Search

State of the Art: Semantic dementia (SD) patients including semantic variant primary progressive aphasia (svPPA) and semantic behavioral variant frontotemporal dementia (sbvFTD) patients show semantic difficulties identifying faces and known people related to right anterior temporal lobe (ATL) atrophy. However, it remains unclear whether they also have perceptual deficits in face recognition., Methodology: We selected 74 SD patients (54 with svPPA and predominant left ATL atrophy and 20 with sbvFTD and predominant right ATL atrophy) and 36 cognitively healthy controls (HC) from UCSF Memory and Aging Center. They underwent a perceptual face processing test (Benton facial recognition test-short version; BFRT-S), and semantic face processing tests (UCSF Famous people battery - Recognition, Naming, Semantic associations - pictures and words subtests), as well as structural magnetic resonance imaging (MRI). Neural correlates with the task's performance were conducted with a Voxel-based morphometry approach using CAT12., Results: svPPA and sbvFTD patients were impaired on all semantic face processing tests, with sbvFTD patients performing significantly lower on the famous faces' recognition task in comparison to svPPA, and svPPA performing significantly lower on the naming task in comparison to sbvFTD. These tasks predominantly correlated with grey matter (GM) volumes in the right and left ATL, respectively. Compared to HC, both svPPA and sbvFTD patients showed preserved performance on the perceptual face processing test (BFRT-S), and performance on the BFRT-S negatively correlated with GM volume in the right posterior superior temporal sulcus (pSTS)., Conclusion: Our results suggest that early in the disease, with the atrophy mostly restricted to the anterior temporal regions, SD patients do not present with perceptual deficits. However, more severe SD cases with atrophy in right posterior temporal regions might show lower performance on face perception tests, in addition to the semantic face processing deficits. Early sparing of face perceptual deficits in SD patients, regardless of hemispheric lateralization, furthers our understanding of clinical phenomenology and therapeutical approaches of this complex disease., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

State of the Art: Semantic dementia (SD) patients including semantic variant primary progressive aphasia (svPPA) and semantic behavioral variant frontotemporal dementia (sbvFTD) patients show semantic difficulties identifying faces and known people related to right anterior temporal lobe (ATL) atrophy. However, it remains unclear whether they also have perceptual deficits in face recognition., Methodology: We selected 74 SD patients (54 with svPPA and predominant left ATL atrophy and 20 with sbvFTD and predominant right ATL atrophy) and 36 cognitively healthy controls (HC) from UCSF Memory and Aging Center. They underwent a perceptual face processing test (Benton facial recognition test-short version; BFRT-S), and semantic face processing tests (UCSF Famous people battery - Recognition, Naming, Semantic associations - pictures and words subtests), as well as structural magnetic resonance imaging (MRI). Neural correlates with the task's performance were conducted with a Voxel-based morphometry approach using CAT12., Results: svPPA and sbvFTD patients were impaired on all semantic face processing tests, with sbvFTD patients performing significantly lower on the famous faces' recognition task in comparison to svPPA, and svPPA performing significantly lower on the naming task in comparison to sbvFTD. These tasks predominantly correlated with gray matter (GM) volumes in the right and left ATL, respectively. Compared to HC, both svPPA and sbvFTD patients showed preserved performance on the perceptual face processing test (BFRT-S), and performance on the BFRT-S negatively correlated with GM volume in the right posterior superior temporal sulcus (pSTS)., Conclusion: Our results suggest that early in the disease, with the atrophy mostly restricted to the anterior temporal regions, SD patients do not present with perceptual deficits. However, more severe SD cases with atrophy in right posterior temporal regions might show lower performance on face perception tests, in addition to the semantic face processing deficits. Early sparing of face perceptual deficits in SD patients, regardless of hemispheric lateralization, furthers our understanding of clinical phenomenology and therapeutical approaches of this complex disease.

The non-fluent/agrammatic variant of primary progressive aphasia (nfvPPA) is a neurodegenerative syndrome primarily defined by the presence of apraxia of speech (AoS) and/or expressive agrammatism. In addition, many patients exhibit dysarthria and/or receptive agrammatism. This leads to substantial phenotypic variation within the speech-language domain across individuals and time, in terms of both the specific combination of symptoms as well as their severity. How to resolve such phenotypic heterogeneity in nfvPPA is a matter of debate. 'Splitting' views propose separate clinical entities: 'primary progressive apraxia of speech' when AoS occurs in the absence of expressive agrammatism, 'progressive agrammatic aphasia' (PAA) in the opposite case, and 'AOS + PAA' when mixed motor speech and language symptoms are clearly present. While therapeutic interventions typically vary depending on the predominant symptom (e.g. AoS versus expressive agrammatism), the existence of behavioural, anatomical and pathological overlap across these phenotypes argues against drawing such clear-cut boundaries. In the current study, we contribute to this debate by mapping behaviour to brain in a large, prospective cohort of well characterized patients with nfvPPA (n = 104). We sought to advance scientific understanding of nfvPPA and the neural basis of speech-language by uncovering where in the brain the degree of MRI-based atrophy is associated with inter-patient variability in the presence and severity of AoS, dysarthria, expressive agrammatism or receptive agrammatism. Our cross-sectional examination of brain-behaviour relationships revealed three main observations. First, we found that the neural correlates of AoS and expressive agrammatism in nfvPPA lie side by side in the left posterior inferior frontal lobe, explaining their behavioural dissociation/association in previous reports. Second, we identified a 'left-right' and 'ventral-dorsal' neuroanatomical distinction between AoS versus dysarthria, highlighting (i) that dysarthria, but not AoS, is significantly influenced by tissue loss in right-hemisphere motor-speech regions; and (ii) that, within the left hemisphere, dysarthria and AoS map onto dorsally versus ventrally located motor-speech regions, respectively. Third, we confirmed that, within the large-scale grammar network, left frontal tissue loss is preferentially involved in expressive agrammatism and left temporal tissue loss in receptive agrammatism. Our findings thus contribute to define the function and location of the epicentres within the large-scale neural networks vulnerable to neurodegenerative changes in nfvPPA. We propose that nfvPPA be redefined as an umbrella term subsuming a spectrum of speech and/or language phenotypes that are closely linked by the underlying neuroanatomy and neuropathology., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Prior research has revealed distinctive patterns of impaired language abilities across the three variants of Primary Progressive Aphasia (PPA): nonfluent/agrammatic (nfvPPA), logopenic (lvPPA) and semantic (svPPA). However, little is known about whether, and to what extent, non-verbal cognitive abilities, such as processing speed, are impacted in PPA patients. This is because neuropsychological tests typically contain linguistic stimuli and require spoken output, being therefore sensitive to verbal deficits in aphasic patients. The aim of this study is to investigate potential differences in processing speed between PPA patients and healthy controls, and among the three PPA variants, using a brief non-verbal tablet-based task (Match) modeled after the WAIS-III digit symbol coding test, and to determine its neural correlates. Here, we compared performance on the Match task between PPA patients (n = 61) and healthy controls (n = 59) and across the three PPA variants. We correlated performance on Match with voxelwise gray and white matter volumes. We found that lvPPA and nfvPPA patients performed significantly worse on Match than healthy controls and svPPA patients. Worse performance on Match across PPA patients was associated with reduced gray matter volume in specific parts of the left middle frontal gyrus, superior parietal lobule, and precuneus, and reduced white matter volume in the left parietal lobe. To conclude, our behavioral findings reveal that processing speed is differentially impacted across the three PPA variants and provide support for the potential clinical utility of a tabled-based task (Match) to assess non-verbal cognition. In addition, our neuroimaging findings confirm the importance of a set of fronto-parietal regions that previous research has associated with processing speed and executive control. Finally, our behavioral and neuroimaging findings combined indicate that differences in processing speed are largely explained by the unequal distribution of atrophy in these fronto-parietal regions across the three PPA variants., Competing Interests: Declaration of competing interest None., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Remote smartphone assessments of cognition, speech/language, and motor functioning in frontotemporal dementia (FTD) could enable decentralized clinical trials and improve access to research. We studied the feasibility and acceptability of remote smartphone data collection in FTD research using the ALLFTD Mobile App (ALLFTD-mApp)., Methods: A diagnostically mixed sample of 214 participants with FTD or from familial FTD kindreds (asymptomatic: CDR®+NACC-FTLD = 0 [ N  = 101]; prodromal: 0.5 [ N  = 49]; symptomatic ≥1 [ N  = 51]; not measured [ N  = 13]) were asked to complete ALLFTD-mApp tests on their smartphone three times within 12 days. They completed smartphone familiarity and participation experience surveys., Results: It was feasible for participants to complete the ALLFTD-mApp on their own smartphones. Participants reported high smartphone familiarity, completed ∼ 70% of tasks, and considered the time commitment acceptable (98% of respondents). Greater disease severity was associated with poorer performance across several tests., Discussion: These findings suggest that the ALLFTD-mApp study protocol is feasible and acceptable for remote FTD research., Highlights: The ALLFTD Mobile App is a smartphone-based platform for remote, self-administered data collection.The ALLFTD Mobile App consists of a comprehensive battery of surveys and tests of executive functioning, memory, speech and language, and motor abilities.Remote digital data collection using the ALLFTD Mobile App was feasible in a multicenter research consortium that studies FTD. Data was collected in healthy controls and participants with a range of diagnoses, particularly FTD spectrum disorders.Remote digital data collection was well accepted by participants with a variety of diagnoses., Competing Interests: Appleby, BS – receives research support from CDC, NIH, Ionis, Alector, and the CJD Foundation. He has provided consultation to Acadia, Ionis, and Sangamo.Boeve, BF – has served as an investigator for clinical trials sponsored by Alector, Biogen and Transposon. He receives royalties from the publication of a book entitled Behavioral Neurology Of Dementia (Cambridge Medicine, 2009, 2017). He serves on the Scientific Advisory Board of the Tau Consortium. He receives research support from NIH, the Mayo Clinic Dorothy and Harry T. Mangurian Jr. Lewy Body Dementia Program, and the Little Family Foundation.Boxer, AL – receives research support from NIH (U19AG063911, R01AG038791, R01AG073482), the Tau Research Consortium, the Association for Frontotemporal Degeneration, Bluefield Project to Cure Frontotemporal Dementia, Corticobasal Degeneration Solutions, the Alzheimer's Drug Discovery Foundation, and the Alzheimer's Association. He has served as a consultant for Aeovian, AGTC, Alector, Arkuda, Arvinas, AviadoBio, Boehringer Ingelheim, Denali, GSK, Life Edit, Humana, Oligomerix, Oscotec, Roche, Transposon, TrueBinding and Wave, and received research support from Biogen, Eisai, and Regeneron. As a co‐inventor of ALLFTD‐mApp tasks, Dr. Boxer has received licensing fees.Brushaber, D – nothing to disclose.Clark, AL – nothing to disclose.Dickerson, BC – Dr Dickerson is a consultant for Acadia, Alector, Arkuda, Biogen, Denali, Eisai, Genentech, Lilly, Merck, Novartis, Takeda, Wave Lifesciences. Dr Dickerson receives royalties from Cambridge University Press, Elsevier, Oxford University Press. Dr Dickerson receives grant funding from the NIA, NINDS, NIMH, and the Bluefield Foundation.Domoto‐Reilly, K – receives research support from NIH, and serves as an investigator for a clinical trial sponsored by Lawson Health Research Institute.Fields, JA – receives research support from NIH.Forsberg, L – receives research support from NIH.Ghoshal, N – has participated or is currently participating in clinical trials of anti‐dementia drugs sponsored by the following companies: Bristol Myers Squibb, Eli Lilly/Avid Radiopharmaceuticals, Janssen Immunotherapy, Novartis, Pfizer, Wyeth, SNIFF (The Study of Nasal Insulin to Fight Forgetfulness) study, and A4 (The Anti‐Amyloid Treatment in Asymptomatic Alzheimer's Disease) trial. She receives research support from Tau Consortium and Association for Frontotemporal Dementia and is funded by the NIH.Gorno‐Tempini, ML – receives research support from NIH. As a co‐inventor of one of the ALLFTD mApp tasks, Dr Gorno‐Tempini's lab receives licensing fees , consistent with UCSF institutional policy.Graff‐Radford, N – receives royalties from UpToDate, has participated in multicenter therapy studies by sponsored by Biogen, TauRx, AbbVie, Novartis, and Lilly. He receives research support from NIH.Grossman, M – receives grant support from NIH, Avid, and Piramal; participates in clinical trials sponsored by Biogen, TauRx, and Alector; serves as a consultant to Bracco and UCB; and serves on the Editorial Board of Neurology.Hall, MGH – nothing to disclose.Heuer, HW – nothing to disclose.Huey, ED – receives research support from NIH.Irwin, D – receives support from NIH, Brightfocus Foundation, and Penn Institute on Aging.Kornak, J – has provided expert witness testimony for Teva Pharmaceuticals in Forest Laboratories Inc. et al. v. Teva Pharmaceuticals USA, Inc., Case Nos. 1:14‐cv‐00121 and 1:14‐cv‐00686 (D. Del. filed Jan. 31, 2014, and May 30, 2014) regarding the drug Memantine; for Apotex/HEC/Ezra in Novartis AG et al. v. Apotex Inc., No. 1:15‐cv‐975 (D. Del. filed Oct. 26, 2015, regarding the drug Fingolimod. He has also given testimony on behalf of Puma Biotechnology in Hsingching Hsu et al, vs. Puma Biotechnology, INC., et al. 2018 regarding the drug Neratinib. He receives research support from the NIH.Kramer, J – receives research support from NIH and royalties from Pearson Inc.Kremers, W—receives research funding from AstraZeneca, Biogen, Roche, DOD, and NIH.Lapid, MI – receives research support from the NIH.Litvan, I – receives research support from the National Institutes of Health grants: 2R01AG038791‐06A, U01NS100610, U01NS80818, R25NS098999; U19 AG063911‐1 and 1R21NS114764‐01A1; the Michael J Fox Foundation, Parkinson Foundation, Lewy Body Association, CurePSP, Roche, Abbvie, Biogen, Centogene. EIP‐Pharma, Biohaven Pharmaceuticals, Novartis, and United Biopharma SRL‐UCB. She is a Scientific advisor for Amydis (Gratis) and Rossy Center for Progressive Supranuclear Palsy University of Toronto. She receives her salary from the University of California San Diego and as Chief Editor of Frontiers in Neurology.Mackenzie, IR – receives research funding from Canadian Institutes of Health Research, Alzheimer's Association US, NIH, Weston Brain Institute.Manoochehri, M – nothing to disclose.Masdeu, JC – is a consultant and received research funding from Eli Lilly, parent co. of Avid Radiopharmaceuticals, manufacturer of 18F‐flortaucipir, receives personal fees from GE Healthcare, grants and personal fees from Eli Lilly, grants from Acadia, Avanir, Biogen, Eisai, Janssen, NIH, Novartis, with no relation to the submitted work.Mendez, MF – receives research support from NIH.Mester, C – nothing to disclose.Nevler, N – receives research funding from the NIH and Department of Defense.Onyike, C – receives research funding from the NIH, Lawton Health Research Institute, National Ataxia Foundation, Alector Inc., and Transposon, Inc. He is also supported by the Robert and Nancy Hall Brain Research Fund, the Jane Tanger Black Fund for Young‐Onset Dementias, and the gift from Joseph Trovato. He is a consultant with Alector, Inc. and Acadia Pharmaceuticals.Pascual, B – receives research support from NIH.Pressman, PS – receives research support from NIH.Rankin, KP – receives research support from NIH and NSF, and serves on a Medical Advisory Board for Eli Lilly.Rao, M – nothing to disclose.Rojas, JC – receives research support from NIH and is a site PI for clinical trials sponsored by Eli‐Lilly and Eisai.Rosen, HJ – has received research support from Biogen Pharmaceuticals, has consulting agreements with Wave Neuroscience and Ionis Pharmaceuticals, and receives research support from NIH.Ratnasiri, B – nothing to disclose.Staffaroni, AM – received research support from the NIA/NIH, Bluefield Project to Cure FTD, and the Larry L. Hillblom Foundation, and has provided consultation to Alector, Lilly/Prevail, Passage Bio, and Takeda. Dr Staffaroni is a co‐inventor of four ALLFTD mApp tasks and receives licensing fees, consistent with UCSF institutional policy.Tartaglia, M – has served as an investigator for clinical trials sponsored by Biogen, Avanex, Green Valley, and Roche / Genentech, Bristol Myers Squibb, Eli Lilly/Avid Radiopharmaceuticals, Janssen. She receives research support from Canadian Institutes of Health Research. Author disclosures are available in the supporting information.Taylor, JC – nothing to disclose.Wise, AB – nothing to disclose.Welch, AE – nothing to disclose.Wong, B – receives research support from the NIH., (© 2023 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Semantic variant primary progressive aphasia is a clinical syndrome characterized by marked semantic deficits, anterior temporal lobe atrophy and reduced connectivity within a distributed set of regions belonging to the functional network associated with semantic processing. However, to fully depict the clinical signature of semantic variant primary progressive aphasia, it is necessary to also characterize preserved neural networks and linguistic abilities, such as those subserving speech production. In this case-control observational study, we employed whole-brain seed-based connectivity on task-free MRI data of 32 semantic variant primary progressive aphasia patients and 46 healthy controls to investigate the functional connectivity of the speech production network and its relationship with the underlying grey matter. We investigated brain-behaviour correlations with speech fluency measures collected through clinical tests (verbal agility) and connected speech (speech rate and articulation rate). As a control network, we also investigated functional connectivity within the affected semantic network. Patients presented with increased connectivity in the speech production network between left inferior frontal and supramarginal regions, independent of underlying grey matter volume. In semantic variant primary progressive aphasia patients, preserved (verbal agility) and increased (articulation rate) speech fluency measures correlated with increased connectivity between inferior frontal and supramarginal regions. As expected, patients demonstrated decreased functional connectivity in the semantic network (dependent on the underlying grey matter atrophy) associated with average nouns' age of acquisition during connected speech. Collectively, these results provide a compelling model for studying compensation mechanisms in response to disease that might inform the design of future rehabilitation strategies in semantic variant primary progressive aphasia., Competing Interests: The authors report no competing interests., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Pneumococcal serotypes differ in antimicrobial susceptibility. However, patterns and causes of this variation are not comprehensively understood., Methods: We undertook a systematic review of epidemiologic studies of pneumococci isolated from carriage or invasive disease among children globally from 2000-2019. We evaluated associations of each serotype with nonsusceptibility to penicillin, macrolides, and trimethoprim/sulfamethoxazole. We evaluated differences in the prevalence of nonsusceptibility to major antibiotic classes across serotypes using random-effects meta-regression models and assessed changes in prevalence of nonsusceptibility after implementation of pneumococcal conjugate vaccines (PCVs). We also evaluated associations between biological characteristics of serotypes and their likelihood of nonsusceptibility to each drug., Results: We included data from 129 studies representing 32 187 isolates across 52 countries. Within serotypes, the proportion of nonsusceptible isolates varied geographically and over time, in settings using and those not using PCVs. Factors predicting enhanced fitness of serotypes in colonization as well as enhanced pathogenicity were each associated with higher likelihood of nonsusceptibility to penicillin, macrolides, and trimethoprim/sulfamethoxazole. Increases in prevalence of nonsusceptibility following PCV implementation were evident among non-PCV serotypes, including 6A, 6C, 15A, 15B/C, 19A, and 35B; however, this pattern was not universally evident among non-PCV serotypes. Postvaccination increases in nonsusceptibility for serotypes 6A and 19A were attenuated in settings that implemented PCV13., Conclusions: In pneumococci, nonsusceptibility to penicillin, macrolides, and trimethoprim/sulfamethoxazole is associated with more frequent opportunities for antibiotic exposure during both prolonged carriage episodes and when serotypes cause disease. These findings suggest multiple pathways leading to resistance selection in pneumococci., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Primary progressive aphasia (PPA) is a clinical syndrome in which patients progressively lose speech and language abilities. Three variants are recognized: logopenic (lvPPA), associated with phonology and/or short-term verbal memory deficits accompanied by left temporo-parietal atrophy; semantic (svPPA), associated with semantic deficits and anterior temporal lobe (ATL) atrophy; non-fluent (nfvPPA) associated with grammar and/or speech-motor deficits and inferior frontal gyrus (IFG) atrophy. Here, we set out to investigate whether the three variants of PPA can be dissociated based on error patterns in a single language task. We recruited 21 lvPPA, 28 svPPA, and 24 nfvPPA patients, together with 31 healthy controls, and analyzed their performance on an auditory noun-to-verb generation task, which requires auditory analysis of the input, access to and selection of relevant lexical and semantic knowledge, as well as preparation and execution of speech. Task accuracy differed across the three variants and controls, with lvPPA and nfvPPA having the lowest and highest accuracy, respectively. Critically, machine learning analysis of the different error types yielded above-chance classification of patients into their corresponding group. An analysis of the error types revealed clear variant-specific effects: lvPPA patients produced the highest percentage of "not-a-verb" responses and the highest number of semantically related nouns (production of baseball instead of throw to noun ball ); in contrast, svPPA patients produced the highest percentage of "unrelated verb" responses and the highest number of light verbs (production of take instead of throw to noun ball ). Taken together, our findings indicate that error patterns in an auditory verb generation task are associated with the breakdown of different neurocognitive mechanisms across PPA variants. Specifically, they corroborate the link between temporo-parietal regions with lexical processing, as well as ATL with semantic processes. These findings illustrate how the analysis of pattern of responses can help PPA phenotyping and heighten diagnostic sensitivity, while providing insights on the neural correlates of different components of language., 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 Lukic, Licata, Weis, Bogley, Ratnasiri, Welch, Hinkley, Miller, Garcia, Houde, Nagarajan, Gorno-Tempini and Borghesani.)

Background: Pneumococcal diseases are a leading cause of morbidity and mortality among children globally, and the burden of these diseases might be worsened by antimicrobial resistance. To understand the effect of pneumococcal conjugate vaccine (PCV) deployment on antimicrobial resistance in pneumococci, we assessed the susceptibility of paediatric pneumococcal isolates to various antimicrobial drugs before and after PCV implementation., Methods: We did a systematic review of studies reporting antimicrobial susceptibility profiles of paediatric pneumococcal isolates between 2000 and 2020 using PubMed and the Antimicrobial Testing Leadership and Surveillance database (ATLAS; Pfizer). Population-based studies of invasive pneumococcal disease or nasopharyngeal colonisation were eligible for inclusion. As primary outcome measures, we extracted the proportions of isolates that were non-susceptible or resistant to penicillin, macrolides, sulfamethoxazole-trimethoprim, third-generation cephalosporins, and tetracycline from each study. Where available, we also extracted data on pneumococcal serotypes. We estimated changes in the proportion of isolates with reduced susceptibility or resistance to each antibiotic class using random-effects meta-regression models, adjusting for study-level and region-level heterogeneity, as well as secular trends, invasive or colonising isolate source, and countries' per-capita gross domestic product., Findings: From 4910 studies screened for inclusion, we extracted data from 559 studies on 312 783 paediatric isolates. Susceptibility of isolates varied substantially across regions both before and after implementation of any PCV product. On average across all regions, we estimated significant absolute reductions in the proportions of pneumococci showing non-susceptibility to penicillin (11·5%, 95% CI 8·6-14·4), sulfamethoxazole-trimethoprim (9·7%, 4·3-15·2), and third-generation cephalosporins (7·5%, 3·1-11·9), over the 10 years after implementation of any PCV product, and absolute reductions in the proportions of pneumococci resistant to penicillin (7·3%, 5·3-9·4), sulfamethoxazole-trimethoprim (16·0%, 11·0-21·2), third-generation cephalosporins (4·5%, 0·3-8·7), macrolides (3·6%, 0·7-6·6) and tetracycline (2·0%, 0·3-3·7). We did not find evidence of changes in the proportion of isolates non-susceptible to macrolides or tetracycline after PCV implementation. Observed changes in penicillin non-susceptibility were driven, in part, by replacement of vaccine-targeted serotypes with non-vaccine serotypes that were less likely to be non-susceptible., Interpretation: Implementation of PCVs has reduced the proportion of circulating pneumococci resistant to first-line antibiotic treatments for pneumonia. This effect merits consideration in assessments of vaccine impact and investments in coverage improvements., Funding: Bill & Melinda Gates Foundation., Competing Interests: JAL has received grants and consulting fees from Pfizer and Merck Sharp & Dohme; and consulting fees from VaxCyte and Kaiser Permanente, unrelated to the submitted work. All other authors declare no competing interests., (© 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.)