services. Published by Elsevier, a division of RELX India Pvt. Ltd.)

The recent rise in nucleic acid-based vaccines and therapies has resulted in an increased demand for plasmid DNA (pDNA). As a result, there is added pressure to streamline the manufacturing of these vectors, particularly their design and construction, which is currently considered a bottleneck. A significant challenge in optimizing pDNA production is the lack of high-throughput and rapid analytical methods to support the numerous samples produced during the iterative plasmid construction step and for batch-to-batch purity monitoring. pDNA is generally present as one of three isoforms: supercoiled, linear, or open circular. Depending on the ultimate use, the desired isoform may be supercoiled in the initial stages for cell transfection or linear in the case of mRNA synthesis. Here, we present a high-throughput microfluidic electrophoresis method capable of detecting the three pDNA isoforms and determining the size and concentration of the predominant supercoiled and linear isoforms from 2 to 7 kb. The limit of detection of the method is 0.1 ng/µL for the supercoiled and linear isoforms and 0.5 ng/µL for the open circular isoform, with a maximum loading capacity of 10-15 ng/µL. The turnaround time is 1 min/sample, and the volume requirement is 10 µL, making the method suitable for process optimization and batch-to-batch analysis. The results presented in this study will enhance the understanding of electrophoretic transport in microscale systems dependent on molecular conformations and potentially aid technological advances in diverse areas relevant to microfluidic devices., (© 2024 Wiley‐VCH GmbH.)

Background: Predictors of long-term survival after resection of adenocarcinoma arising from intraductal papillary mucinous neoplasms are unknown. This study determines predictors of long-term (>5 years) disease-free survival and recurrence in adenocarcinoma arising from intraductal papillary mucinous neoplasms and derives a prognostic model for disease-free survival., Methods: Consecutive patients who underwent pancreatic resection for adenocarcinoma arising from intraductal papillary mucinous neoplasms in 18 academic pancreatic centers in Europe and Asia between 2010 to 2017 with at least 5-year follow-up were identified. Factors associated with disease-free survival were determined using Cox proportional hazards model. Internal validation was performed, and discrimination and calibration indices were assessed., Results: In the study, 288 patients (median age, 70 years; 52% male) were identified; 140 (48%) patients developed recurrence after a median follow-up of 98 months (interquartile range, 78.4-123), 57 patients (19.8%) developed locoregional recurrence, and 109 patients (37.8%) systemic recurrence. At 5 years after resection, the overall and disease-free survival was 46.5% (134/288) and 35.0% (101/288), respectively. On Cox proportional hazards model analysis, multivisceral resection (hazard ratio, 2.20; 95% confidence interval, 1.06-4.60), pancreatic tail location (hazard ratio, 2.34; 95% confidence interval, 1.22-4.50), poor tumor differentiation (hazard ratio, 2.48; 95% confidence interval, 1.10-5.30), lymphovascular invasion (hazard ratio, 1.74; 95% confidence interval, 1.06-2.88), and perineural invasion (hazard ratio, 1.83; 95% confidence interval, 1.09-3.10) were negatively associated with long-term disease-free survival. The final predictive model incorporated 8 predictors and demonstrated good predictive ability for disease-free survival (C-index, 0.74; calibration, slope 1.00)., Conclusion: A third of patients achieve long-term disease-free survival (>5 years) after pancreatic resection for adenocarcinoma arising from intraductal papillary mucinous neoplasms. The predictive model developed in the current study can be used to estimate the probability of long-term disease-free survival., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Neoadjuvant therapy (NAT) has become routine in patients with borderline resectable pancreatic cancer. Pathologists examine pancreatic cancer resection specimens to evaluate the effect of NAT. However, an automated scoring system to objectively quantify residual pancreatic cancer (RPC) is currently lacking. Herein, we developed and validated the first automated segmentation model using artificial intelligence techniques to objectively quantify RPC. Digitized histopathological tissue slides were included from resected pancreatic cancer specimens from 14 centers in 7 countries in Europe, North America, Australia, and Asia. Four different scanner types were used: Philips (56%), Hamamatsu (27%), 3DHistech (10%), and Leica (7%). Regions of interest were annotated and classified as cancer, non-neoplastic pancreatic ducts, and others. A U-Net model was trained to detect RPC. Validation consisted of by-scanner internal-external cross-validation. Overall, 528 unique hematoxylin and eosin (H & E) slides from 528 patients were included. In the individual Philips, Hamamatsu, 3DHistech, and Leica scanner cross-validations, mean F1 scores of 0.81 (95% CI, 0.77-0.84), 0.80 (0.78-0.83), 0.76 (0.65-0.78), and 0.71 (0.65-0.78) were achieved, respectively. In the meta-analysis of the cross-validations, the mean F1 score was 0.78 (0.71-0.84). A final model was trained on the entire data set. This ISGPP model is the first segmentation model using artificial intelligence techniques to objectively quantify RPC following NAT. The internally-externally cross-validated model in this study demonstrated robust performance in detecting RPC in specimens. The ISGPP model, now made publically available, enables automated RPC segmentation and forms the basis for objective NAT response evaluation in pancreatic cancer., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Acinar cystic transformation (ACT) of the pancreas is a rare non-neoplastic cystic lesion. It is difficult to distinguish from more concerning pathology, particularly a side-branch duct intraductal papillary mucinous neoplasm (IPMN). All reported cases of ACT have been clinically benign with no evidence of recurrence or malignant transformation. The Fukuoka guidelines is a classification system designed to help guide the management of IPMNs and mucinous cystic neoplasms. We report a case of ACT that was preoperatively diagnosed as a suspected side-branch IPMN. Through the application of current guidelines, the patient underwent a Whipple's procedure. We highlight the difficulties in obtaining an accurate preoperative diagnosis in cases of ACT and the current radiological and cytological methods available to clinicians., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Epidermoid cysts (ECs) are rare, benign lesions which comprise less than 1 % of all spinal tumors. Calcification of spinal ECs is rare, and EC ossification within the lumbar spine has never been documented. We report the only known congenital lumbar epidermoid tumor with ossification and a literature review of intradural lumbar ECs., Methods: Studies meeting the following criteria were included: 1) EC as the primary tumor type, 2) intradural location, 3) involvement of the lumbar spinal level, and 4) primary presentation. Studies lacking individual patient data or published in a non-English language were excluded., Results: A total of 172 studies were reviewed and 43 were included in analysis. Of the 83 total patients, 37 (45.1 %) were male and 45 (54.9 %) female, at an average age of 26 years. The L3 and L4 spinal levels were most frequently involved. Acquired etiology was reported in 49 (59.0 %) patients, and 24 (28.9 %) cases were congenital. Multivariate analyses demonstrated trends between decreased age and improved outcome, decreased delay in diagnosis and improved outcome, and increased extent of resection with reduced recurrence. Nine calcified spinal ECs were identified, with no previous report of EC ossification in the lumbar spine., Conclusion: We present a case report of the only known ossified epidermoid tumor of the lumbar spine and a comprehensive literature review of 83 patients with intradural lumbar ECs. This review demonstrated trends between reduced age and improved outcome, reduced delay in diagnosis and improved outcome, and increased extent of resection with reduced recurrence., Competing Interests: All authors declare that they have no personal, financial, or institutional conflict of interest. From: Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021; 372:n71. https://doi.org/10.1136/bmj.n71. For more information, visit: http://www.prisma-statement.org/The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Published by Elsevier Ltd.)

The opioid receptors play a pivotal role in the treatment of several neuropsychiatric and neurological disorders. Oroxylum indicum (L.) Kurtz is a very important medicinal plant with several therapeutic applications. It is a main constituent of the Ayurvedic formulation 'Dashmool' used for multifaceted disorders by the Indians. However, the constituents of this plant in neurological conditions have not been well studied. Here, we performed activity-guided isolation of compounds for opioid receptor modulator activity. In the study, we found that the isolated compound baicalein ( 3 ) has shown the most potent and competitive antagonistic activity at 20 mg/kg dose in vivo experiments. The acute dose of 3 (20 mg/kg) and pan opioid receptor antagonist naloxone (20 mg/kg) block the morphine-induced antinociception and the paw withdrawal latency decreases up to 8.3 s and 9.6 s, respectively. The in silico studies also support our in vitro data that compound 3 binds with MOR and KOR.

Background Answer script presentation is an effective means of conveying knowledge and understanding. It reflects clarity of thought and organization, which can positively influence scoring. Additionally, well-structured answers reduce the chances of misinterpretation, ensuring that your knowledge is accurately assessed. Despite its importance, there is limited research focusing on the specific errors students make in presenting their answers. Hence, this study explored common errors in answer script presentation from the perspectives of both teachers and students. Methods A cross-sectional study was conducted involving 240 students and 50 teachers in July 2024 at Mata Gujri Memorial Medical College, Bihar, India. A questionnaire was developed by a three-member panel of experts in education and assessment to ensure it was comprehensive and relevant to the study's objectives. The questionnaire comprised 12 items rated on a 5-point Likert scale where a higher score indicates higher perceptions of the error. Data were collected from teachers and students using the pre-tested self-administered printed questionnaire. The scores among the different perceived errors were compared by ANOVA and the scores between teachers and students were compared by unpaired t-test. Results Students perceived that their highest error was inconsistent handwriting (2.72±1.4), followed by incomplete diagrams (2.52±1.2) and disorganization (2.47±1.17). The error perceived to be least important was incorrect numbering (1.53±0.97), F=12.49, p-value<0.0001. Teachers perceived the error in illegible handwriting (4.36±0.48), followed by lack of emphasis (4.16±0.62) and disorganization (3.94±0.91) as the errors most likely to contribute to poor performance. The error perceived to be least important was inconsistent handwriting (2.4±1.01), F=18.22, p-value<0.0001. When the data were compared between teachers and students, except for inconsistent handwriting, the perceived error score by teachers was higher than the students perceived. Conclusion There was a significant disparity between students' and teachers' perceptions of common presentation errors, with teachers consistently rating the severity of errors higher than students. Both groups identified inconsistent handwriting as a prominent error. This underscores the need for better alignment and communication between students and educators regarding the importance of specific aspects of written presentation in assessments., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Institutional Ethics Committee of Mata Gujri Memorial Medical College issued approval MGM/IEC/102/2024. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Deb Roy et al.)