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Background: Teriflunomide has been associated with an increased risk of hypertension. Real-world studies including adequate control groups are lacking. We hypothesized that patients with multiple sclerosis (MS) treated with teriflunomide would be at higher risk of developing hypertension than those treated with dimethyl fumarate., Methods: We conducted a cohort study linking the Danish Multiple Sclerosis Registry with national health registries during a 10-year period. Teriflunomide ( N = 2656) and dimethyl fumarate ( N = 2237) exposure was defined by the first treatment record lasting ⩾ 3 months, at which time follow-up started. We included 4893 adult patients without hypertension at baseline. Hypertension was defined as an International Classification of Diseases 10th Revision code for hypertension and by dispensed prescription drugs identified by the respective Anatomical Therapeutic Chemical codes. We used multivariable-adjusted Cox regression., Results: We found 40.6 (teriflunomide) and 13.1 (dimethyl fumarate) hypertension events per 1000 person-years. Compared to dimethyl fumarate-treated patients, patients treated with teriflunomide had a higher risk of developing hypertension (adjusted hazard ratio = 2.80; 95% confidence interval = 2.19-3.56). The number needed to harm was 16 and 9 at 3 and 5 years of follow-up, respectively., Conclusion: We found an increased risk of hypertension in adult patients with MS treated with teriflunomide., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Elisabeth Framke has nothing to disclose. Finn Sellebjerg has served on scientific advisory boards for, served as consultant for, received support for congress participation or received speaker honoraria from Alexion, Biogen, Bristol Myers Squibb, Merck, Novartis, Roche, and Sanofi Genzyme. His laboratory has received research support from Biogen, Merck, Novartis, Roche, and Sanofi Genzyme. Morten Stilund has served on scientific advisory boards for, received support for congress participation or received speaker honoraria from Biogen, Merck, Novartis, Roche, and Sanofi Genzyme. Henrik Boye Jensen has served on advisory boards for Merck and Roche, and as a speaker for Biogen. Zsolt Illes has received speakers’ honoraria and/or research grants from Biogen, Roche, Sanofi, Novartis, Merck, Alexion, Bristol Myers Squibb, Lundbeckfonden, Jascha Fonden, Scleroseforeningen, has been member of advisory boards at Alexion, Biogen, Sanofi, Merck, Roche, Novartis, has been member of adjudication relapse (clinical endpoint) committees in phase 3 trials, and has been principal investigator in studies sponsored by Biogen, Merck, and Sanofi. Tobias Sejbaek has served on scientific advisory boards for, served as consultant for, received support for congress participation or received speaker honoraria from, Biogen, Merck, Novartis, Roche, and Sanofi. His research group has received research support from Biogen, Merck, Roche, and Sanofi. Michael Broksgaard Jensen has served on scientific advisory boards, served as a consultant, received support for congress participation or received speaker honoraria from Biogen, Merck, Novartis, Roche, Sanofi Genzyme, and Teva. Jakob Schäfer has been member of advisory boards at Merck, Sanofi and received speaker honoraria from Merck and Novartis, has received support for congress participation from Merck, Sanofi, and Roche. Peter Vestergaard Rasmussen has served on scientific advisory boards, served as consultant, received support for congress participation or received speaker honoraria from Alexion, Biogen, Bristol Myers Squibb, Merck, Novartis, Roche, and Sanofi Genzyme. Jeppe Romme Christensen has received speaker honoraria from Biogen. Arkadiusz Weglewski served on scientific advisory boards for Merck, Roche, Sanofi. He has also received conference travel support from Biogen, Merck, Roche, Sanofi, and Novartis and speaker honoraria from Roche, Merck, and Sanofi. Sivagini Prakash received support for congress participation and honoraria from Merck, Sanofi Genzyme, Biogen, Roche. Melinda Magyari has served on scientific advisory board, as consultant, received support for congress participation or speaker honoraria from Biogen, Sanofi, Roche, Novartis, Merck, Alexion, Bristol Myers Squibb. The Danish MS Registry received research support from Biogen, Genzyme, Roche, Merck, Novartis. Matthias Kant, Nasrin Asgari, and Lena Christina Roug have nothing to disclose.

Background: Alemtuzumab is approved in the European Union for treating highly active relapsing-remitting multiple sclerosis (RRMS). Patient-reported outcomes measure the treatment impact on quality of life (QoL), including fatigue, a common symptom in multiple sclerosis (MS). Chronic diseases like MS also affect the patient's caregiver. Thus, understanding the impact on both patients and caregivers is essential for a comprehensive view of MS treatment outcomes., Methods: This multi-center prospective, observational study assessed RRMS patients undergoing alemtuzumab treatment, and their caregivers across three European countries (Denmark, Norway, and Italy). The study visits were conducted at baseline, and at Months 3, 6, 12, 18, 24, and 36 (± 1 month). The primary endpoint assessed the effect of alemtuzumab on MS-related fatigue (Fatigue Scale for Motor and Cognitive Functions [FSMC] score). Secondary endpoints included changes in cognition (Symbol Digit Modalities Test [SDMT]), depression (Beck Depression Inventory-Version II [BDI-II]), QoL (29-item Multiple Sclerosis Impact Scale [MSIS-29]), treatment satisfaction (Treatment Satisfaction Questionnaire for Medication [TSQM]), working capacity/daily life activity (Health-Related Productivity Questionnaire [HRPQ]), and clinical evaluation (number of relapses, improvement in Expanded Disability Status Scale [EDSS] score, and need for re-treatment with alemtuzumab/any other treatment). Exploratory endpoints included caregiver perception of patient's QoL, caregiver QoL, and caregiver burden. The sample size (N = 80) was determined based on the 2-sided t-test at 5 % significance level. Data were analyzed descriptively. Safety was also evaluated., Results: Of 87 enrolled patients, 72.4 % (n = 63) completed all follow-ups. Significant improvement was observed in fatigue (p < 0.01), with a median (min, max) FSMC score change of -7.3 (-56.0, 34.0) units at the end-of-study (EOS), and clinically relevant improvement (≥ 9 units) noted in approximately 12.5 months. SDMT (3-5 units, p<0.05), BDI-II (median score of 9.5, i.e., no depression, p<0.01), and MSIS-29 (median change in physical and psychological impact scores -9.2, p < 0.01 and -14.8, p < 0.001, respectively) improved significantly from baseline to EOS. Global treatment satisfaction (p < 0.001), effectiveness (p < 0.05), and side effects (p < 0.05) significant improved exept at EOS, whereas treatment convenience remained same throughout the study. The percentage of patients with at least one relapse was similar each year of the study (10.8-13.2 %). A statistically significant improvement (p < 0.05) in EDSS was reported over time. At EOS, 4.5 % patients needed retreatment with alemtuzumab. Caregivers also reported improvement in patients' QoL over time, but the median change from baseline (physical and psychological impact scores:10.0 and -14.8, respectively) was not statistically significant (p > 0.05). Caregivers reported similar QoL and caregiver burden at baseline and EOS, apart from an increase in emotional QoL. Headache (51.2 %), pyrexia (44.2 %), and rash (34.9 %) were the most common adverse events (AEs). Majority of the AEs were either mild or moderate, apart from 25 severe AEs. Three patients discontinued prematurely, of which one patient died of sepsis related to treatment., Conclusion: This real-world study showed beneficial impact of alemtuzumab on fatigue, cognition, depression, QoL, and treatment satisfaction. Improvement in patient disability, and caregiver-reported outcomes indicated enhanced patients' QoL., Competing Interests: Declaration of competing interest Jette Lautrup Frederiksen: Served on scientific advisory boards for and received funding for travel related to these activities as well as honoraria from Biogen Idec, Merck Serono, Sanofi-Aventis, Teva, Novartis, and Almirall. Received speaker honoraria from Biogen Idec, Teva, and Novartis. Luca Massacesi: Received educational grants and/or research funds from Biogen, Merck-Serono, Genzyme, and Roche and honoraria or consultation fees from Biogen, Roche, Merck-Serono, Sanofi, Viatris, Horizon, Alexion, and Novartis. Helle Hvilsted Nielsen: Received research support, travel grants, and/or teaching honoraria from Biogen Inc., Merck Serono, Novartis, Sanofi, Teva, and Roche. Augusto Rini: Received a grant for the organization of a scientific congress or speaker honoraria from Biogen Idec, Sanofi, Merck Serono, Bristol, and Roche. Eleonora Baldi: Received a grant for the organization of a scientific congress from Biogen Idec and also received travel or speaker honoraria from Biogen Idec, Sanofi, Merck Serono, Novartis, and Roche. Massimiliano Mirabella: Reported scientific advisory board membership with Bayer Schering, Biogen, Sanofi, Merck, Novartis, and Roche; received consulting and/or speaking fees and research support or travel grants from Almirall, Alexion, Bayer Schering, Bristol-Myers-Squibb, Biogen, Janssen, Sanofi, Merck, Novartis, Roche, and Viatris; reported to be a principal investigator in clinical trials conducted by Biogen, Merck, Novartis, Roche, and Sanofi. Falzone Francesca Maria Antonella: Received travel or speaker honoraria and grants to attend scientific congresses from Biogen, Sanofi, Merck Serono, and Teva. Received a grant for the organization of a scientific congress from Biogen. Giacomo Lus: Received speaker, travel, and advisory board membership honoraria from Almirall, Alexion, Bayer, Biogen, Novartis, Sanofi, Merck, Bristol-Myers-Squibb, and Horizon Therapeutics. Damiano Paolicelli: Received speaker honoraria from Novartis, Sanofi, Biogen Idec, Merck-Serono, Roche, BMS, and Almirall. Matthias Kant: Has nothing to disclose. Giuseppe Salemi: Received grants to attend scientific congresses or speaker honoraria from Biogen, Merck-Serono, Novartis, Roche, Sanofi, and Teva. Umberto Aguglia: Received grants to attend scientific congresses or speaker honoraria from Biogen, Merck-Serono, Novartis, Roche, Sanofi, and Teva. Cristoforo Comi: Received grants to attend scientific congresses or speaker honoraria from Merck-Serono, Novartis, Roche, Sanofi, and Almirall. Milena De Riz: Received grants to attend scientific congresses or speaker honoraria from Merck-Serono, Novartis, Roche, Sanofi, Biogen, Teva, Almirall, Bristol-Myers-Squibb, and Horizon Therapeutics. Valeria Barcella: Received grants to attend scientific congresses or speaker honoraria from Biogen, Merck-Serono, Novartis, Roche, Sanofi, and Teva. Heidi Ø. Flemmen: Received unrestricted research grants from Biogen and Novartis and advisory board and/or speaker honoraria from Sanofi, Merck, and Biogen. Alessandra Protti: Has nothing to disclose. Elisabeth Farbu: Received unrestricted grants from Novartis and participated in advisory boards from Biogen, Merck, Novartis, Roche, and Sanofi. Job van Exel: Received research funds from AstraZeneca, GSK, Janssen, Merck, Novartis, Pfizer, Sanofi, and Takeda. Øivind Torkildsen: Received speaker honoraria from and served on scientific advisory boards of Biogen, Sanofi-Aventis, Merck, and Novartis., (Copyright © 2024. Published by Elsevier B.V.)

Currently, there are limited therapeutic options for patients with non-active secondary progressive multiple sclerosis. Therefore, real-world studies have investigated differences between patients with relapsing-remitting multiple sclerosis, non-active secondary progressive multiple sclerosis and active secondary progressive multiple sclerosis. Here, we explore patterns and predictors of transitioning between these phenotypes. We performed a cohort study using data from The Danish Multiple Sclerosis Registry. We included patients with a relapsing-remitting phenotype, registered changes to secondary progressive multiple sclerosis and subsequent transitions between relapsing and non-relapsing secondary progressive multiple sclerosis, which was defined by the presence of relapses in the previous 2 years. We analysed predictors of transitioning from relapsing-remitting multiple sclerosis to relapsing and non-relapsing secondary progressive multiple sclerosis, as well as between the secondary progressive states using a multi-state Markov model. We included 4413 patients with relapsing-remitting multiple sclerosis. Within a median follow-up of 16.2 years, 962 were diagnosed with secondary progressive multiple sclerosis by their treating physician. Of these, we classified 729 as non-relapsing and 233 as relapsing secondary progressive multiple sclerosis. The risk of transitioning from relapsing-remitting to non-relapsing secondary progressive multiple sclerosis included older age (hazard ratio per increase of 1 year in age: 1.044, 95% confidence interval: 1.035-1.053), male sex (hazard ratio for female: 0.735, 95% confidence interval: 0.619-0.874), fewer relapses (hazard ratio per each additional relapse: 0.863, 95% confidence interval: 0.823-0.906), higher expanded disability status scale (hazard ratio per each additional point: 1.522, 95% confidence interval: 1.458-1.590) and longer time on disease-modifying therapies (hazard ratio per increase of 1 year in treatment, high-efficacy disease-modifying therapy: 1.095, 95% confidence interval: 1.051-1.141; hazard ratio, moderate-efficacy disease-modifying therapy: 1.073, 95% confidence interval: 1.051-1.095). We did not find significant predictors associated with the transition from relapsing secondary progressive multiple sclerosis to non-relapsing secondary progressive multiple sclerosis, whereas older age (hazard ratio per increase of 1 year in age: 0.956, 95% confidence interval: 0.942-0.971) prevented the transition from non-relapsing secondary progressive multiple sclerosis to relapsing secondary progressive multiple sclerosis. Our study suggests that transitioning from relapsing-remitting multiple sclerosis to non-relapsing secondary progressive multiple sclerosis depends on well-known factors affecting diagnosing secondary progressive multiple sclerosis. Further transitions between non-relapsing and relapsing secondary progressive multiple sclerosis are only affected by age. These findings add to the knowledge of non-active secondary progressive multiple sclerosis, a patient group with unmet needs in terms of therapies., Competing Interests: N.G. and S.S.G. are employees of Sanofi and may hold shares and/or stock options in the company. M.F.W.-H. has served on the scientific advisory board for Sanofi and has received honoraria for lecturing for Novartis and Sanofi. H.B.J. has served as advisory board member for Merck and Roche and has received speaker honoraria from Biogen and Novartis. Z.I. has received speakers’ honoraria and/or research grants from Biogen, Roche, Sanofi, Novartis, Merck, Alexion, Bristol Myers Squibb, Lundbeckfonden, Jascha Fonden and Scleroseforeningen, has been member of advisory boards at Alexion, Biogen, Sanofi, Merck, Roche and Novartis, has been member of adjudication relapse (clinical endpoint) committees in Phase 3 trials and has been principal investigator in studies sponsored by Biogen, Merck and Sanofi. R.M.J. has served on scientific advisory boards for Novartis and Merck and has received conference travel support from Biogen. T.S. has served in scientific advisory board for Biogen, Merck, Novartis, Roche and Sanofi and has received honoraria for lecturing from Biogen, Merck, Novartis, Roche and Sanofi. A.W. has served on scientific advisory boards for Merck, Roche and Sanofi, has received conference travel support from Biogen, Merck, Roche, Sanofi and Novartis and speaker honoraria from Roche, Merck and Sanofi. M.R.M. has received support for participation in scientific meetings from Merck and Novartis, as well as travel grants from The Danish Multiple Sclerosis Society. M.B.P. has served on scientific advisory boards for Merck and support for conference participation from Novartis and Merck. S.P. received honoraria for contributing to making a magazine and support for congress participation from Merck. M.S. has served on scientific advisory boards for, received support for congress participation or received speaker honoraria from Biogen, Merck, Novartis, Roche and Sanofi Genzyme. P.V.R. has served on scientific advisory boards for, served as consultant for, received support for congress participation or received speaker honoraria from Alexion, Biogen, Bristol Myers Squibb, Merck, Novartis, Roche and Sanofi Genzyme. K.B.S. has served as consultant for Takeda, has received travel grants from TEVA, Biogen Merck and Novartis and has been principal investigator in studies sponsored by Alexion, Roche and Sanofi. F.S. has served on scientific advisory boards for, served as consultant for, received support for congress participation or received speaker honoraria from Alexion, Biogen, Bristol Myers Squibb, Lundbeck, Merck, Novartis, Roche and Sanofi Genzyme. His laboratory has received research support from Biogen, Merck, Novartis, Roche and Sanofi Genzyme. M.M. has served on scientific advisory boards, served as a consultant, received support for congress participation or received speaker honoraria from Roche, Sanofi, Biogen, Merck, Novartis, Bristol Myers Squibb, Medscape, Alexion and Moderna. Her research group has contracts with Biogen, Merck, Novartis, Roche, Sanofi and Bristol Myers Squibb. All other authors report no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Clinicians frequently rely on relapse counts, T2 MRI lesion load (T2L) and Expanded Disability Status Scale (EDSS) scores to guide treatment decisions for individuals diagnosed with multiple sclerosis (MS). This study evaluates how these factors, along with age and sex, influence prognosis during treatment with teriflunomide (TFL)., Methods: We conducted a nationwide cohort study using data from the Danish Multiple Sclerosis Registry.Eligible participants had relapsing-remitting MS or clinically isolated syndrome and initiated TFL as their first treatment between 2013 and 2019. The effect of age, pretreatment relapses, T2L and EDSS scores on the risk of disease activity on TFL were stratified by sex., Results: In total, 784 individuals were included (57.4% females). A high number of pretreatment relapses (≥2) was associated with an increased risk of disease activity in females only (OR and (95% CI): 1.76 (1.11 to 2.81)). Age group 50+ was associated with a lower risk of disease activity in both sexes (OR females=0.28 (0.14 to 0.56); OR males=0.22 (0.09 to 0.55)), while age 35-49 showed a different impact in males and females (OR females=0.79 (0.50 to 1.23); OR males=0.42 (0.24 to 0.72)). EDSS scores and T2L did not show any consistent associations., Conclusion: A high number of pretreatment relapses was only associated with an increased risk of disease activity in females, while age had a differential impact on the risk of disease activity according to sex. Clinicians may consider age, sex and relapses when deciding on TFL treatment., Competing Interests: Competing interests: MRM has received support from Merck for participation in a scientific meeting. MM has served on scientific advisory boards, served as a consultant, received support for congress participation, or received speaker honoraria from Roche, Sanofi, Biogen, Merck, Novartis, Bristol Myers Squibb, Medscape, Alexion, and Moderna. Her research group has contracts with Biogen, Merck, Novartis, Roche, Sanofi, and Bristol Myers Squibb. FE has received speaker honoraria from Roche and Sanofi. RPH has received speaker honoraria from Sanofi and Novartis, has served on an advisory board for Novartis, and has received a travel grant from The Danish Multiple Sclerosis Society. AW has served on advisory boards for Merck, Sanofi, Roche, and Biogen. He has also received honoraria for lecturing and manuscript writing from Sanofi, Merck, and Roche and has received financial support for congress participation from Biogen, Sanofi, Novartis, Merck and Roche. MBP reports support for congress participation from Novartis and Merck. ZI has received speaker honoraria, been a member of an advisory board, and received support for congress participation from Sanofi. TS has received travel grants from Sanofi and Merck, research grants from Biogen, Merck and Roche, served on advisory boards for Biogen, Merck, Novartis and Sanofi, and received honoraria for lecturing from Biogen, Merck, Novartis and Sanofi. MLS has received support for congress participation from Biogen, Merck, and Roche and has participated on advisory boards for Sanofi and Roche. PVR has served on scientific advisory boards, received support for congress participation or received speaker honoraria from Biogen, Merck, Novartis, Roche and Sanofi. FS has served on scientific advisory boards, served as a consultant, received support for congress participation or received speaker honoraria from Biogen, Bristol Myers Squibb, H. Lundbeck A/S, Merck, Novartis, Roche and Sanofi. His laboratory has received research support from Biogen, Merck, Novartis, Roche and Sanofi. In addition, FS is section editor of the journal Multiple Sclerosis and Related Disorders, chairman of the research board for the Danish Multiple Sclerosis Society, and member of the scientific steering committee for the International Progressive MS Alliance., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Skin conditions form a major bulk of diseases in the community. With a disproportionately low number of dermatologists in the country, and a greatly unequal distribution between urban versus rural areas, ineffective treatment and mismanagement of skin conditions are, however, commonplace., Objective: To develop standard treatment workflows (STWs) for certain skin diseases for use by clinicians at primary, secondary, and tertiary care centers., Methodology: Seven members, from various academic institutes across the country, were selected for formulation of the STWs. They were provided logistic and technical support by the ICMR, Department of Health Research (DHR), and WHO India office. Multiple rounds of online and physical discussions were performed to identify topics that would be most useful in the management of skin diseases for the health care personnel (HCP) and subsequently to frame the STW content., Results: The selected diseases included acne and rosacea, alopecia, bacterial skin infections, cutaneous adverse drug reactions, dermatophytosis, eczema/dermatitis, immunobullous dermatoses, psoriasis, scabies, varicella and herpes, vitiligo, and urticaria. There was one separate module on rational use of topical corticosteroids. The STWs for these conditions have been finalised and are available as physical posters in health centers and can also be accessed online and through mobile applications., Conclusion: Thirteen STW modules have been prepared with a view to optimize management of skin diseases at various levels of health care system of the country., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Indian Dermatology Online Journal.)

Background: An adequate diagnosis for interstitial lung disease (ILD) is important for clinical decision making and prognosis. In most patients with ILD, an accurate diagnosis can be made by clinical and radiological data assessment, but in a considerable proportion of patients, a lung biopsy is required. Surgical lung biopsy (SLB) is the most common method to obtain tissue, but it is associated with high morbidity and even mortality. More recently, transbronchial cryobiopsy has been introduced, with fewer adverse events but a lower diagnostic yield than SLB. The aim of this study is to compare two diagnostic strategies: a step-up strategy (transbronchial cryobiopsy, followed by SLB if the cryobiopsy is insufficiently informative) versus immediate SLB., Methods: The COLD study was a multicentre, randomised controlled trial in six hospitals across the Netherlands. We included patients with ILD with an indication for lung biopsy as assessed by a multidisciplinary team discussion. Patients were randomly assigned in a 1:1 ratio to the step-up or immediate SLB strategy, with follow-up for 12 weeks from the initial procedure. Patients, clinicians, and pathologists were not masked to the study treatment. The primary endpoint was unexpected chest tube drainage, defined as requiring any chest tube after transbronchial cryobiopsy, or prolonged (>24 h) chest tube drainage after SLB. Secondary endpoints were diagnostic yield, in-hospital stay, pain, and serious adverse events. A modified intention-to-treat analysis was performed. This trial is registered with the Dutch Trial Register, NL7634, and is now closed., Findings: Between April 8, 2019, and Oct 24, 2021, 122 patients with ILD were assessed for study participation; and 55 patients were randomly assigned to the step-up strategy (n=28) or immediate SLB (n=27); three patients from the immediate SLB group were excluded. Unexpected chest tube drainage occurred in three of 28 patients (11%; 95% CI 4-27%) in the step-up group, and the number of patients for whom the chest tube could not be removed within 24 h was 11 of 24 patients (46%; 95% CI 2-65%) in the SLB group, with an absolute risk reduction of 35% (11-56%; p=0·0058). In the step-up strategy, the multidisciplinary team diagnostic yield after transbronchial cryobiopsy alone was 82% (64-92%), which increased to 89% (73-96%) when subsequent SLB was performed after inconclusive transbronchial cryobiopsy. In the immediate surgery strategy, the multidisciplinary team diagnostic yield was 88% (69-97%). Total in-hospital stay was 1 day (IQR 1-1) in the step-up group versus 5 days (IQR 4-6) in the SLB group. One (4%) serious adverse event occurred in step-up strategy versus 12 (50%) in the immediate SLB strategy., Interpretation: In ILD diagnosis, if lung tissue assessment is required, a diagnostic strategy starting with transbronchial cryobiopsy, followed by SLB when transbronchial cryobiopsy is inconclusive, appears to result in a significant reduction of patient burden and in-hospital stay with a similar diagnostic yield versus immediate SLB., Funding: Netherlands Organisation for Health Research and Development (ZonMW) and Amsterdam University Medical Centers., Competing Interests: Declaration of interests All authors declare no competing interests. The workshop in Tübingen to assure harmonisation of the transbronchial cryobiopsy procedure was, in part, sponsored by Erbe Elektromedizin, Tübingen, Germany., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

The base excision repair (BER) pathway is a precise and versatile mechanism of DNA repair that is initiated by DNA glycosylases. Endonuclease VIII-like 1 (NEIL1) is a bifunctional glycosylase/abasic site (AP) lyase that excises a damaged base and subsequently cleaves the phosphodiester backbone. NEIL1 is able to recognize and hydrolyze a broad range of oxidatively-induced base lesions and substituted ring-fragmented guanines, including aflatoxin-induced 8,9-dihydro-8-(2,6-diamino-4-oxo-3,4-dihydropyrimid-5-yl-formamido)-9-hydroxyaflatoxin B 1 (AFB 1 -FapyGua). Due to NEIL1's protective role against these and other pro-mutagenic lesions, it was hypothesized that naturally occurring single nucleotide polymorphic (SNP) variants of NEIL1 could increase human risk for aflatoxin-induced hepatocellular carcinoma (HCC). Given that populations in South Asia experience high levels of dietary aflatoxin exposures and hepatitis B viral infections that induce oxidative stress, investigations on SNP variants of NEIL1 that occur in this region may have clinical implications. In this study, the most common South Asian variants of NEIL1 were expressed, purified, and functionally characterized. All tested variants exhibited activities and substrate specificities similar to wild type (wt)-NEIL1 on high-molecular weight DNA containing an array of oxidatively-induced base lesions. On short oligodeoxynucleotides (17-mers) containing either a site-specific apurinic/apyrimidinic (AP) site, thymine glycol (ThyGly), or AFB 1 -FapyGua, P206L-NEIL1 was catalytically comparable to wt-NEIL1, while the activities of NEIL1 variants Q67K and T278I on these substrates were ≈2-fold reduced. Variant T103A had a greatly diminished ability to bind to 17-mer DNAs, limiting the subsequent glycosylase and lyase reactions. Consistent with this observation, the rate of excision by T103A on 17-mer oligodeoxynucleotides containing ThyGly or AFB 1 -FapyGua could not be measured. However, the ability of T103A to excise ThyGly was improved on longer oligodeoxynucleotides (51-mers), with ≈7-fold reduced activity compared to wt-NEIL1. Our studies suggest that NEIL1 variant T103A may present a pathogenic phenotype that is limited in damage recognition, potentially increasing human risk for HCC., 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. Certain equipment, instruments, software, or materials are identified in this paper in order to specify the experimental procedure adequately. Such identification is not intended to imply recommendation or endorsement of any product or service by NIST, nor is it intended to imply that the materials or equipment identified are necessarily the best available for the purpose., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: The likelihood of return of spontaneous circulation with conventional advanced life support is known to have an exponential decline and therefore neurological outcome after 20 min in patients with a cardiac arrest is poor. Initiation of venoarterial ExtraCorporeal Membrane Oxygenation (ECMO) during resuscitation might improve outcomes if used in time and in a selected patient category. However, previous studies have failed to significantly reduce the time from cardiac arrest to ECMO flow to less than 60 min. We hypothesize that the initiation of Extracorporeal Cardiopulmonary Resuscitation (ECPR) by a Helicopter Emergency Medical Services System (HEMS) will reduce the low flow time and improve outcomes in refractory Out of Hospital Cardiac Arrest (OHCA) patients., Methods: The ON-SCENE study will use a non-randomised stepped wedge design to implement ECPR in patients with witnessed OHCA between the ages of 18-50 years old, with an initial presentation of shockable rhythm or pulseless electrical activity with a high suspicion of pulmonary embolism, lasting more than 20, but less than 45 min. Patients will be treated by the ambulance crew and HEMS with prehospital ECPR capabilities and will be compared with treatment by ambulance crew and HEMS without prehospital ECPR capabilities. The primary outcome measure will be survival at hospital discharge. The secondary outcome measure will be good neurological outcome defined as a cerebral performance categories scale score of 1 or 2 at 6 and 12 months., Discussion: The ON-SCENE study focuses on initiating ECPR at the scene of OHCA using HEMS. The current in-hospital ECPR for OHCA obstacles encompassing low survival rates in refractory arrests, extended low-flow durations during transportation, and the critical time sensitivity of initiating ECPR, which could potentially be addressed through the implementation of the HEMS system. When successful, implementing on-scene ECPR could significantly enhance survival rates and minimize neurological impairment., Trial Registration: Clinicaltyrials.gov under NCT04620070, registration date 3 November 2020., (© 2024. The Author(s).)