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Introduction: Hyperlipidaemia is characterised by elevated or abnormally high levels of lipids and/or lipoproteins in the blood. The current medication for hyperlipidaemia only alleviates symptoms temporarily and is not without any unfavorable side effects. Therefore, it is necessary to find innovative medications from the plant kingdom that could provide a therapeutic solution that is both affordable and free of unfavorable side effects. We conducted an experiment to evaluate the antihyperlipidemic properties of an aqueous corm extract (CE) using acute hyperlipidaemia models. Methods: For our experiment, we employed 60 Wistar rats of both sex, which were divided into five separate groups (n = 6 each) for each model. Poloxamer-407 (P-407) and d-fructose were used to induce hyperlipidemic activity in the rats, and the standard used was fenofibrate (250 mg/kg p.o.). For a period of 15 days for P-407 and 21 days for d-fructose, our study assessed the efficacy of an aqueous corm extract at dosages of 200 and 300 mg/kg (p.o.). Hyperlipidemic activity was assessed using a variety of parameters. The histopathology of rat liver was also estimated. Results: The corm extract treatment led to a notable decrease in the cholesterol, and triglycerides in the elevated lipid levels that were induced by P-407 and d- fructose. The extract also showed a significant decrease in the LDL and VLDL levels. Conclusion: Our study indicates that the CE has the potential as an antihyperlipidemic agent, possibly due to its ability to inhibit the synthesis of cholesterol, and facilitate the catabolism and excretion of the other lipids. The CE is rich in nutrients and phytochemicals like flavonoids and saponins, which may contribute to its hypolipidemic effect.

During the cooling process of embryonated eggs, there is a natural air flux from the surface to the inner part of the eggs, carrying contaminants such as bacteria and fungi through the shell's pores, infecting embryos and resulting in the inability to hatch or poor chick quality. Formaldehyde, a toxic product, is still the most used disinfectant for embryonated eggs in the aviculture industry. In order to evaluate the antimicrobial activity of the green propolis ethanolic extract as an alternative to formaldehyde, 140 hatching eggs from laying hens were collected and submitted to disinfection with five different treatments: T1 - without disinfection; T2 - formaldehyde fumigated eggs; T3, T4 and T5 disinfection by immersion in propolis solution in the concentrations of 2,400 µg, 240 µg and 24 µg, respectively. The contamination levels by total mesophiles and fungi of the egg shells (Aspergillus sp. and other moulds) after disinfection with propolis were lower than when compared to the control without disinfection. In comparison with formaldehyde, the 240 µg and 24 µg propolis concentrations did not differ regarding antibacterial activity, but for antifungal activity the 2,400 µg and 240 µg concentrations were more efficient. The 2,400 µg and 240 µg propolis treatments presented a hatching rate of 94.1%, compared to only 84.6% for the formaldehyde treatment. The green propolis ethanolic extract presented antibacterial and antifungal activities in embryonated eggs showing that it can be a new natural disinfectant product substituting formaldehyde.

Penicillium paradoxum has an enigmatic Aspergillus-like anamorphic state; earlier named as Aspergillus paradoxus with a teleomorph state Hemicarpenteles paradoxus. The present paper describes the rediscovery of this species from India after five decades and includes a phylogenetic study of this strain. This is the first record of this strain from peninsular India including the Western Ghats.

Objective: To design a specific advanced life support (ALS) tape based on recent Indian multicenter height/length and weight data to accurately estimate the weight from the recumbent length., Methods: We designed the new ALS tape by matching the median weights to median heights/lengths from the recently published Indian multicenter growth data, maintaining the same color codes as the Broselow tape. The accuracy of weight estimation for the newly designed ALS tape was validated and compared with the Broselow estimated weights at a tertiary care hospital., Results: The color (weight) band matched median heights (cm) from the new ALS tape were higher (53.0 vs 53.9 for grey, 63.1 vs 67.4 for pink, 70.6 vs 76.4 for red, 79 vs 85.5 for purple, 89.6 vs 95.5 for yellow, 101.9 vs 107.5 for white, 126.1 vs 130.5 for orange and 137 vs 140.5 for green) than the Broselow tape. For every color band on the newly designed ALS tape, a sizable proportion of children (27% for grey, 78% for pink, 83% for red, 38% for purple, 63% for yellow, 41% for white, 35% for blue, 54% for orange) recorded a higher Broselow color band, suggesting overestimated weights at each color band. The percentage difference in the estimated weight from the actual weight was very small (-0.5% for under-5 years and 0.2% for older children) using the new ALS tape as compared to Broselow tape., Conclusion: This Indianized ALS tape estimated Indian children's weights more accurately. Use of the newly designed ALS tape may reduce the errors in calculating emergency medications, fluids and equipment sizes. Further studies are required to validate this tape in pediatric emergency departments in India.

Objective: Sporadic optic chiasmatic-hypothalamic gliomas (OCHGs), though histologically low-grade tumors, manifest as aggressive neoplasms radiologically, leading to difficulty in diagnosis. Molecular alterations of the BRAF gene are detectable in a majority of sporadic OCHGs. The purpose of our study was to elucidate the characteristic imaging features of sporadic OCHGs and to investigate whether imaging phenotypes could potentially correlate with specific BRAF gene alterations associated with these tumors., Methods: We retrospectively reviewed baseline magnetic resonance (MR) images and medical records of 26 patients with histopathologically proven sporadic OCHGs. MR imaging (MRI) features were systematically evaluated. Statistical analysis was performed to determine whether there was a significant association between imaging findings and BRAF molecular alterations., Results: Twenty-two cases (84.6%) presented with solid-cystic masses, while four (15.4%) presented with purely solid lesions. In all 26 cases, the solid component revealed central necrosis; there was minimal necrosis in 11 cases (42.3%), moderate in 8 (30.7%), and marked in 7 (26.9%). The presence of multiple cysts (>4) and minimal necrosis showed a significant association with BRAFV600E mutation (P < 0.005). Marked necrosis in the solid component significantly correlated with BRAF wild genotype (P < 0.001). The presence of a single peripheral cyst significantly correlated with BRAF fusion (P = 0.04)., Conclusion: Sporadic OCHGs have a distinctive appearance on imaging. The solid-cystic composition coupled with varying degrees of central necrosis are clues to the radiological diagnosis of this entity and can facilitate early recognition in clinical practice. Imaging could potentially serve as a non-invasive predictor of the BRAF alteration status, thereby serving as a prognostic marker and guiding personalized management., (Copyright © 2024 Copyright: © 2024 Neurology India, Neurological Society of India.)

Background: Adults with refractory, mechanical chronic low back pain associated with impaired neuromuscular control of the lumbar multifidus muscle have few treatment options that provide long-term clinical benefit. This study hypothesized that restorative neurostimulation, a rehabilitative treatment that activates the lumbar multifidus muscles to overcome underlying dysfunction, is safe and provides relevant and durable clinical benefit to patients with this specific etiology., Materials and Methods: In this prospective five-year longitudinal follow-up of the ReActiv8-B pivotal trial, participants (N = 204) had activity-limiting, moderate-to-severe, refractory, mechanical chronic low back pain, a positive prone instability test result indicating impaired multifidus muscle control, and no indications for spine surgery. Low back pain intensity (10-cm visual analog scale [VAS]), disability (Oswestry Disability Index), and quality of life (EuroQol's "EQ-5D-5L" index) were compared with baseline and following the intent-to-treat principle, with a supporting mixed-effects model for repeated measures that accounted for missing data., Results: At five years (n = 126), low back pain VAS had improved from 7.3 to 2.4 cm (-4.9; 95% CI, -5.3 to -4.5 cm; p < 0.0001), and 71.8% of participants had a reduction of ≥50%. The Oswestry Disability Index improved from 39.1 to 16.5 (-22.7; 95% CI, -25.4 to -20.8; p < 0.0001), and 61.1% of participants had reduction of ≥20 points. The EQ-5D-5L index improved from 0.585 to 0.807 (0.231; 95% CI, 0.195-0.267; p < 0.0001). Although the mixed-effects model attenuated completed-case results, conclusions and statistical significance were maintained. Of 52 subjects who were on opioids at baseline and had a five-year visit, 46% discontinued, and 23% decreased intake. The safety profile compared favorably with neurostimulator treatments for other types of back pain. No lead migrations were observed., Conclusion: Over a five-year period, restorative neurostimulation provided clinically substantial and durable benefits with a favorable safety profile in patients with refractory chronic low back pain associated with multifidus muscle dysfunction., Clinical Trial Registration: The Clinicaltrials.gov registration number for the study is NCT02577354; registration date: October 15, 2016; principal investigator: Christopher Gilligan, MD, Brigham and Women's Hospital, Boston, MA, USA. The study was conducted in Australia (Broadmeadow, New South Wales; Noosa Heads, Queensland; Welland, South Australia; Clayton, Victoria), Belgium (Sint-Niklaas; Wilrijk), The Netherlands (Rotterdam), UK (Leeds, London, Middlesbrough), and USA (La Jolla, CA; Santa Monica, CA; Aurora, CO; Carmel, IN; Indianapolis, IN; Kansas City, KS; Boston, MA; Royal Oak, MI; Durham, NC; Winston-Salem, NC; Cleveland, OH; Providence, RI; Spartanburg, SC; Spokane, WA; Charleston, WV)., Competing Interests: Conflict of Interest Christopher Gilligan reports stock options received from Mainstay, personal fees from Mainstay, Saluda, Persica, and Iliad Lifesciences, expert witness testimony personal fees, and serving as editor-in-chief of Pain Practice; Willem Volschenk reports personal fees from Mainstay; Marc Russo reports personal fees from Mainstay; Matthew Green reports personal fees from Mainstay; Christopher Gilmore reports personal fees and other from SPR, and personal fees from Nevro, Nalu, Biotronik, Boston Scientific, and Saluda; Vivek Mehta reports grants and honoraria from Mainstay and Abbott, personal fees from Boston Scientific, personal fees and honoraria from Medtronic, patent fees from EEPIN-Executive Education Program in Neuromodulation, and leadership/fiduciary role as Chair, Faculty of Pain Medicine UK; Kris De Smedt reports personal fees from Mainstay; Usman Latif reports personal fees from Hydrocision, Spinal Simplicity, Omnia Medical, SPR Therapeutics, and Vertos, and honoraria and personal fees from Nevro and Nalu; Dawood Sayed reports personal fees from Abbott, Boston Scientific, Flowonix, Medtronic, Nevro, Saluda, and Vertiflex, personal fees and stock options from Mainstay, SPR Therapeutics, PainTEQ, and Vertos, and stock options from Neuralace and Surgentec; Peter Georgius reports personal fees from Boston Scientific and Medtronic, lecture support and personal fees from Tilray, lecture support from CSL Seqirus, patent pending personal fees for Arch Bar Wire Application, and personal fees and data safety monitoring/advisory board membership for Presidio; Jonathan Gentile reports personal fees from Mainstay; Bruce Mitchell reports personal fees from Mainstay; Meredith Langhorst reports personal fees from Mainstay and Vivex; Frank Huygen reports grants, personal fees, and honoraria from Abbott and personal fees and honoraria from Saluda; Ganesan Baranidharan reports a grant from Mainstay, grants and personal fees from Nevro, Abbott, Boston Scientific, and personal fees from Nalu and Stryker; Vivek Patel reports personal fees from Mainstay, grants from Orthofix, Pfizer, Premia Spine, Medicrea, Globus, 3-Spine, and Spinal Kinetics, contracts and grants from Aesculap and Medtronic, contracts from Zimmer Biomet Spine, Inc, J&J Medical Device Business Services, NCS America, Simplify Medical, SI Bone, Orthobond Corp, and Cerapedics, consulting fees from Spine Welding, SI Bone, expert testimony for Ogborn Mihm, LLP—Expert Witness Deposition, and support attending meetings from Ecential Robotics and Johnson & Johnson Medical; Alexios Carayannopolous reports consulting fees from Pain Spine and Rehabilitation Consulting, Inc, royalties from Springer Press, grants from Aspen Medical, National Institutes of Health, Defense Advanced Research Projects Agency, and Medtronic, expert testimony as PSR Consulting, Inc, meeting/travel support from American Society of Regional Anesthesia and Pain Medicine, National Board of Osteopathic Medical Examiners, American Alliance of Orthopaedic Executives (AAOE), and American Orthopedic Association, and leadership/fiduciary roles for AAOE, and Rhode Island Society of Pain Physicians; Salim Hayek reports data safety/advisory board membership as immediate past president of North American Neuromodulation Society; Adish Gulve reports personal fees, honoraria, and data safety/advisory board membership from Medtronic, grants and honoraria from Boston Scientific and Abbott, honoraria from Mainstay Medical, grants, honoraria, and safety/advisory board membership from Nevro, and other services from Medtronic and Abbott; Jean-Pierre Van Buyten reports personal fees from Mainstay and grants and personal fees from Medtronic, Nevro, Boston Scientific, and Abbott; Antoine Tohmeh reports stock ownership and personal fees with two spine companies; Jeffrey Fischgrund reports personal fees from Stryker, Relievant, FzioMed, and Asahi Kasei, expert testimony from multiple sources, and data safety/advisory board personal fees for OssDesign; Shivanand Lad reports personal fees from Mainstay; Farshad Ahadian reports institutional grants from Mainstay Medical, Sollis Therapeutics, Boston Scientific, Semnur Pharma, and SI Bone, consulting fees for PainScan, expert testimony for the US Department of Justice, patent personal fees from US Patent 62/949,876, data safety/advisory board personal fees and institutional grant from SKK, institutional payments for leadership/fiduciary roles with the AAMP as Director at Large, Treasurer, President-Elect, as President; Timothy Deer reports grants from, Boston Scientific, PainTEQ; grants, personal fees, and stock from Saluda, grants, personal fees, and data safety/monitoring board membership from SPR Therapeutics, grants, patent pending, data safety/monitoring board membership, and personal fees from Abbott, personal fees from Boston Scientific, SpineThera, Cornerloc, PainTeq, and Spinal Simplicity, personal and institution fees from Mainstay Medical, data safety monitoring/advisory board and personal fees from Biotronik and Vertos, leadership/fiduciary role with American Society of Pain and Neuroscience, and stock (personal) from SpineThera; William R. Klemme reports personal fees, meeting support, and data safety/advisory board membership with Mainstay Medical and Sollis Therapeutics; Richard Rauck reports grants from SPR, Nalu, and Nevro, personal fees from Presidio, and grants and personal fees from Boston Scientific and Saluda; James Rathmell reports a leadership/fiduciary role on the editorial board from American Society of Anesthesiology; Greg Maislin provides biostatistical consulting services concerning statistical analysis methods and presentation for Mainstay Medical; Jan Pieter Heemels provides full-time executive consultancy receiving monthly retainer and stock options from Mainstay Medical; Sam Eldabe reports personal fees and nonfinancial support from Mainstay, personal fees from Saluda, institutional grants and personal fees from Medtronic, institutional grants from Boston Scientific, leadership/fiduciary roles as chair of European Diploma of Pain Medicine and European Society of Regional Anaesthesia and Pain Therapy, examination faculty, chair of neuromodulation device Expert Working Group at National Health Service England, and chair International Association for the Study of Pain Neuromodulation Special Interest Group. The remaining authors reported no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

People who are managed by the National Probation Service and convicted of high risk offences will often meet criteria for antisocial personality disorder and have complex psychosocial needs; this group of people present with high risk behavior which may professionals have been reluctant to work with in the past who are associated with higher rates of recidivism. This study investigated the experiences of probation officers in managing people who meet the criteria for Anti Social Personality Disorder. Semi structured interviews were conducted with six participants to capture their experiences of working with this population, the challenges they faced, and coping mechanisms employed, through analysis using Interpretative Phenomenological Analysis (IPA). Three superordinate themes were identified which revealed participants internal feeling, strategies employed, and external challenges. They spoke about internal negative feelings, specifically feeling controlled, having mistrust, a lack of confidence, being overwhelmed with emotion, and experiencing a fear of risk behaviors. Other themes involved external pressures as well as different coping responses. Implications are discussed to help probation officers to understand this population, for the organization to support staff to work with challenging behaviors and prevent burn out, to enable positive outcomes, and for potentially reducing reoffending., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: The aim of this study was to evaluate the biodistribution and dosimetry of lutetium-177-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (177Lu-DOTA)-rituximab in CD20+ non-Hodgkin's lymphoma and other hematological malignancies treated with rituximab., Methods: The standard dosimetry protocol was used, with cold rituximab infusion, then a diagnostic activity of 177Lu-DOTA-rituximab. Planar images were acquired at multiple time points. Normal organs and tumor dosimetry were performed by using organ and tumor-specific regions of interest and whole-body counts were obtained serially after pixel matched, background, scatter, and attenuation correction. The mean radiation absorbed doses were obtained from OLINDA/EXM v2.1.1 and ORIGIN software., Results: A total of 22 patients were included in this study. Prolonged blood pool clearance of 177Lu-DOTA-rituximab with long residence time in the blood pool and normal organs were observed. The whole body effective half-life was 104.5 ± 22 h. The mean total body radiation absorbed dose was 0.208 ± 0.03 mGy/MBq and the mean total body effective dose was 0.196 ± 0.05 mGy/MBq of 177Lu-DOTA-rituximab. The mean radiation absorbed doses of 0.613 ± 0.21, 1.68 ± 2, 1.01 ± 0.42, and 0.136 ± 0.02mGy/MBq were seen for the liver, spleen, kidneys, and bone marrow, respectively. Tumor lesion uptake was noticed in two patients with tumor radiation absorbed doses were 0.842 mGy/MBq in one and 9.9 mGy/MBq in the other patient. A strong correlation was obtained between the cumulative activities of radiation-absorbed doses derived from ORIGIN and OLINDA software methods at a significant P value less than 0.001., Conclusion: The results of our study demonstrated favorable biodistribution and dosimetry of indigenously produced 177Lu-DOTA-rituximab in patients with CD20+ lymphoma. These results can be used for future studies of radioimmunotherapy employing 177Lu-DOTA-rituximab., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Essential tremor (ET) is one of the most common movement disorders worldwide. In medically refractory ET, deep brain stimulation (DBS) of the ventral intermediate nucleus of the thalamus is the current standard of care. However, DBS carries an inherent 2% to 3% risk of hemorrhage, a risk that can be much higher in patients with concomitant coagulopathy. Magnetic resonance imaging-guided focused ultrasound (MRgFUS) thalamotomy is a surgical alternative that is highly effective in treating ET, with no reports of intracranial hemorrhage to date., Observations: This is the first documented case of successful MRgFUS thalamotomy in a patient with von Willebrand disease (VWD). A 60-year-old left-handed male had medically refractory ET, VWD type 2B, and a family history of clinically significant hemorrhage after DBS. He underwent right-sided MRgFUS thalamotomy and received a perioperative course of VONVENDI (recombinant von Willebrand factor) to ensure appropriate hemostasis. Postprocedure imaging confirmed a focal lesion in the right thalamus without evidence of hemorrhage. The patient reported 90% improvement of his left-hand tremor and significant improvement in his quality of life without obvious side effects., Lessons: MRgFUS thalamotomy with peri- and postoperative hematological management is a promising alternative to DBS for patients with underlying coagulopathies.

Objective: The aim of this study was to assess the biodistribution and dosimetry of 177 Lu-DOTA-trastuzumab in patients with HER2-positive breast carcinoma using whole-body (WB) planar imaging at multiple time points., Patients and Methods: This study was a prospective evaluation of HER2-positive metastatic/locally advanced breast carcinoma patients who underwent gamma camera imaging for dosimetry and biodistribution studies by using 177 Lu-DOTA-trastuzumab. The standard diagnostic dosimetry protocol was followed, which included cold trastuzumab injection followed by in-house produced 177 Lu-DOTA-trastuzumab. Serial WB planar images (anterior and posterior) were obtained on gamma camera after the infusion of 177 Lu-DOTA-trastuzumab at multiple time points. Whole-body and organ regions of interest were drawn, and the numbers of disintegrations were obtained. The mean absorbed doses for the liver, spleen, kidneys, heart, red marrow, and tumor were obtained from OLINDA EXM v2.1.1 and ORIGIN software., Results: The study included a cohort of 21 female breast carcinoma patients. Tracer activity ( 177 Lu-DOTA-trastuzumab) was noted in the physiological organs such as the liver, spleen, kidneys, heart, as well as in the tumors. On visual analysis of 177 Lu-DOTA-trastuzumab biodistribution, the liver activity showed gradual clearance over time, and although spleen was comparatively faintly visualized than liver and similarly, kidneys were faintly visualized suggestive of the alternate route of tracer excretion. The maximum number of patients (n = 12) showed 2 components of clearance, namely, fast and slow. The average effective half-life of all the patients (including single and 2 components of clearance) was 106.25 ± 22.14 hours (84.11-128.39 hours). The mean absorbed dose for the liver, spleen, kidneys, heart, whole body, and red marrow was 1.0702 ± 0.731, 1.4114 ± 0.462, 1.4232 ± 0.364, 1.4719 ± 0.602, 0.2412 ± 0.0295, and 0.1485 ± 0.0213 mGy/MBq, respectively, by OLINDA EXM and 0.5741 ± 0.333, 0.8096 ± 0.224, 0.7943 ± 0.235, 1.8971 ± 0.713, and 0.09619 ± 0.0144 for liver, spleen, kidneys, heart and whole body respectively by ORIGIN. The absorbed radiation dose for tumor was 1.94E+2 by OLINDA EXM software and 1.78E+2 by ORIGIN software. In this study, during and after infusion of 177 Lu-DOTA-trastuzumab, no major adverse effects were noted in any patient except 1 patient who had grade 1 nausea and managed conservatively by antiemetic drug., Conclusions: The results of our study demonstrated expected and favorable biodistribution and dosimetry with 177 Lu-DOTA-trastuzumab in HER2-positive breast carcinoma patients. We noticed the mean absorbed dose to the normal organs within the limits of maximum tolerable dose, and also tumor dose was higher than the normal liver dose. Therefore, we conclude that 177 Lu-DOTA-trastuzumab radioimmunotherapy is feasible and a safe treatment option for treating HER2-positive breast carcinoma patients., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Aims: The use of metagenomics for pathogen identification in clinical practice has been limited. Here we describe a workflow to encourage the clinical utility and potential of NGS for the screening of bacteria, fungi, and antimicrobial resistance genes (ARGs)., Methods and Results: The method includes target enrichment, long-read sequencing, and automated bioinformatics. Evaluation of several tools and databases was undertaken across standard organisms (n = 12), clinical isolates (n = 114), and blood samples from patients with suspected bloodstream infections (n = 33). The strategy used could offset the presence of host background DNA, error rates of long-read sequencing, and provide accurate and reproducible detection of pathogens. Eleven targets could be successfully tested in a single assay. Organisms could be confidently identified considering ≥60% of best hits of a BLAST-based threshold of e-value 0.001 and a percent identity of >80%. For ARGs, reads with percent identity of >90% and >60% overlap of the complete gene could be confidently annotated. A kappa of 0.83 was observed compared to standard diagnostic methods. Thus, a workflow for the direct-from-sample, on-site sequencing combined with automated genomics was demonstrated to be reproducible., Conclusion: NGS-based technologies overcome several limitations of current day diagnostics. Highly sensitive and comprehensive methods of pathogen screening are the need of the hour. We developed a framework for reliable, on-site, screening of pathogens., (© The Author(s) 2024. Published by Oxford University Press on behalf of Applied Microbiology International.)

The development of humanized monoclonal antibodies (MAbs) with Lutetium-177 ([ 177 Lu]Lu 3+ ) has brought a paradigm shift in the arena of targeted therapy of various cancers. [ 177 Lu]Lu-DOTA-Rituximab and [ 177 Lu]Lu-DOTA-Trastuzumab have gained prominence due to their improved therapeutic efficacy in the treatment of lymphoma and breast cancer. The clinical dose formulation of these radiolabeled MAbs, using low specific activity [ 177 Lu]LuCl 3 , requires extensive optimization of the radiolabeling protocol. The present study merits the development of a single protocol which has been optimized for conjugation of Rituximab and Trastuzumab with p-NCS-benzyl-DOTA and further radiolabeling these immunoconjugates (ICs) with low specific activity [ 177 Lu]LuCl 3 . Herein, we report a consistent and reproducible protocol for clinical dose formulations of [ 177 Lu]Lu-DOTA-Rituximab and [ 177 Lu]Lu-DOTA-Trastuzumab (~9.25 GBq each, equivalent to ~2 patient doses) with radiochemical yield (RCY) between 84 and 86% and radiochemical purities (RCP) >99%. The in vitro stabilities of both these radioimmunoconjugates (RICs) were retained up to 120 h post-radiolabeling, upon storage with L-ascorbic acid as stabilizer (concentration: ~ 220-240 μg/37MBq) at -20 °C. The ready-to-use formulation of clinical doses[ 177 Lu]Lu-DOTA-Rituximab and [ 177 Lu]Lu-DOTA-Trastuzumab has been successfully achieved by employing a single optimized protocol. While [ 177 Lu]Lu-DOTA-Rituximab has exhibited a high degree of localization in retroperitoneal nodal mass of refractory lymphoma patient, high uptake of [ 177 Lu]Lu-DOTA-Trastuzumab has been observed in metastatic breast carcinoma patient with multiple skeletal metastases., (© 2023. The Author(s), under exclusive licence to World Molecular Imaging Society.)

Objectives: The present work describes the automated radiochemical synthesis of different PET tracers like [ 68 Ga]Ga-Pentixafor, [ 68 Ga]Ga-FAPI-4 and [ 68 Ga]Ga-DOTATATE using optimized single protocol in the non-cassette based Eckert & Ziegler (EZ) Modular Lab (fixed tubing system) without any modification in the inbuilt human machine interface (HMI) software. Recently, PET agents viz. [ 68 Ga]Ga-Pentixafor and [ 68 Ga]Ga-FAPI-4 are gaining prominence for the diagnosis of overexpressed Chemokine Receptor-4 (CXCR4) and Fibroblast Activation Protein (FAP) receptor, respectively, in the microenvironment of numerous cancer types. The promising results observed with the clinical usage of [ 68 Ga]Ga-DOTATATE produced using the automated protocol, provided impetus for the clinical translation of [ 68 Ga]Ga-Pentixafor and [ 68 Ga]Ga-FAPI-4 using the in-house developed automated radiolabeling protocol., Methods: Herein we report a single radiolabeling protocol for the automated preparation of [ 68 Ga]Ga-Pentixafor and [ 68 Ga]Ga-FAPI-4 in the non-cassette based EZ Modular-Lab Standard radiochemistry module, without any changes in schematic, graphical user interface (GUI) software and time list, from that used for routine production of [ 68 Ga]Ga-DOTATATE in our centre, since 2015. Physico-chemical quality control and in-vitro stability analyses were carried out using radio-TLC and radio-HPLC., Results: The automated protocol yielded reliable and consistent non-decay corrected (ndc) radiochemical yield (RCY) of (84.4%±0.9%) and (85.5%±1.4%) respectively, for [ 68 Ga]Ga-Pentixafor and [ 68 Ga]Ga-FAPI-4, with RCP>98%, which are comparable to the RCY of (84.4%±1.2%) and RCP (99.1%±0.3%) for [ 68 Ga]Ga-DOTATATE. The biological quality control studies confirmed the formulations to be of ready-to-use pharmaceutical grade., Conclusion: The consistent and reliable RCY and RCP of multiple 68 Ga-labeled PET tracers by single automated radiochemistry protocol exhibits the versatility of the EZ Modular Lab., (© 2024 mums.ac.ir All rights reserved.)

Objective: The objective of this study was to evaluate the 24-month durability of pain relief, function, quality of life, and safety outcomes for patients with nonsurgical refractory back pain (NSRBP) treated with high-frequency spinal cord stimulation (SCS) within a large, national, multicenter randomized controlled trial (RCT)., Methods: Following the completion of an RCT comparing high-frequency SCS plus CMM with CMM alone for the treatment of NSRBP, patients gave additional consent for a follow-up extension to 24 months. Presented is the cohort analysis of all patients treated with high-frequency SCS following the optional crossover at 6 months. The outcomes assessed to 24 months included responder rate of ≥ 50% pain relief measured according to the visual analog scale [VAS]), disability (Oswestry Disability Index [ODI]), quality of life (EQ-5D 5-level [EQ-5D-5L]), opioid reduction., Results: Of the 125 patients who received a permanent implant, 121 completed the 12-month follow-up, 101 gave additional consent for extended follow-up, and 98 completed the 24-month follow-up. At 24 months after implantation, the mean back pain VAS score was reduced by 73% and the responder rate was 82%. ODI and EQ-5D-5L both improved by at least double the minimal clinically important difference for each measure. No unexpected adverse events were observed, and the rates of serious adverse events (3.4%) and device explantations (4.8%) were low., Conclusions: The addition of high-frequency SCS to CMM in patients with NSRBP offers profound improvements at 24 months in pain, function, quality of life, and reduced opioid use. This study provides much-needed evidence to inform current clinical practice for managing patients with NSRBP.

Background: US racial and ethnic minorities have well-established elevated rates of comorbidities, which, compounded with healthcare access inequity, often lead to worse health outcomes. In the current COVID-19 pandemic, it is important to understand existing disparities in minority groups' critical care outcomes and mechanisms behind these-topics that have yet to be well-explored., Objective: Assess for disparities in racial and ethnic minority groups' COVID-19 critical care outcomes., Design: Retrospective cohort study., Participants: A total of 2125 adult patients who tested positive for COVID-19 via RT-PCR between March and December 2020 and required ICU admission at the Cleveland Clinic Hospital Systems were included., Main Measures: Primary outcomes were mortality and hospital length of stay. Cohort-wide analysis and subgroup analyses by pandemic wave were performed. Multivariable logistic regression models were built to study the associations between mortality and covariates., Key Results: While crude mortality was increased in White as compared to Black patients (37.5% vs. 30.5%, respectively; p = 0.002), no significant differences were appraised after adjustment or across pandemic waves. Although median hospital length of stay was comparable between these groups, ICU stay was significantly different (4.4 vs. 3.4, p = 0.003). Mortality and median hospital and ICU length of stay did not differ significantly between Hispanic and non-Hispanic patients. Neither race nor ethnicity was associated with mortality due to COVID-19, although APACHE score, CKD, malignant neoplasms, antibiotic use, vasopressor requirement, and age were., Conclusions: We found no significant differences in mortality or hospital length of stay between different races and ethnicities. In a pandemic-influenced critical care setting that operated outside conditions of ICU strain and implemented standardized protocol enabling equitable resource distribution, disparities in outcomes often seen among racial and ethnic minority groups were successfully mitigated., (© 2022. W. Montague Cobb-NMA Health Institute.)

Background: Restorative neurostimulation is a rehabilitative treatment for patients with refractory chronic low back pain (CLBP) associated with dysfunction of the lumbar multifidus muscle resulting in impaired neuromuscular control. The ReActiv8-B randomized, sham-controlled trial provided evidence of the effectiveness and safety of an implanted, restorative neurostimulator. The two-year analysis previously published in this journal demonstrated accrual of clinical benefits and long-term durability., Objective: Evaluation of three-year effectiveness and safety in patients with refractory, disabling CLBP secondary to multifidus muscle dysfunction and no indications for spine surgery., Materials and Methods: Prospective, observational follow-up of the 204 implanted trial participants. Low back pain visual analog scale (VAS), Oswestry Disability Index (ODI), EuroQol quality of life survey, and opioid intake were assessed at baseline, six months, and one, two, and three years after activation. The mixed-effects model repeated measures approach was used to provide implicit imputations of missing data for continuous outcomes and multiple imputation for proportion estimates., Results: Data were collected from 133 participants, and 16 patients missed their three-year follow-up because of coronavirus disease restrictions but remain available for future follow-up. A total of 62% of participants had a ≥ 70% VAS reduction, and 67% reported CLBP resolution (VAS ≤ 2.5cm); 63% had a reduction in ODI of ≥ 20 points; 83% had improvements of ≥ 50% in VAS and/or ≥ 20 points in ODI, and 56% had these substantial improvements in both VAS and ODI. A total of 71% (36/51) participants on opioids at baseline had voluntarily discontinued (49%) or reduced (22%) opioid intake. The attenuation of effectiveness in the imputed (N = 204) analyses was relatively small and did not affect the statistical significance and clinical relevance of these results. The safety profile remains favorable, and no lead migrations have been observed to date., Conclusion: At three years, 83% of participants experienced clinically substantial improvements in pain, disability, or both. The results confirm the long-term effectiveness, durability, and safety of restorative neurostimulation in patients with disabling CLBP associated with multifidus muscle dysfunction., Clinical Trial Registration: The Clinicaltrials.gov registration number for the study is NCT02577354., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

The summer of 2020 riveted the attention of our nation with a sense of urgency to address structural racism. Cities declared racism a public health crisis, and organizations called for increased awareness of persistent historic racial inequities and advocacy for change. In medical education, students and institutional leaders felt compelled to transition from passive advocacy to energetic action in order to build a culture of anti-racism. In our institution, we applied J Mierke and V. Williamson's 6-step framework to achieve organizational culture change which is as follows: 1. Identify the catalyst for change; 2. Strategically plan for successful change; 3. Engage and empower organizational members; 4. Cultivate leaders at all levels; 5. Foster innovation, creativity, and risk-taking; 6. Monitor progress, measure success, and celebrate (even the small changes) along the way. In addition, we noted two key considerations for the success of the process: A. Transparency in communication, and B. Flexibility and adjustment to emerging situations. We share our approach using this framework which we believe is generalizable to other organizations. We draw from literature on organizational psychology and lastly call for the continuation and sustainability of the work that will continue to build a diverse, equitable, inclusive, antiracist and vibrant education community., (© The Author(s), under exclusive licence to Springer Nature Switzerland AG 2023, 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: Impaired neuromuscular control and degeneration of the multifidus muscle have been linked to the development of refractory chronic low back pain (CLBP). An implantable restorative-neurostimulator system can override the underlying multifidus inhibition by eliciting episodic, isolated contractions. The ReActiv8-B randomized, active-sham-controlled trial provided effectiveness and safety evidence for this system, and all participants received therapeutic stimulation from four months onward., Objective: This study aimed to evaluate the two-year effectiveness of this restorative neurostimulator in patients with disabling CLBP secondary to multifidus muscle dysfunction and no indications for spine surgery., Materials and Methods: Open-label follow-up of 204 participants implanted with a restorative neurostimulation system (ReActiv8, Mainstay Medical, Dublin, Ireland) was performed. Pain intensity (visual analog scale [VAS]), disability (Oswestry disability index [ODI]), quality-of-life (EQ-5D-5L), and opioid intake were assessed at baseline, six months, one year, and two years after activation., Results: At two years (n = 156), the proportion of participants with ≥50% CLBP relief was 71%, and 65% reported CLBP resolution (VAS ≤ 2.5 cm); 61% had a reduction in ODI of ≥20 points, 76% had improvements of ≥50% in VAS and/or ≥20 points in ODI, and 56% had these substantial improvements in both VAS and ODI. A total of 87% of participants had continued device use during the second year for a median of 43% of the maximum duration, and 60% (34 of 57) had voluntarily discontinued (39%) or reduced (21%) opioid intake., Conclusions: At two years, 76% of participants experienced substantial, clinically meaningful improvements in pain, disability, or both. These results provide evidence of long-term effectiveness and durability of restorative neurostimulation in patients with disabling CLBP, secondary to multifidus muscle dysfunction., Clinical Trial Registration: The study is registered on clinicaltrials.gov with identifier NCT02577354., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

During the past 4 decades, the Sultanate of Oman has undergone a remarkable change in all the fields of civilization and modernization, including education, health care, social services, and many other improvements. In the present article, we address the history of neurosurgery in the Sultanate of Oman from the early beginning to the present time. Neurosurgery Departments in the Sultanate of Oman have come a long way to reach their current status. Along the development journey over the past few decades, there have been many bumps and obstacles. The establishment of Khoula Hospital in 1974 has opened the gates for a new era of surgical services in the country which resembles the national neurosurgical center in Oman., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Tau aggregates are present in multiple neurodegenerative diseases known as "tauopathies," including Alzheimer's disease, Pick's disease, progressive supranuclear palsy, and corticobasal degeneration. Such misfolded tau aggregates are therefore potential sources for selective detection and biomarker discovery. Six human tau isoforms present in brain tissues and both 3R and 4R isoforms have been observed in the neuronal inclusions. To develop selective markers for AD and related rare tauopathies, we first used an engineered tau protein fragment 4RCF as the substrate for ultrasensitive real-time quaking-induced conversion analyses (RT-QuIC). We showed that misfolded tau from diseased AD and other tauopathy brains were able to seed recombinant 4RCF substrate. We further expanded to use six individual recombinant tau isoforms as substrates to amplify misfolded tau seeds from AD brains. We demonstrated, for the first time to our knowledge, that misfolded tau from the postmortem AD brain tissues was able to specifically seed all six full-length human tau isoforms. Our results demonstrated that RT-QuIC analysis can discriminate AD and other tauopathies from non-AD normal controls. We further uncovered that 3R-tau isoforms displayed significantly faster aggregation kinetics than their 4R-tau counterparts under conditions of both no seeding and seeding with AD brain homogenates. In summary, our work offers potential new avenues of misfolded tau detection as potential biomarkers for diagnosis of AD and related tauopathies and provides new insights into isoform-specific human tau aggregation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wu, Wang, Lad, Gilyazova, Dougharty, Marcus, Henderson, Ray, Siedlak, Li, Helm, Zhu, Bloom, Wang, Zou and Xu.)

Pharmaceutical grade 3'-deoxy-3'-[ 18 F]fluorothymidine [ 18 F]FLT was synthesized using 3-N-Boc-5'-O-dimethoxytrityl-3'-O-nosyl-thymidine (BOC-Nosyl) precursor, in the general purpose TRACERlab FX modules. Purification of [ 18 F]FLT, via solid phase extraction (SPE) after radiosynthesis, using a combination of different SPE cartridges, yielded satisfactory results, with radiochemical and chemical purity >99%. While the non-decay corrected radiochemical yield (RCY) with 20 mg (24 μmole) of BOC-Nosyl precursor was found to be 6.80 ± 0.16%, the decay corrected radiochemical yield (RCY) was 9.95 ± 0.24%. Residual acetone, acetonitrile, and ethanol levels were found to be 22.97 ± 0.76, 109.08 ± 0.93, and 7,666.45 ± 3.7 ppm, respectively. A simplified method for solid-phase purification of [ 18 F]FLT was developed, circumventing the need for HPLC purification. Biodistribution in C57BL/6 mice with B16F10 cell line-induced melanoma showed tumor to blood ratio of ~3.8 at 90 min. PET/CT imaging of normal rabbit injected with [ 18 F]FLT shows selective uptake in the bone marrow and small intestine. [ 18 F]FLT was found to be excreted through the kidneys and get collected in the urinary bladder, 120 min post injection. PET/CT imaging performed in rabbit model at 30, 60, 90, and 120 min post [ 18 F]FLT injections showed concordance with tissue distribution kinetics of mice tumor model., (© 2022 John Wiley & Sons, Ltd.)

The aim of the current study was to evaluate the results of a novel dichoptic training program using an online platform in a group of subjects with refractive amblyopia, performing a comparative analysis of unilateral and bilateral amblyopic cases. For this purpose, a retrospective study analysis of data of 161 children (4−13 years) who underwent dichoptic treatment with the Bynocs® platform (Kanohi Eye Pvt. Ltd., Mumbai, India) was performed. In all cases, the therapy protocol consisted of sessions of training of 30 min daily 5 times a week for 6 weeks. Best corrected visual acuity (BCVA) in the non-dominant eye improved significantly with the treatment, with a mean change of 0.39 logMAR in the whole sample (p < 0.001). Regarding binocularity, the binocular function (BF) score also experienced a significant improvement (p < 0.001), with a mean change of 1.55 with therapy in the whole sample. The BCVA of the dominant eye only improved significantly (p < 0.001) in the isometropic amblyopic subgroup. In conclusion, the use of the dichoptic therapy with the digital platform evaluated allows an effective restoration of visual acuity and binocular function in children with anisometropic and isometropic amblyopia.

Objectives: Bacterial endotoxin test (BET) for detection and quantification of endotoxin in radiopharmaceuticals (RPs), used for therapy or diagnosis, is prerequisite to administration in patients. Out of the two established methods used for this purpose (Kinetic Chromogenic Assay: KCM and Gel Clot Bacterial Endotoxin Test: GC-BET), GC-BET is recommended by pharmacopeias to evaluate the interferences exhibited during the assay due to presence of various ingredients in samples. In the present study, the influence of excess of cations in [ 177 Lu]Lu-DOTATATE, used for Peptide Receptor Radionuclide Therapy (PRRT), were studied and a protocol to negate the enhancement observed was developed. Additionally, a protocol for carrying out GC-BET for extremely viscous [ 131 I]I-Lipiodol was standardized., Methods: GC-BET was performed for [ 177 Lu]Lu-DOTATATE and [ 131 I]I-Lipiodol at maximum valid dilution (MVD), using LRW as a diluent. To negate the false positivity observed in case of [ 177 Lu]Lu-DOTATATE, various concentrations of calcium chloride (CaCl 2 ) were added and evaluated for the reversal of the interference observed initially. To prevail the difficulty in performing GC-BET for [ 131 I]I-Lipiodol various modification in the protocols like orbital vortexing at different rpm and time intervals were performed. KCM assays were also performed for studied RPs at MVD., Results: It was observed that at MVD, [ 177 Lu]Lu-DOTATATE exhibited false positivity in GC-BET. However, all the individual reagents used in labeling of [ 177 Lu]Lu-DOTATATE did not show any false positivity. Finally, performing the assay with an addition of 2mM CaCl 2 (final concentration) nullified the false positivity. Further, intricacy in performing GC-BET for [ 131 I]I-Lipiodol due to its viscosity was resolved by orbital vortexing at 3000 rpm for 5 minutes., Conclusions: Our study proved that false positivity was observed in GC-BET for [ 177 Lu]Lu-DOTATATE due to the presence excess M 3+ ions. Further, our study is the first of its kind which demonstrated methods for negating these false positive results by using modified protocol and hypothesizing the reason behind the enhancement. Additionally, ours is the first study which proved that a simple step of vortexing the viscous RPs like [ 131 I]I-Lipiodol can resolved the problems encountered during performing GC-BET due to viscosity of RPs., (© 2022 mums.ac.ir All rights reserved.)

Objective: To determine the efficacy and safety of intravenous (IV) labetalol in the management of hypertensive crisis in children., Methods: A retrospective chart review of 56 consecutive children (age > 1 mo to ≤ 12 y) with hypertensive crisis admitted to a pediatric intensive care unit (PICU) from July 2009 to 2019., Results: The proportion of children attaining the primary endpoint (target 95th percentile in > 12 to ≤ 48 h) was significantly more in the group receiving labetalol as first-line or add-on (n = 23) as compared to those not receiving labetalol (n = 33) (62% vs. 30.3%, p = 0.03). Higher proportion of neurological recovery was seen in the labetalol group (56.2% vs. 18.7%, p = 0.02). The proportion of children with hypotension before 12 h was similar in both treatment groups (13% vs. 15%, p = 0.82). The practice variations between two periods of 5 y each (2009-2013 and 2014-2019) showed significantly more use of labetalol in the latter cohort (53% for 2014-2019 vs. 25% for 2009-2013, p = 0.03)., Conclusion: Labetalol, when used alone or as an add-on drug, was more efficacious than IV nitroprusside/nitroglycerine in attaining the primary endpoint in children up to ≤ 12 y of age with hypertensive crisis. Labetalol was safe and associated with higher neurological recovery., (© 2021. Dr. K C Chaudhuri Foundation.)

Objective: Prior research has identified a variety of embedded performance validity indicators on the Conners' Continuous Performance Test-II (CPT-II). The purpose of this study was to examine embedded validity indicators within the updated third edition of the Conners Continuous Performance Test (CPT-3)., Method: This study used a retrospective chart review from an ADHD evaluation clinic at a Mid-Atlantic VA hospital. Participants were 197 military veterans who completed a clinical assessment for ADHD. All participants were consecutive referrals to the ADHD clinic who completed the CPT-3 and the Test of Memory Malingering, Trial 1 (TOMM1)., Results: Logistic regression analyses indicated that the following five variables were able to significantly predict validity status on the TOMM1: detectability (d'), omissions (OMI), commissions (COM), hit reaction time (HRT) standard deviation (SD), and HRT inter-stimulus interval (ISI) change. Among these measures, HRT SD and HRT ISI change were identified as the scores with the highest AUC values. Optimal cutoffs for all significant predictors were identified. A number of composite EVIs were created using various combinations of CPT-3 scores. All composite EVIs significantly differentiated between pass and fail status on the TOMM1., Conclusions: Several CPT-3 variables have clinical utility as embedded validity indicators; however, due to low sensitivity, they should not be used in isolation. These scores may be used as indicators of invalid performance but should not be used to rule out invalid performance. Identified CPT-3 scores may be useful as one component in a multivariate, multi-point continuous approach to performance validity sampling.

Abstract: Chronic low back pain can be caused by impaired control and degeneration of the multifidus muscles and consequent functional instability of the lumbar spine. Available treatment options have limited effectiveness and prognosis is unfavorable. We conducted an international randomized, double-blind, sham-controlled trial at 26 multidisciplinary centers to determine safety and efficacy of an implantable, restorative neurostimulator designed to restore multifidus neuromuscular control and facilitate relief of symptoms (clinicaltrials.gov identifier: NCT02577354). Two hundred four eligible participants with refractory mechanical (musculoskeletal) chronic LBP and a positive prone instability test indicating impaired multifidus control were implanted and randomized to therapeutic (N = 102) or low-level sham (N = 102) stimulation of the medial branch of the dorsal ramus nerve (multifidus nerve supply) for 30 minutes twice daily. The primary endpoint was the comparison of responder proportions (≥30% relief on the LBP visual analogue scale without analgesics increase) at 120 days. After the primary endpoint assessment, participants in the sham-control group switched to therapeutic stimulation and the combined cohort was assessed through 1 year for long-term outcomes and adverse events. The primary endpoint was inconclusive in terms of treatment superiority (57.1% vs 46.6%; difference: 10.4%; 95% confidence interval, -3.3% to 24.1%, P = 0.138). Prespecified secondary outcomes and analyses were consistent with a modest but clinically meaningful treatment benefit at 120 days. Improvements from baseline, which continued to accrue in all outcome measures after conclusion of the double-blind phase, were clinically important at 1 year. The incidence of serious procedure- or device-related adverse events (3.9%) compared favorably with other neuromodulation therapies for chronic pain., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

Introduction: [ 177 Lu]Lu-prostate-specific membrane antigen (PSMA)-617 has emerged as a promising radiopharmaceutical for targeting PSMA in metastatic castrate-resistant prostate carcinoma (mCRPC). We have optimized the radiolabeling protocol for a multidose formulation (27-28.8 GBq equivalent to 6-7 patient-doses) of [ 177 Lu]Lu-PSMA-617 using [ 177 Lu]Lu 3+ produced via 176 Lu(n,γ) 177 Lu route with moderate specific activity (0.66-0.81 GBq/μg). Methods: [ 177 Lu]Lu-PSMA-617 was synthesized using moderate specific activity [ 177 Lu]LuCl 3 (0.74 GBq/μg) with PSMA-617 having metal-to-ligand molar ratio ∼1: 2.5 in CH 3 COONH 4 buffer (0.1 M) containing gentisic acid at pH 4.0-4.5. Human prostate carcinoma cell line LNCaP cell (high PSMA expression) was used for in vitro cell-binding studies and generating tumor xenograft models in nude mice for tissue biodistribution studies. Several batches of the present formulation have been clinically administered in mCRPC patients (single patient dose: 4.44-5.55 GBq per cycle). Results: In this study we report a consistent and reproducible protocol for multidose formulations of [ 177 Lu]Lu-PSMA-617 for adopting in a hospital radiopharmacy setting. Although the radiochemical yield of [ 177 Lu]Lu-PSMA-617 was found to be 97.30% ± 1.03%, the radiochemical purity was 98.24% ± 0.50% ( n  = 19). In vitro and serum stability of [ 177 Lu]Lu-PSMA-617 was retained up to 72 and 120 h after radiolabeling and upon storage at -20°C with a radioactive concentration between 0.37 and 0.74 GBq/mL upon using stabilizer concentration as low as 43-48 μg/mCi. Preclinical cell-binding studies of [ 177 Lu]Lu-PSMA-617 revealed specific binding with LNCaP cells of 17.4% ± 2.4%. The uptake in LnCaP xenografted tumor (nude mice) was 7.5 ± 2.6% ID/g for ∼1.5-2.0 cm 3 tumor volume at 24-h post-injection. Post-therapy (24 h) SPECT image of mCRPC patients with prior orchidectomy and various hormone therapy showed specific localization of [ 177 Lu]Lu-PSMA-617 in the tumor region. Conclusions: Formulation of a ready-to-use multidose formulation of [ 177 Lu]Lu-PSMA-617 was successfully achieved and the procedure was optimized for routine preparation at a hospital radiopharmacy set-up. High degree of localization of [ 177 Lu]Lu-PSMA-617 in post-therapy SPECT scan and the post-therapeutic response confirms its therapeutic efficacy. Clinical Trials.gov ID: RPC/51/Minutes/Final dated 16th October, 2019.

Novel species of fungi described in this study include those from various countries as follows: Algeria , Phaeoacremonium adelophialidum from Vitis vinifera. Antarctica , Comoclathris antarctica from soil. Australia , Coniochaeta salicifolia as endophyte from healthy leaves of Geijera salicifolia , Eremothecium peggii in fruit of Citrus australis , Microdochium ratticaudae from stem of Sporobolus natalensis , Neocelosporium corymbiae on stems of Corymbia variegata , Phytophthora kelmanii from rhizosphere soil of Ptilotus pyramidatus , Pseudosydowia backhousiae on living leaves of Backhousia citriodora , Pseudosydowia indooroopillyensis , Pseudosydowia louisecottisiae and Pseudosydowia queenslandica on living leaves of Eucalyptus sp. Brazil , Absidia montepascoalis from soil. Chile , Ilyonectria zarorii from soil under Maytenus boaria. Costa Rica , Colletotrichum filicis from an unidentified fern. Croatia , Mollisia endogranulata on deteriorated hardwood. Czech Republic , Arcopilus navicularis from tea bag with fruit tea, Neosetophoma buxi as endophyte from Buxus sempervirens , Xerochrysium bohemicum on surface of biscuits with chocolate glaze and filled with jam. France , Entoloma cyaneobasale on basic to calcareous soil, Fusarium aconidiale from Triticum aestivum , Fusarium juglandicola from buds of Juglans regia. Germany , Tetraploa endophytica as endophyte from Microthlaspi perfoliatum roots . India , Castanediella ambae on leaves of Mangifera indica , Lactifluus kanadii on soil under Castanopsis sp., Penicillium uttarakhandense from soil. Italy , Penicillium ferraniaense from compost. Namibia , Bezerromyces gobabebensis on leaves of unidentified succulent, Cladosporium stipagrostidicola on leaves of Stipagrostis sp., Cymostachys euphorbiae on leaves of Euphorbia sp., Deniquelata hypolithi from hypolith under a rock, Hysterobrevium walvisbayicola on leaves of unidentified tree, Knufia hypolithi and Knufia walvisbayicola from hypolith under a rock, Lapidomyces stipagrostidicola on leaves of Stipagrostis sp., Nothophaeotheca mirabibensis (incl. Nothophaeotheca gen. nov.) on persistent inflorescence remains of Blepharis obmitrata , Paramyrothecium salvadorae on twigs of Salvadora persica , Preussia procaviicola on dung of Procavia sp., Sordaria equicola on zebra dung, Volutella salvadorae on stems of Salvadora persica . Netherlands , Entoloma ammophilum on sandy soil, Entoloma pseudocruentatum on nutrient poor (acid) soil, Entoloma pudens on plant debris, amongst grasses. New Zealand , Amorocoelophoma neoregeliae from leaf spots of Neoregelia sp., Aquilomyces metrosideri and Septoriella callistemonis from stem discolouration and leaf spots of Metrosideros sp., Cadophora neoregeliae from leaf spots of Neoregelia sp., Flexuomyces asteliae (incl. Flexuomyces gen. nov.) and Mollisia asteliae from leaf spots of Astelia chathamica , Ophioceras freycinetiae from leaf spots of Freycinetia banksii , Phaeosphaeria caricis-sectae from leaf spots of Carex secta. Norway , Cuphophyllus flavipesoides on soil in semi-natural grassland, Entoloma coracis on soil in calcareous Pinus and Tilia forests, Entoloma cyaneolilacinum on soil semi-natural grasslands, Inocybe norvegica on gravelly soil. Pakistan , Butyriboletus parachinarensis on soil in association with Quercus baloot. Poland , Hyalodendriella bialowiezensis on debris beneath fallen bark of Norway spruce Picea abies. Russia , Bolbitius sibiricus on à moss covered rotting trunk of Populus tremula , Crepidotus wasseri on debris of Populus tremula , Entoloma isborscanum on soil on calcareous grasslands, Entoloma subcoracis on soil in subalpine grasslands, Hydropus lecythiocystis on rotted wood of Betula pendula , Meruliopsis faginea on fallen dead branches of Fagus orientalis , Metschnikowia taurica from fruits of Ziziphus jujube , Suillus praetermissus on soil, Teunia lichenophila as endophyte from Cladonia rangiferina. Slovakia , Hygrocybe fulgens on mowed grassland, Pleuroflammula pannonica from corticated branches of Quercus sp. South Africa , Acrodontium burrowsianum on leaves of unidentified Poaceae , Castanediella senegaliae on dead pods of Senegalia ataxacantha , Cladophialophora behniae on leaves of Behnia sp., Colletotrichum cliviigenum on leaves of Clivia sp., Diatrype dalbergiae on bark of Dalbergia armata , Falcocladium heteropyxidicola on leaves of Heteropyxis canescens , Lapidomyces aloidendricola as epiphyte on brown stem of Aloidendron dichotomum , Lasionectria sansevieriae and Phaeosphaeriopsis sansevieriae on leaves of Sansevieria hyacinthoides , Lylea dalbergiae on Diatrype dalbergiae on bark of Dalbergia armata , Neochaetothyrina syzygii (incl. Neochaetothyrina gen. nov.) on leaves of Syzygium chordatum , Nothophaeomoniella ekebergiae (incl. Nothophaeomoniella gen. nov.) on leaves of Ekebergia pterophylla , Paracymostachys euphorbiae (incl. Paracymostachys gen. nov.) on leaf litter of Euphorbia ingens , Paramycosphaerella pterocarpi on leaves of Pterocarpus angolensis , Paramycosphaerella syzygii on leaf litter of Syzygium chordatum , Parateichospora phoenicicola (incl. Parateichospora gen. nov.) on leaves of Phoenix reclinata , Seiridium syzygii on twigs of Syzygium chordatum , Setophoma syzygii on leaves of Syzygium sp., Starmerella xylocopis from larval feed of an Afrotropical bee Xylocopa caffra , Teratosphaeria combreti on leaf litter of Combretum kraussii , Teratosphaericola leucadendri on leaves of Leucadendron sp., Toxicocladosporium pterocarpi on pods of Pterocarpus angolensis. Spain , Cortinarius bonachei with Quercus ilex in calcareus soils, Cortinarius brunneovolvatus under Quercus ilex subsp . ballota in calcareous soil, Extremopsis radicicola (incl. Extremopsis gen. nov.) from root-associated soil in a wet heathland, Russula quintanensis on acidic soils, Tubaria vulcanica on volcanic lapilii material, Tuber zambonelliae in calcareus soil. Sweden , Elaphomyces borealis on soil under Pinus sylvestris and Betula pubescens. Tanzania , Curvularia tanzanica on inflorescence of Cyperus aromaticus. Thailand , Simplicillium niveum on Ophiocordyceps camponoti-leonardi on underside of unidentified dicotyledonous leaf. USA , Calonectria californiensis on leaves of Umbellularia californica , Exophiala spartinae from surface sterilised roots of Spartina alterniflora , Neophaeococcomyces oklahomaensis from outside wall of alcohol distillery. Vietnam , Fistulinella aurantioflava on soil. Morphological and culture characteristics are supported by DNA barcodes. Citation : Crous PW, Cowan DA, Maggs-Kölling, et al. 2021. Fungal Planet description sheets: 1182-1283. Persoonia 46: 313-528. https://doi.org/10.3767/persoonia.2021.46.11., (© 2021 Naturalis Biodiversity Center & Westerdijk Fungal Biodiversity Institute.)

Background: Traumatic spinal cord injury (SCI) is a serious public health problem. Outcomes are determined by severity of immediate injury, mitigation of secondary downstream effects, and rehabilitation. This study aimed to understand how the center type a patient presents to and whether they are transferred influence management and outcome., Methods: The National Trauma Data Bank was used to identify patients with SCI. The primary objective was to determine association between center type, transfer, and surgical intervention. A secondary objective was to determine association between center type, transfer, and surgical timing. Multivariable logistic regression models were fit on surgical intervention and timing of the surgery as binary variables, adjusting for relevant clinical and demographic variables., Results: There were 11,744 incidents of SCI identified. A total of 2,883 patients were transferred to a Level I center and 4,766 presented directly to a level I center. Level I center refers to level I trauma center. Those who were admitted directly to level I centers had a higher odd of receiving a surgery (odds ratio, 1.703; 95% confidence interval, 1.47-1.97; p < 0.001), but there was no significant difference in terms of timing of surgery. Patients transferred into a level I center were also more likely to undergo surgery than those at a level II/III/IV center, although this was not significant (odds ratio, 1.213; 95% confidence interval, 0.099-1.48; p = 0.059)., Conclusion: Patients with traumatic SCI admitted to level I trauma centers were more likely to have surgery, particularly if they were directly admitted to a level I center. This study provides insights into a large US sample and sheds light on opportunities for improving pre hospital care pathways for patients with traumatic SCI, to provide the timely and appropriate care and achieve the best possible outcomes., Level of Evidence: Care management, Level IV., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: The quality control parameters of in-house-produced 90 Y-Acetate from high-level liquid waste (HLLW) using supported liquid membrane (SLM) technology were validated and compared with the pharmacopeia standard. The radiolabeling of DOTATATE yielding 90 Y-DOTATATE in acceptable radiochemical purity (RCP), with expected pharmacological behavior in in vivo models, establish the quality of 90 Y-Acetate. Clinical translation of 90 Y-Acetate in formulation of 90 Y-DOTATATE adds support toward its use as clinical-grade radiochemical. Methods: Quality control parameters of 90 Y-Acetate, namely radionuclide purity (RNP), were evaluated using β - spectrometry, γ-spectroscopy, and liquid scintillation counting. RCP and metallic impurities were established using high-performance liquid chromatography and inductively coupled plasma optical emission spectrometry, respectively. The suitability of 90 Y-Acetate as an active pharmaceutical ingredient radiochemical was ascertained by radiolabeling with DOTATATE. In vivo biodistribution of 90 Y-DOTATATE was carried out in nude mice bearing AR42J xenografted tumor. Clinical efficacy of 90 Y-DOTATATE was established after using in patients with large-volume neuroendocrine tumors (NET). Bremsstrahlung imaging was carried out in dual-head gamma camera with a wide energy window setting (100-250 keV). Results: In-house-produced 90 Y-Acetate was clear, colorless, and radioactive concentration (RAC) in the range of 40-50 mCi/mL. RCP was >98%. 90 Sr content was <0.85 μCi/Ci of 90 Y. Gross λ content was <0.8 nCi/Ci of 90 Y and no γ peak was observed. Fe 3+ , Cu 2+ , Zn 2+ , Cd 2+ , and Pb 2+ contents were <1.7 μg/Ci. The radiolabeling yield (RLY) of 90 Y-DOTATATE was >94%, RCP was >98%. The in vitro stability of 90 Y-DOTATATE was up to 72 h postradiolabeling, upon storage at -20°C. Post-therapy (24 h) Bremsstrahlung image of patients with large NET exhibit complete localization of 90 Y-DOTATATE in tumor region. Conclusions: This study demonstrates that the in-house-produced 90 Y-Acetate from HLLW can be used for the formulation of various therapeutic 90 Y-based radiopharmaceuticals. Since 90 Y is an imported radiochemical precursor available at a high cost in India, this study which demonstrates the suitability of indigenously sourced 90 Y, ideally exemplifies the recovery of "wealth from waste." The Clinical Trial Registration number: (P17/FEB/2019).

The inflammatory response is an obstacle to success in both allogeneic and autologous islet transplantation. In autologous islet transplantation (AIT), however, the recipient is also the donor, permitting pretreatment of donor/recipient for a controlled duration prior to transplantation. We sought to exploit this feature of (AIT) by pretreating donor/recipients with chronic pancreatitis undergoing total pancreatectomy and autologous islet transplantation (TPAIT) to test the hypothesis that peri-transplant treatment with the FDA-approved anti-inflammatory hydroxychloroquine (HCQ) improves graft function. In this randomized placebo-controlled pilot clinical study, patients ( n = 6) were treated with oral HCQ for 30 days prior to and 90 days after TPAIT. In vivo islet function was assessed via Mixed Meal Tolerance Testing before HCQ treatment, 6- and 12-months after surgery. In vitro islet bioenergetics were assessed at the time of transplantation via extracellular flux analysis of islet preparation samples from the clinical trial cohort and six additional patients ( n = 12). Our study shows that HCQ did not alter clinical endpoints, but HCQ-treated patients showed greater spare respiratory capacity (SRC) compared to samples from control patients ( P =0.028). Glycolytic metabolism of islet preparations directly correlated with stimulated C-peptide secretion both before and after TPAIT ( P =0.01, R 2 =0.489 and P =0.03, R 2 =0.674, respectively), and predicted in vivo islet function better than mitochondrial metabolism of islet preps or islet equivalents infused. Overnight culture of islet preparations altered bioenergetic function, significantly decreasing SRC and maximal respiration ( P <0.001). In conclusion, while HCQ did not alter clinical outcomes, it was associated with significantly increased SRC in islet preparations. Bioenergetic analyses of islet preparations suggests that culture should be avoided and that glycolysis may be a more sensitive indicator of in vivo islet function than current metrics, including islet oxygen consumption and islet equivalents infused.

This article is the 13th contribution in the Fungal Diversity Notes series, wherein 125 taxa from four phyla, ten classes, 31 orders, 69 families, 92 genera and three genera incertae sedis are treated, demonstrating worldwide and geographic distribution. Fungal taxa described and illustrated in the present study include three new genera, 69 new species, one new combination, one reference specimen and 51 new records on new hosts and new geographical distributions. Three new genera, Cylindrotorula ( Torulaceae ), Scolecoleotia ( Leotiales genus incertae sedis ) and Xenovaginatispora ( Lindomycetaceae ) are introduced based on distinct phylogenetic lineages and unique morphologies. Newly described species are Aspergillus lannaensis , Cercophora dulciaquae , Cladophialophora aquatica , Coprinellus punjabensis , Cortinarius alutarius , C. mammillatus , C. quercoflocculosus , Coryneum fagi , Cruentomycena uttarakhandina , Cryptocoryneum rosae , Cyathus uniperidiolus , Cylindrotorula indica , Diaporthe chamaeropicola , Didymella azollae , Diplodia alanphillipsii , Dothiora coronicola , Efibula rodriguezarmasiae , Erysiphe salicicola , Fusarium queenslandicum , Geastrum gorgonicum , G. hansagiense , Helicosporium sexualis , Helminthosporium chiangraiensis , Hongkongmyces kokensis , Hydrophilomyces hydraenae , Hygrocybe boertmannii , Hyphoderma australosetigerum , Hyphodontia yunnanensis , Khaleijomyces umikazeana , Laboulbenia divisa , Laboulbenia triarthronis , Laccaria populina , Lactarius pallidozonarius , Lepidosphaeria strobelii , Longipedicellata megafusiformis , Lophiotrema lincangensis , Marasmius benghalensis , M. jinfoshanensis , M. subtropicus , Mariannaea camelliae , Melanographium smilaxii , Microbotryum polycnemoides , Mimeomyces digitatus , Minutisphaera thailandensis , Mortierella solitaria , Mucor harpali , Nigrograna jinghongensis , Odontia huanrenensis , O. parvispina , Paraconiothyrium ajrekarii , Parafuscosporella niloticus , Phaeocytostroma yomensis , Phaeoisaria synnematicus , Phanerochaete hainanensis , Pleopunctum thailandicum , Pleurotheciella dimorphospora , Pseudochaetosphaeronema chiangraiense , Pseudodactylaria albicolonia , Rhexoacrodictys nigrospora , Russula paravioleipes , Scolecoleotia eriocamporesi , Seriascoma honghense , Synandromyces makranczyi , Thyridaria aureobrunnea , Torula lancangjiangensis , Tubeufia longihelicospora , Wicklowia fusiformispora , Xenovaginatispora phichaiensis and Xylaria apiospora . One new combination, Pseudobactrodesmium stilboideus is proposed. A reference specimen of Comoclathris permunda is designated. New host or distribution records are provided for Acrocalymma fici , Aliquandostipite khaoyaiensis , Camarosporidiella laburni , Canalisporium caribense , Chaetoscutula juniperi , Chlorophyllum demangei , C. globosum , C. hortense , Cladophialophora abundans , Dendryphion hydei , Diaporthe foeniculina , D. pseudophoenicicola , D. pyracanthae , Dictyosporium pandanicola , Dyfrolomyces distoseptatus , Ernakulamia tanakae , Eutypa flavovirens , E. lata , Favolus septatus , Fusarium atrovinosum , F. clavum , Helicosporium luteosporum , Hermatomyces nabanheensis , Hermatomyces sphaericoides , Longipedicellata aquatica , Lophiostoma caudata , L. clematidis-vitalbae , Lophiotrema hydei , L. neoarundinaria , Marasmiellus palmivorus , Megacapitula villosa , Micropsalliota globocystis , M. gracilis , Montagnula thailandica , Neohelicosporium irregulare , N. parisporum , Paradictyoarthrinium diffractum , Phaeoisaria aquatica , Poaceascoma taiwanense , Saproamanita manicata , Spegazzinia camelliae , Submersispora variabilis , Thyronectria caudata , T. mackenziei , Tubeufia chiangmaiensis , T. roseohelicospora , Vaginatispora nypae , Wicklowia submersa , Xanthagaricus necopinatus and Xylaria haemorrhoidalis . The data presented herein are based on morphological examination of fresh specimens, coupled with analysis of phylogenetic sequence data to better integrate taxa into appropriate taxonomic ranks and infer their evolutionary relationships., Competing Interests: Conflict of interestThe authors declare that they have no conflict of interest., (© MUSHROOM RESEARCH FOUNDATION 2021.)

The NADase SARM1 is a central switch in injury-activated axon degeneration, an early hallmark of many neurological diseases. Here, we present cryo-electron microscopy (cryo-EM) structures of autoinhibited (3.3 Å) and active SARM1 (6.8 Å) and provide mechanistic insight into the tight regulation of SARM1's function by the local metabolic environment. Although both states retain an octameric core, the defining feature of the autoinhibited state is a lock between the autoinhibitory Armadillo/HEAT motif (ARM) and catalytic Toll/interleukin-1 receptor (TIR) domains, which traps SARM1 in an inactive state. Mutations that break this lock activate SARM1, resulting in catastrophic neuronal death. Notably, the mutants cannot be further activated by the endogenous activator nicotinamide mononucleotide (NMN), and active SARM1 is product inhibited by Nicotinamide (NAM), highlighting SARM1's functional dependence on key metabolites in the NAD salvage pathway. Our studies provide a molecular understanding of SARM1's transition from an autoinhibited to an injury-activated state and lay the foundation for future SARM1-based therapies to treat axonopathies., Competing Interests: Declaration of Interests M.B., D.A.T., S.L., P.M., Y.-S.Y., G.D., T.C.B., J.D., A.C., J.A.K., S.P.B., and S.S. are employees or former employees of Nura Bio and hold Nura Bio stock., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Donor safety is of prime importance in allogeneic hematopoietic cell transplantation. The Worldwide Network for Blood and Marrow Transplantation (WBMT) standing committee on donor issues has issued a consensus statement regarding suitability criteria for related adult donors. This committee recommends that donors with a history of immune-mediated glomerulonephritis and abnormal urine tests should preferably undergo bone marrow harvest, to avoid the theoretical risk of granulocyte colony-stimulating factor (G-CSF) induced immune flare-up. We discuss here a unique situation where a related donor with a history of IgA nephropathy (IgAN) insisted on a peripheral blood stem cell harvest. We propose a management plan for this situation, which posed challenges about donor suitability., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Hypoglycaemic due to congenital hyperinsulinism in Beckwith-Wiedemann syndrome is commonly seen. It is usually transient and is managed by enteral feeds, high glucose-containing intravenous fluids and medications like diazoxide. We describe a case of an infant with genetically proven Beckwith-Wiedemann syndrome with prolonged hyperinsulinemic hypoglycaemia. Despite treatment with high glucose-containing intravenous fluids, diazoxide and octreotide, her hypoglycaemia persisted. In addition to this, she also developed features of intestinal obstruction, which further complicated the management of hypoglycaemia. She underwent a rectal biopsy for this, which was highly suggestive of Hirschprung's disease. Following surgery, her abdominal distension and feed intolerance were settled and sugar control was improved. We present a rare association of Hirschsprung's disease with Beckwith-Wiedemann syndrome. To the best of our knowledge, this association has not been previously reported and this added to the difficulty in managing hyperinsulinemic hypoglycaemia in our patient., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Few nuclear reactors in the world producing high specific activity (HSA) 99Mo using enriched 235U (HEU), are aging and are planned for shut down in the near future. Further, HEU will not be freely available, due to safeguards, and the technology for 99Mo from low-enriched 235U (LEU) is not yet widely accepted since 239Pu contamination in the product is an issue. Production of 99mTc from low specific activity (LSA) 99Mo obtained from 98Mo(n,)99Mo reaction in research reactor and 100Mo(,n)99Mo reaction in accelerator or directly from 100Mo(p,2n)99mTc nuclear reaction in cyclotron, has been explored [1]. The methyl ethyl ketone (MEK) based solvent extraction technique is n well known method for the separation of 99mTc from low specific activity 99Mo. The 99Mo/99mTc autosolex generator [2], a computer controlled automated module, utilizes the conventional MEK solvent extraction method for extraction of 99mTc. Herein, we have validated the usage of autosolex for preparation of pharmacopoeia grade 99mTcO4- from 7.40-27.5 GBq of LSA 99Mo-SodiumMolybdate (99MoO42-) solution and validated the quality of the 99mTcO4- by preparing wide range of 99mTc-radiopharmaceuticals (99mTc-RP)., Materials and Methods: The 99mTcO4- was extracted from the autosolex as described in [2] starting from 7.40-27.5 GBq of LSA 99MoO42- and subjected to the required physico-chemical and biological quality control (QC) tests. The eluted 99mTcO4- labeled various fourth generation 99mTc radiopharmaceuticals cold kits (99mTc-cold kits) apart from regular 99mTc-cold kits in our centre. Various 99mTc-RP extracted 99mTcO4- using standard procedures [3] were prepared and subjected to required QC as Indian Pharmacopeia monograph [4] and used in scintigraphic imaging in patients. The radiation exposure dose to the operator were compared between autosolex and manual MEK based solvent extraction generator., Results: The extracted 99mTcO4- from autosolex is a clear and colorless solution with pH between 5.0-6.5. The elemental molybdenum (Mo) and aluminum (Al) content <10µg/mL, MEK levels <0.1%, 99Mo breakthrough <0.030% and radiochemical purity (RCP) >98%. All the extracted 99mTcO4- batches complies sterility test, endotoxin limit (EL) <5EU/mL. The RCP of all the labeled 99mTc-RP >95%. The autosolex delivers much less radiation dose to the operator than the convention manually handled MEK based solvent extraction generator., Conclusions: Autosolex Generator was successfully used to obtain pharmaceutical grade 99mTcO4- from LSA 99MoO42- and generator is safe in radiological and pharmacological point of view. The suitability of the autosolex for use in hospital radiopharmacy was shown by using the 99mTcO4- to prepare various 99mTc-RP and using these 99mTc-RP for scintigraphic imaging in patients.

The protocol described here is a reliable method of harvesting primary keratinocytes from adult female mice (54 ± 2 days old) yielding approximately 30 x 10 6 viable cells per mouse. Primary adult mouse keratinocytes are harvested from the dorsal skin of female mice. Male mice (~6 weeks old) can be used for keratinocyte harvesting depending on the requirements of the experiment. Euthanized mice are shaved and sterilized with serial washes in povidone iodine and ethanol solutions (70% alcohol). After disinfecting the mice, the dorsal skin is removed and the subcutaneous fat and muscle are removed with a scalpel and discarded. The skins are cut into small pieces and treated with a mild, low temperature trypsinization to detach the lower dermis from the epidermis. The scraped epidermises are stirred at low speed, filtered to remove the hairs, counted, and re-suspended in culture medium. This method provides an excellent single cell suspension of highly culturable cells for many downstream applications.

We used allogeneic bone marrow transplantation (BMT) and a mouse multistage cutaneous carcinogenesis model to probe recruitment of bone marrow-derived epithelial cells (BMDECs) in skin tumors initiated with the carcinogen, dimethylbenz[a]anthracene (DMBA), and promoted with 12-O-tetradecanolyphorbol-13-acetate (TPA). BMDECs clustered in the lesional epithelium, expressed cytokeratins, proliferated, and stratified. We detected cytokeratin induction in plastic-adherent bone marrow cells (BMCs) cultured in the presence of filter-separated keratinocytes (KCs) and bone morphogenetic protein 5 (BMP5). Lineage-depleted BMCs migrated towards High Mobility Group Box 1 (HMGB1) protein and epidermal KCs in ex vivo invasion assays. Naive female mice receiving BMTs from DMBA-treated donors developed benign and malignant lesions after TPA promotion alone. We conclude that BMDECs contribute to the development of papillomas and dysplasia, demonstrating a systemic contribution to these lesions. Furthermore, carcinogen-exposed BMCs can initiate benign and malignant lesions upon tumor promotion. Ultimately, these findings may suggest targets for treatment of non-melanoma skin cancers.

Hmga2 protein, a transcription factor involved in chromatin architecture, is expressed chiefly during development, where it has many key biological functions. When expressed in adult tissues from in various organs, Hmga2 is always related to cancer development. The role of Hmga2 in skin tumorigenesis is, however, not yet understood. We demonstrated that Hmga2 can be found in non-transformed epidermis, specifically located to the membrane of keratinocytes (KCs) in epidermis. Ex vivo culture of KCs and development of skin carcinomas in DMBA and TPA mouse models was associated with translocation of the Hmga2 protein from the membrane into the nucleus, where Hmga2 induced its own expression by binding to the Hmga2 promoter. Panobinostat, an HDAC inhibitor, downregulated Hmga2 expression by preventing Hmga2 to bind its own promoter, and thus inhibiting Hmga2 promoter activity. Hmga2 translocation to the nucleus could in part be prevented by an inhibitor for ROCK1. Our findings demonstrate that upon program of benign papilloma to malignant cSCC of skin tumorigenesis, Hmga2 translocates in a ROCK-dependent manner from the membrane to the nucleus, where it serves as an autoregulatory transcription factor, causing cell transformation.

The objective of the present work is to formulate 170 Tm-EDTMP using an in-house freeze-dried EDTMP kit and evaluate its potential as a bone pain palliation agent. Patient dose of 170 Tm-EDTMP was prepared with high radiochemical purity using the lyophilized kit at room temperature within 15min. Pre-clinical evaluation in normal Wistar rats revealed selective skeletal accumulation with extended retention. Preliminary clinical investigation in 8 patients with disseminated skeletal metastases exhibited selective uptake in the bone and retention therein for a long duration., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

ZFP57 is necessary for maintaining repressive epigenetic modifications at Imprinting control regions (ICRs). In mouse embryonic stem cells (ESCs), ZFP57 binds ICRs (ICRBS) and many other loci (non-ICRBS). To address the role of ZFP57 on all its target sites, we performed high-throughput and multi-locus analyses of inbred and hybrid mouse ESC lines carrying different gene knockouts. By using an allele-specific RNA-seq approach, we demonstrate that ZFP57 loss results in derepression of the imprinted allele of multiple genes in the imprinted clusters. We also find marked epigenetic differences between ICRBS and non-ICRBS suggesting that different cis-acting regulatory functions are repressed by ZFP57 at these two classes of target loci. Overall, these data demonstrate that ZFP57 is pivotal to maintain the allele-specific epigenetic modifications of ICRs that in turn are necessary for maintaining the imprinted expression over long distances. At non-ICRBS, ZFP57 inactivation results in acquisition of epigenetic features that are characteristic of poised enhancers, suggesting that another function of ZFP57 in early embryogenesis is to repress cis-acting regulatory elements whose activity is not yet required., (© The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Macrophages have been shown to play a role in acetaminophen (APAP)-induced hepatotoxicity, contributing to both pro- and anti-inflammatory processes. In these studies, we analyzed the role of the spleen as an extramedullary source of hepatic macrophages. APAP administration (300mg/kg, i.p.) to control mice resulted in an increase in CD11b(+) infiltrating Ly6G(+) granulocytic and Ly6G(-) monocytic cells in the spleen and the liver. The majority of the Ly6G(+) cells were also positive for the monocyte/macrophage activation marker, Ly6C, suggesting a myeloid derived suppressor cell (MDSC) phenotype. By comparison, Ly6G(-) cells consisted of 3 subpopulations expressing high, intermediate, and low levels of Ly6C. Splenectomy was associated with increases in mature (F4/80(+)) and immature (F4/80(-)) pro-inflammatory Ly6C(hi) macrophages and mature anti-inflammatory (Ly6C(lo)) macrophages in the liver after APAP; increases in MDSCs were also noted in the livers of splenectomized (SPX) mice after APAP. This was associated with increases in APAP-induced expression of chemokine receptors regulating pro-inflammatory (CCR2) and anti-inflammatory (CX3CR1) macrophage trafficking. In contrast, APAP-induced increases in pro-inflammatory galectin-3(+) macrophages were blunted in livers of SPX mice relative to control mice, along with hepatic expression of TNF-α, as well as the anti-inflammatory macrophage markers, FIZZ-1 and YM-1. These data demonstrate that multiple subpopulations of pro- and anti-inflammatory cells respond to APAP-induced injury, and that these cells originate from distinct hematopoietic reservoirs., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2016. Published by Elsevier Inc.)