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Multisociety multispecialty position statement on corticosteroid injections and influenza and COVID-19 vaccine administration
Benzon, Honorio T, FitzGerald, John, Flaherty, John P., Cohen, Steven Paul, Doshi, Tina L , Mina, Maged, Abd-Elsayed, Alaa, Eckmann, Maxim , Elmofty, Dalia , Hirsch, Joshua Adam, Hoang, Thanh Tuan , Manchikanti, Laxmaiah, Pino, Carlos, Rana, Maunak V., Rivera, Jessica , Shah, Shalini, Schneider, Byron J. , Souza, Dmitri , Stout, Alison, Maus, Tim, Cohen, Steven P. , Benzon, Honorio T. , FitzGerald, John , Benzon, Honorio T , Cohen, Steven P , Chadwick, Andrea , Hunt, Christine , Nagpal, Ameet S , Nelson, Ariana M , Pino, Carlos A , Provenzano, David Anthony , Shankar, Hariharan , Wasan, Ajay D , Narouze, Samer , Doshi, Tina L , FitzGerald, John D , FitzGerald, John, Abdi, Salahadin , Abd-Elsayed, Alaa A , Manchikanti, Laxmaiah , Nagpal, Ameet , Nelson, Ariana M. , Pino, Carlos A. , Provenzano, David , Rivera, Jessica, Shankar, Hariharan , Shanthanna, Harsha , Wasan, Ajay D. , Narouze, Samer , Maus, Timothy P.

Regional Anesthesia & Pain Medicine | February 27, 2026 | Volume: No volume available | Issue: No issue available | Pages: rapm-2025-107556

10.1136/rapm-2025-107556 | PMID 41760373 Get It

Background Corticosteroid injections (CSIs) are widely employed for chronic pain. These injections include peripheral nerve blocks and trigger point injections, injections of large appendicular joints, the axial facet and sacroiliac joints, and the epidural space. These injections may be performed in patients who have been recently vaccinated or plan to be vaccinated. This multisociety multispecialty position statement aims to develop evidence-based statements and recommendations (SRs) on the safe interval between CSIs and COVID-19 and influenza vaccine administration. Methods Development of the position statement was approved by the American Society of Regional Anesthesia and Pain Medicine Board of Directors and several other societies that agreed to participate. The scope of the SRs was agreed on to include the efficacy of COVID-19 and influenza vaccines, adverse events related to the CSIs, specifically the effect of CSIs on the hypothalamic–pituitary axis, incidence of COVID-19 in patients who had CSIs during the pandemic, incidence of influenza in patients who had CSIs during the influenza season, and recommend a reasonable interval between CSIs and COVID-19 and influenza vaccination 20 mg/day of prednisone s. Experts were assigned topics to perform a comprehensive literature review and draft SRs, which were refined and voted for consensus (≥75% agreement) using a modified Delphi process. A modified version of the US Preventive Services Task Force grading of evidence and strength of recommendation was followed. Results All SRs were approved by all participants after four rounds of discussion. The Practice Guidelines Committees and Boards of Directors of the participating societies also approved all SRs. If a vaccine has been recently administered or planned, then for non-urgent indications, the CSI should be offered at least 1 week before or after vaccine administration. For healthy patient(s), CSI, or vaccine administration may be performed without a 7-day interval after informed discussion with the patient and consent regarding the risk of blunted vaccine efficacy. For non-healthy patients, shared decision-making should include discussion of diminished vaccine effectiveness and the possibility of influenza or COVID-19 infection. Conclusions In this position statement, we provide recommendations on the optimal timing between CSIs and COVID-19 or influenza vaccine.
Feasibility of decentralized real-world monitoring of SARS-CoV-2 booster vaccines and COVID-19 outcomes in myeloma
Wood, William A, Kumar, Shaji K, Semmel, Emily, James, Shandra, Chung, David J., Rosenberg, Aaron S., Zonder, Jeffrey A. , Rubinstein, Samuel M., D'Souza, A, Martin, Thomas, Chari, Ajai, Vij, Ravi, Nooka, Ajay K., Anderson, Kenneth C., NEUBERG, D, Torres, Kathleen, Weiss, Brendan M. , Pederson, Levi , Geyer, Susan, Usmani, Saad Z., Wood, William A. , D’Souza, Anita , Rosenberg, Aaron S. , Wood, William A , Kumar, Shaji K , Chung, David J , Rosenberg, Aaron , D'Souza, Anita , Pederson, Levi D , Derkach, Andriy , Kumar, Shaji , Semmel, Emily A., Schroeder, Mark A. , Rubinstein, Samuel M. , Martin, Thomas, Nooka, Ajay K. , Anderson, Kenneth C., Neuberg, Donna , Richard, Shambavi , Torres, Kathleen, Derkach, Andriy , Usmani, Saad Z.

Blood Advances | February 24, 2026 | Volume: 10 | Issue: 9 | Pages: 3094-3102

10.1182/bloodadvances.2025018963 | PMID 41734388 Get It

Abstract Patients with multiple myeloma have an elevated risk of severe complications from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; COVID-19) infection. To demonstrate proof of concept for a pandemic preparedness and response network, the American Society of Hematology Research Collaborative Multiple Myeloma Program developed a prospective, decentralized study within a site-based provider network. In the COVID-19 outcomes in myeloma and the impact of vaccines (COSMIC) study, patients provided consent, permitted electronic health record data collection, completed patient-reported outcomes at baseline, day 30, and day 180 through an electronic study portal, and were compensated for participation. Clinicians at participating sites facilitated study recruitment and shared best practices monthly to accelerate study execution. The COSMIC study rapidly consented 201 patients from 8 participating sites over 4 months (22 January 2024 through 17 May 2024). Consented participants were 30 to 93 years old, with a median age of 67; 46% were female, 69% were non-Hispanic White, 17% were non-Hispanic Black, and 8% were Hispanic/Latino. Patient-reported data completion was 97% at baseline, 81% at 1 month, and 79% at 6 months. At baseline, 55% of patients reported a history of COVID-19 infection and had received a median of 4 SARS-CoV-2 vaccines. For all patients, there were an additional 18 COVID-19 infections and 57 vaccines received during the 6-month observation period. There were no significant differences in health-related quality of life over time or by history of COVID-19 infection. COSMIC demonstrates the feasibility of an innovative evidence generation strategy to drive rapid accrual of patients to address an evolving area of need. This trial was registered at www.clinicaltrials.gov as #NCT05831787.
Abstract PS3-07-23: Survivor plots for quantitated adjunctive statistically standardized ER, PgR, and HER2 in adjuvant postmenopausal breast cancer: Canadian Cancer Trials Group MA.27 trial of exemestane versus anastrozole
Chapman, J. W., Bayani, Jane , SenGupta, S., Bartlett, J. M. S., Piper, T., Quintayo, M. A., Virk, Shakeel , Goss, P. E., Ingle, J. N., Ellis, M. J., Sledge, G. W., Budd, G. T., Ansari, R. H., Tozer, Richard , D'Souza, D. P., Chalchal, H., Spadafora, S., Stearns, V., Perez, E. A., Gelmon, K. A., Whelan, T. J., Elliott, C., Shepherd, L. E., Chen, B. E., Taylor, K. J., Whelan, Timothy J. , Bartlett, J. M. S., Quintayo, Mary Anne , Ingle, J. N., Budd, G.T., Rabaglio, Manuela , D’Souza, David , Chalchal, H., Stearns, Vered , Shepherd, Lois E. , Chen, B. E., Taylor, K. J.

Clinical Cancer Research | February 20, 2026 | Volume: 32 | Issue: 4_Supplement | Pages: PS3-07-23-PS3-07-23

10.1158/1557-3265.sabcs25-ps3-07-23 Get It

Abstract Background: Survivor plots permit adjustment by baseline demographics and clinical characteristics; log-normal survival analysis may be more robust than a Cox model under departures from model assumptions. We depicted distant disease-free survival (DDFS) for statistically standardized quantitated ER, PgR, and HER2. Methods: We utilized CCTG MA.27 (NCT00066573), an adjuvant phase III trial of exemestane versus anastrozole in postmenopausal women with ER+ and/or PgR+ tumours. IHC ER, PgR, and HER2 HSCORE were centrally assessed by machine image quantitation, and statistically standardized to mean of 0, standard deviation (SD) of 1 following Box-Cox variance stabilization transformations of square for ER, natural logarithm (ln) and square root for PgR, and ln for HER2. For the ln transformation, 0.1 was added to 0 HSCOREs for a stable transformation. The primary endpoint was DDFS at the longest trial follow-up of 4.1 years. For log-normal survival analysis, ln(time) is a linear function of covariates and had a normal distribution; the Cox models were log-linear for covariates. Survival was depicted with log-normal and Cox survivor plots adjusted at the means of age, T and N stage, grade, lymphovascular invasion, treatment, and baseline patient demographics. We examined ER and PgR ASCO/CAP cut-points at (0; >0), HER2 cut-points at (IHC 0, 0 stain; IHC 0, (0,10%] stain; IHC 1+; IHC 2+; IHC 3+), and ER/PgR/HER2 standardized cut-points at standard deviations about mean of 0 (<-1; (-1,0]; (0,1]; >1). P was based on the likelihood ratio criterion (∼Χ2 (1)) for the addition of ER/PgR/HER2 to the model of baseline covariates, and had nominal significance if P<0.05. Log-normal and Cox multivariable regressions with unstandardized and standardized categorical, and continuous, ER, PgR, and HER2 were adjusted by baseline covariates; 2-sided Wald tests had nominal significance if P<0.05. Results: Of 7576 MA.27 patients, 2325 patients had quantitated image analysis assessments for ER, PgR, and HER2; 113 of 2325 (4.9%) patients experienced a DDFS event during follow-up. Multivariable log-normal survival analysis indicated DDFS was significantly longer for patients with T1 (p=0.01), N0 (p=.002), and grade 1/2 tumors (p=0.01); similar significance levels were found with a Cox model. Log-normal survivor plots were smooth, while Cox survivor plots were step-wise discontinuous at events. Adjusted log-normal survivor plots indicated similar 5-year DDFS for patients by standardized ER categories (p=0.43): 95.4% for those with ER <-1.0 (n=401); 95.8%, for (-1.0,0.0] (n=737); 96.1%, for (0.0,1.0] (n=737); and 96.4%, for >1.0 (n=450). The log-normal standardized PgR survivor plots indicated patients had significantly different 5-year DDFS (p<.001) by categories, with both ln and square root transformations of HSCORE: with a ln transformation, 93.7% for <-1.0 (n=607); 95.4%, for (-1.0,0.0] (n=390); 96.8%, for (0.0,1.0] (n=826); and 97.8%, for >1.0 (n=502). Patients had similar 5-year DDFS by standardized HER2 categories (p=0.71): 96.2% for <-1.0 (n=83); 96.0%, for (-1.0,0.0] (n=1201); 95.9%, for (0.0,1.0] (n=527); and 95.7%, for >1.0 (n=514). In full fit multivariable log-normal survival analyses, DDFS was not significantly different for ER (p=0.51-0.89) and HER2 (p=0.12-0.98); higher PgR was associated with significantly better DDFS (p=0.01 to <.001). Adjusted Cox survival analyses had similar results. Conclusions: Survivor plots adjusted for baseline demographic and clinical characteristics provided similar indications of significance for standardized ER, PgR, and HER2 as those seen in multivariable models with both log-normal and Cox survival analyses. Higher PgR was associated with significantly better DDFS. Citation Format: J. W. Chapman, J. Bayani, S. SenGupta, J. M. S. Bartlett, T. Piper, M. A. Quintayo, S. Virk, P. E. Goss, J. N. Ingle, M. J. Ellis, G. W. Sledge, G. T. Budd, M. Rabaglio, R. H. Ansari, R. Tozer, D. P. D'Souza, H. Chalchal, S. Spadafora, V. Stearns, E. A. Perez, K. A. Gelmon, T. J. Whelan, C. Elliott, L. E. Shepherd, B. E. Chen, K. J. Taylor. Survivor plots for quantitated adjunctive statistically standardized ER, PgR, and HER2 in adjuvant postmenopausal breast cancer: Canadian Cancer Trials Group MA.27 trial of exemestane versus anastrozole [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-07-23.
Patient-Controlled Analgesia
D’Souza, Ryan, Hao, David, Hao, David , D'Souza, Ryan, Cho, James , D'Souza, Ryan S

New England Journal of Medicine | February 18, 2026 | Volume: 394 | Issue: 8 | Pages: No page available

10.1056/nejmvcm2500240 | PMID 41707140 Get It

Multisociety multispecialty consensus recommendations on corticosteroid injections for facet joint and sacroiliac joint pain
Benzon, Honorio T , Doshi, Tina L , Maus, Tim, FitzGerald, John, Hoang, Thanh D., Shankar, Hariharan , Mina, Maged, Eckmann, Maxim , Elmofty, Dalia , Nelson, Ariana M, Pino, Carlos, Rana, Maunak V., Rivera, Jessica, Schneider, Byron J. , Souza, Dmitri , Stout, Alison, Wasan, Ajay, Provenzano, David Anthony, Benzon, Honorio T. , FitzGerald, John , Chadwick, Andrea , Hunt, Christine , Nagpal, Ameet S , Nelson, Ariana M , Pino, Carlos A , Narouze, Samer , Provenzano, David Anthony , Cohen, Steven P , Doshi, Tina L , FitzGerald, John D , Shankar, Hariharan , Maus, Timothy P. , Nagpal, Ameet , Nelson, Ariana M. , Pino, Carlos A. , Shanthanna, Harsha , Narouze, Samer , Wasan, Ajay D. , Provenzano, David , Cohen, Steven P.

Regional Anesthesia & Pain Medicine | February 17, 2026 | Volume: No volume available | Issue: No issue available | Pages: rapm-2025-107347

10.1136/rapm-2025-107347 | PMID 41571428 Get It

Background Corticosteroid injections (CSIs) are widely employed in facet and sacroiliac joint pain. Similar to CSIs at other sites (peripheral nerve blocks, joints, epidural), these injections are associated with potential adverse events. These multisociety consensus recommendations aim to develop evidence-based statements and recommendations on the safe use of CSIs in facet joint and sacroiliac joint injections. Methods Development of the consensus recommendations was approved by the American Society of Regional Anesthesia and Pain Medicine Board of Directors and several other societies that agreed to participate. The scope of statements and recommendations was agreed on to include safety of the injection technique (landmark-guided, ultrasound, or radiology-aided injections); effect of the addition of the corticosteroid on effectiveness (vs local anesthetic or saline); and adverse events related to the injection. Experts were assigned topics to perform a comprehensive literature review and draft statements and recommendations, which were refined and voted for consensus (>75% agreement) using a modified Delphi process. A modified version of the US Preventive Services Task Force grading of evidence and strength of recommendation was followed. Results All statements and recommendations were approved by all participants after four rounds of discussion. The Practice Guidelines Committees and Boards of Directors of the participating societies also approved all statements and recommendations. Injection of corticosteroid into the facet joint in patients with joint inflammation may relieve pain and improves function. Intra-articular, extra-articular (periarticular), and combined administration are effective for sacroiliac joint injections. No dose-response studies exist, but CSIs containing 10 mg of methylprednisolone or triamcinolone per facet joint and 40 mg per sacroiliac joint (SIJ) (or their respective pharmacologic equivalents) are reasonable. Conclusions In this practice recommendation, we provide statements and recommendations on facet and sacroiliac joint CSIs, the optimal doses, and intervals and criteria for repeating the CSIs in patients with facet joint and sacroiliac joint pain.
Effectiveness of an Educational Intervention With Home Visits and Telephone Follow‐Up on Knowledge and Quality of Life in Patients With Heart Failure: A Randomized Clinical Trial
Marques, Cleidinaldo Ribeiro de Góes , Santos, Eduesley Santana , Silva, Luciane Souza da , Guimarães, Eryck Araujo de Castro, Santos, Tarcisio Gois dos, Sales, Vinícius Barbosa dos Santos , Silva, Wanessa Alves , Sousa, Antônio Carlos Sobral , de Goes Marques, Cleidinaldo Ribeiro , Dos Santos, Tarcisio Gois, Dos Santos Sales, Vinícius Barbosa , Guimarães, Eryck Araujo, Sousa, Antônio Carlos Sobral

Nursing & Health Sciences | February 17, 2026 | Volume: 28 | Issue: 1 | Pages: No page available

10.1111/nhs.70309 | PMID 41699990 Get It

ABSTRACT Cardiovascular diseases, particularly heart failure (HF), are leading causes of morbidity and mortality worldwide. Limited patient knowledge about HF is associated with poor treatment adherence and worse health outcomes, emphasizing the importance of educational interventions. This randomized clinical trial evaluated the effectiveness of a nurse‐led educational intervention combining home visits and telephone follow‐up on patients' knowledge and quality of life (QoL). Conducted in six Brazilian hospitals, the study included 120 patients hospitalized with decompensated HF and randomly assigned to a control group (CG) or an intervention group (IG). The IG received structured education at discharge, followed by home visits on days 7, 30, and 60 and telephone follow‐up on days 15 and 45, while the CG received usual care. Outcomes were assessed at 60 days. At this time point, adequate HF knowledge was observed in 82% of patients in the IG compared with 38% in the CG, and good QoL in 73% versus 33%, respectively ( p < 0.001). The intervention was effective in improving knowledge and QoL in patients with HF.
Autologous conditioned plasma is not platelet-rich plasma
Buchheit, Thomas Edward , Eshraghi, Yashar , Eldrige, Jason S. , Hunt, Christine , Souza, Dmitri , Buchheit, Thomas , Hunt, Christine

Regional Anesthesia & Pain Medicine | February 11, 2026 | Volume: No volume available | Issue: No issue available | Pages: rapm-2026-107629

10.1136/rapm-2026-107629 | PMID 41672585 Get It

Categorizing Trends in Anesthesiology Residency Applicants’ Research Portfolios and Impact on Matching: A Program-Level Study
Holloway, Jordan , Kossbiel, Briana J. , Yu, Yue , Palettas, Marilly , Stahl, David, Baumann, Amy, Essandoh, Michael, D’Souza, Ryan, Hussain, Nasir, Stahl, David L. , Baumann, Amy, Essandoh, Michael , D'Souza, Ryan S , Hussain, Nasir

Anesthesia & Analgesia | February 9, 2026 | Volume: 143 | Issue: 3 | Pages: 636-647

10.1213/ane.0000000000007977 | PMID 41662701 Get It

BACKGROUND: Recent years have seen considerable growth and significant changes in the anesthesiology residency application process. Although the National Residency Match Program provides data on attributes of successfully matching applicants, it does not provide detailed characteristics of applicants’ research portfolio. This single-program retrospective analysis aims to characterize granular aspects of applicant research experiences to determine whether research involvement is linked to higher odds of matching. METHODS: Applications from interviewed United States allopathic (US-MD) and osteopathic (US-DO) applicants at a single anesthesiology residency program were analyzed for research experience. The primary outcome assessed was the association of any research experience with odds of ranked-to-match and the association of specific types of research experience with ranked-to-match. Secondary outcomes included the association of medical degree type (US-MD vs US-DO) or affiliation of medical school with an anesthesiology residency program to the number of research experiences, and the association of research experiences with the United States Medical Licensing Examination (USMLE) Step 1 score type (Pass/Fail vs Scored). RESULTS: Applicants with at least one research experience were more likely to be ranked-to-match than applicants without research experience (odds ratio [OR]: 2.16, 95% confidence interval [CI], [1.55–3.02], P < .001). Similar odds were demonstrated for applicants with at least one peer-reviewed publication compared to no peer-reviewed publications (OR: 2.25, 95% CI, [1.79–2.82], P < .001), and at least one anesthesiology-related research experience compared to no anesthesiology-related research experience (OR: 1.76, 95% CI, [1.36–2.26], P < .001. Applicants from US-MD schools were more likely to have research experience than those from US-DO schools ( P < .001); applicants from a medical school affiliated with an anesthesiology residency were more likely to have research experience than applicants from unaffiliated medical schools ( P < .001); and applicants with Pass/Fail USMLE Step 1 examinations were more likely than their Scored counterparts to report at least one research experience ( P < .001). CONCLUSIONS: Applicant research is associated with greater odds of being ranked-to-match in anesthesiology residency. Applicants from US-MD schools and schools affiliated with anesthesiology residency programs have significantly greater rates of reporting at least one research experience. There is a trend toward a higher incidence of reporting at least one research experience with the change of USMLE Step 1 policy toward a Pass/Fail examination.
Clinical Features and Dental Pathologies in Maxillary Sinus Fungal Balls and Odontogenic Sinusitis
Im, E., Donaldson, Lane , Adappa, Nithin D, Chen, Y. P., Chapurin, Nikita , Espinosa, Maria, Fu, Chia‐Hsiang , Fox, Meha G, Garg, Rohit, Kohanski, Michael A. , Li, Kevin L. , Liu, Duxuan , Locke, Tran Bao, Lin, Chih‐Feng, Ottavi, Alice, Papagiannopoulos, Peter , Je, Palmer, Tong, C., Tajudeen, Bobby A. , Venkatesh, Sanjena , Wei, Kimberly , Yoo, Frederick , Yu, Alison J. , Jin, Jun, Saibene, Alberto Maria , Craig, John, Im, Eunice , Douglas, Jennifer E , Eide, Jacob, Espinosa, Maria , Fox, Meha G , Locke, Tran Bao , Makary, Chadi , Venkatesh, Sanjena , Saibene, Alberto M , Adelman, Avraham E. , Adappa, Nithin D. , D’Souza, Glen , Eide, Jacob G. , Fox, Meha G. , Garg, Rohit , Kuan, Edward C , Kwiatkowska, Marta Aleksandra , Liu, Derek H., Locke, Tran B. , Jin, Jun

The Laryngoscope | February 8, 2026 | Volume: 136 | Issue: 7 | Pages: 2913-2924

10.1002/lary.70429 | PMID 41654324 Get It

ABSTRACT Objectives While maxillary sinus fungal balls (MSFB) can be associated with odontogenic conditions (MSFBO), MSFBO clinical and dental features have not been compared to odontogenic sinusitis (ODS). This multicenter study aimed to compare characteristics of MSFB, MSFBO, and ODS. Methods A multicenter international retrospective cohort study was conducted on adults with MSFBs and ODS who underwent sinus surgery. First in MSFBs, it was determined whether different dental conditions were more likely in FB versus non‐FB sides. Second, clinical features and dental pathologies were compared between MSFBO and ODS. For analyses, dental conditions were considered individually and as two groups: infectious pathologies and dental/oral procedures with indwelling metallic materials. Results After exclusions, there were 203 MSFBs and 163 ODS. Among MSFBs, 141 were MSFBOs. FB sides were associated with sinus protrusion of root canal treatment (RCT) materials ( p = 0.040) and dental implants ( p = 0.040). Compared to MSFBO, ODS patients were younger, more likely to have MS purulence (OR = 40.9, p < 0.010), more likely associated with apical periodontitis (OR = 2.59, p = 0.010) and oroantral fistulas (OR = 6.94, p = 0.020), and less likely associated with extruded RCT materials (OR = 0.01, p = 0.010) and protruded midface screws (OR < 0.01, p = 0.010). Comparing purulent MSFBO and ODS, ODS was more associated with infectious dental pathologies ( p < 0.009). Conclusion Compared to MSFBs, MSFBOs were associated with RCT extrusion and implant protrusion. Compared to MSFBOs, ODS was more likely purulent and associated with infectious dental pathologies. While ODS is often distinct from MSFBO, the two conditions can coexist, and surgeons must determine whether patients have infectious dental pathology requiring treatment with both conditions. Level of Evidence 4.
Blocking RAN translation without altering repeat RNAs rescues C9ORF72 -related ALS and FTD phenotypes
Jiang, Xin , Schaeffer, Laure, Patni, Divya, Russo, Tommaso , Lee, Chao-Zong, Aguilar, Corey, Marques, Christine , Jansen-West, Karen, Hruška-Plocháň, Marián , Ray-Soni, Ananya, Lim, Su Min , Held, Aaron , Yue, Mei, Otero, Paula Castellanos, Aryal, Sandeep , Beaussant, Hortense D. A. M. , Basu, Himanish , Takakuwa, Hiro , Daughrity, Lillian M. , Ramesh, Nandini , Costa, Paulo J. da, Quadros, Ana Rita A. A., Nolan, Matthew , Reyes, Charles Jourdan , Wheeler, Hayden J., Moran, Laura C. , Griesman, Grant , Wymann, Benjamin , Trombetta, Bianca A. , Lopez-De-Silanes, Emma Sofia , Canori, Michael, Silva, Yasmim Vieira Souza Da, Eriani, Gilbert , Albers, Mark W. , Arnold, Steven E. , Song, Yuyu , Jain, Ankur, Chiu, I., Zhang, Yong-Jie, Gao, Fen‐Biao , Wainger, Brian J. , Polymenidou, Magdalini , Petrucelli, Leonard, Martin, Franck , Lagier-Tourenne, Clotilde, Lagier‐Tourenne, Clotilde , Jansen-West, Karen R , Castellanos Otero, Paula, Da Costa, Paulo , A A Quadros, Ana Rita , Eriani, Gilbert , Albers, Mark W , Arnold, Steven E , Song, Yuyu , Chiu, Isaac M , Zhang, Yong-Jie , Gao, Fen-Biao , Wainger, Brian J , Polymenidou, Magdalini , Petrucelli, Leonard , Martin, Franck , Lagier-Tourenne, Clotilde , Lee, Chao-Zong , Jansen‐West, Karen , Ray-Soni, Ananya, Krishnan, Gopinath , Jain, Ankur , Petrucelli, Leonard

Science | February 5, 2026 | Volume: 391 | Issue: 6785 | Pages: No page available

10.1126/science.adv2600 | PMID 41643021 Get It

GGGGCC (G 4 C 2 ) repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Toxicity is thought to result from the accumulation of either repeat RNAs and/or dipeptide repeat proteins (DPRs) translated from repeat-containing transcripts through repeat-associated non-AUG (RAN) translation. To disentangle RNA from DPR toxicity, we mutated a CUG codon predominantly used to initiate DPR translation from all three reading frames. This mutation disrupted DPR synthesis while preserving the expression of repeat-containing RNAs. Despite the accumulation of RNA foci, behavioral deficits and pathological abnormalities, including p-TDP-43 inclusions, STING activation, motor neuron loss, neuroinflammation, and increased plasma neurofilament concentration, were alleviated in C9ORF72 mice. Base editing of the CUG codon also improved molecular phenotypes and survival in patient induced pluripotent stem cell–derived neurons, which highlights the potential of therapeutically targeting DPR production rather than repeat RNAs.