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Identifying cell type-specific enhancers in the brain is critical to building genetic tools for investigating the mammalian brain. Computational methods for functional enhancer prediction have been proposed and validated in the fruit fly and not yet the mammalian brain. We organized the 'Brain Initiative Cell Census Network (BICCN) Challenge: Predicting Functional Cell Type-Specific Enhancers from Cross-Species Multi-Omics' to assess machine learning and feature-based methods designed to nominate enhancer DNA sequences to target cell types in the mouse cortex. Methods were evaluated based on in vivo validation data from hundreds of cortical cell type-specific enhancers that were previously packaged into individual AAV vectors and retro-orbitally injected into mice. We find that open chromatin was a key predictor of functional enhancers, and sequence models improved prediction of non-functional enhancers that can be deprioritized as opposed to pursued for in vivo testing. Sequence models also identified cell type-specific transcription factor codes that can guide designs of in silico enhancers. This community challenge establishes a benchmark for enhancer prioritization algorithms and reveals computational approaches and molecular information that are crucial for the identification of functional enhancers for mammalian cortical cell types. The results of this challenge bring us closer to understanding the complex gene regulatory landscape of the mammalian brain and help us design more efficient genetic tools and potential gene therapies for human neurological diseases., Competing Interests: Declaration of interests: None declared.

Introduction: The rapid development of artificial intelligence (AI) in healthcare has exposed the unmet need for growing a multidisciplinary workforce that can collaborate effectively in the learning health systems. Maximizing the synergy among multiple teams is critical for Collaborative AI in Healthcare., Methods: We have developed a series of data, tools, and educational resources for cultivating the next generation of multidisciplinary workforce for Collaborative AI in Healthcare. We built bulk-natural language processing pipelines to extract structured information from clinical notes and stored them in common data models. We developed multimodal AI/machine learning (ML) tools and tutorials to enrich the toolbox of the multidisciplinary workforce to analyze multimodal healthcare data. We have created a fertile ground to cross-pollinate clinicians and AI scientists and train the next generation of AI health workforce to collaborate effectively., Results: Our work has democratized access to unstructured health information, AI/ML tools and resources for healthcare, and collaborative education resources. From 2017 to 2022, this has enabled studies in multiple clinical specialties resulting in 68 peer-reviewed publications. In 2022, our cross-discipline efforts converged and institutionalized into the Center for Collaborative AI in Healthcare., Conclusions: Our Collaborative AI in Healthcare initiatives has created valuable educational and practical resources. They have enabled more clinicians, scientists, and hospital administrators to successfully apply AI methods in their daily research and practice, develop closer collaborations, and advanced the institution-level learning health system., Competing Interests: This work was supported by the grants from the National Institutes of Health (NIH) Yuan Luo, Kristi Holmes, Luke Rasmussen, Andrew Naidech, Lazaro Sanchez‐Pinto, Richard Wunderink, Jennifer Pacheco, Matthew Carson, Susan Clare. Kristi Holmes is a member of Learning Health Systems Editorial Board. Donald Lloyd‐Jones serves as a board member of the American Heart Association. Michael Markl receives grant support by Siemens and Circle Cardiovascular Imaging; co‐founder and co‐owner of Third Coast Dynamics. Susanna McColley reports grants from the NIH National Center for Advancing Translational Science, the Centers for Disease Control and Prevention, the Cystic Fibrosis Foundation, and the Rosenau Family Research Foundation. She receives compensation as an advisor to Vertex Pharmaceuticals, Inc. Huiping Liu is the scientific co‐founder of ExoMira Medicine. Justin Starren reports grants from the NIH and Greenwall Foundation. Theresa Walunas receives research funding from Gilead Sciences. Kelly Michelson reports grants from the NIH, Greenwall Foundation, and the Patient‐Centered Outcomes Research Institute. Richard D’Aquila reports grants from the NIH, serving on external advisory boards for NIH‐funded projects, serving on the NIAID AIDS Research Advisory Council, and serving on the editorial board of the Journal of Clinical Investigation. Abel Kho is an advisor to Datavant. Sanjiv Shah is supported by grants from the NIH and AHA. Lee Cooper reports grants from the NIH and has invention disclosures registered at the Northwestern Office of Innovation and New Ventures, consults for Tempus, and advises Veracyte and Targeted Bioscience. Feng Yue is supported by grants from NIH and is a co‐founder of Sariant Therapeutics, Inc. Deyu Fang is co‐founder of ExoMira Medicine. Ronald Ackermann is supported by grants from the NIH, CDC, and the UnitedHealth Group., (© 2024 The Authors. Learning Health Systems published by Wiley Periodicals LLC on behalf of University of Michigan.)

Background: although being central for the biology and druggability of hormone-receptor positive, HER2 negative metastatic breast cancer (MBC), ESR1 and PIK3CA mutations are simplistically dichotomized as mutated or wild type in current clinical practice., Methods: The study analyzed a multi-institutional cohort comprising 703 patients with luminal-like MBC characterized for circulating tumor DNA through next generation sequencing (NGS). Pathway classification was defined based on previous work (i.e., RTK, RAS, RAF, MEK, NRF2, ER, WNT, MYC, P53, cell cycle, notch, PI3K). Single nucleotide variations (SNVs) were annotated for their oncogenicity through OncoKB. Only pathogenic variants were included in the models. Associations among clinical characteristics, pathway classification, and ESR1/PIK3CA codon variants were explored., Results: The results showed a differential pattern of associations for ESR1 and PIK3CA codon variants in terms of co-occurring pathway alterations patterns of metastatic dissemination, and prognosis. ESR1 537 was associated with SNVs in the ER and RAF pathways, CNVs in the MYC pathway and bone metastases, while ESR1 538 with SNVs in the cell cycle pathway and liver metastases. PIK3CA 1047 and 542 were associated with CNVs in the PI3K pathway and with bone metastases., Conclusions: The study demonstrated how ESR1 and PIK3CA codon variants, together with alterations in specific oncogenic pathways, can differentially impact the biology and clinical phenotype of luminal-like MBC. As novel endocrine therapy agents such as selective estrogen receptor degraders (SERDS) and PI3K inhibitors are being developed, these results highlight the pivotal role of ctDNA NGS to describe tumor evolution and optimize clinical decision making., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Human brain organoids provide unique platforms for modeling several aspects of human brain development and pathology. However, current brain organoid systems mostly lack the resolution to recapitulate the development of finer brain structures with subregional identity, including functionally distinct nuclei in the thalamus. Here, we report a method for converting human embryonic stem cells (hESCs) into ventral thalamic organoids (vThOs) with transcriptionally diverse nuclei identities. Notably, single-cell RNA sequencing revealed previously unachieved thalamic patterning with a thalamic reticular nucleus (TRN) signature, a GABAergic nucleus located in the ventral thalamus. Using vThOs, we explored the functions of TRN-specific, disease-associated genes patched domain containing 1 (PTCHD1) and receptor tyrosine-protein kinase (ERBB4) during human thalamic development. Perturbations in PTCHD1 or ERBB4 impaired neuronal functions in vThOs, albeit not affecting the overall thalamic lineage development. Together, vThOs present an experimental model for understanding nuclei-specific development and pathology in the thalamus of the human brain., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Invasive cervical cancer (ICC) is a serious public health burden in Nigeria, where human immunodeficiency virus (HIV) remains highly prevalent. Previous research suggested that epigenetic age acceleration (EAA) could play a role in detection of HIV-associated ICC. However, little research has been conducted on this topic in Africa where the population is most severely affected by HIV-associated ICC. Here, we investigated the association between ICC and EAA using cervical tissues of ICC-diagnosed Nigerian women living with HIV., Methods: We included 116 cervical tissue samples from three groups of Nigerian women in this study: (1) HIV+/ICC+ ( n = 39); (2) HIV+/ICC- ( n = 53); and (3) HIV-/ICC + ( n = 24). We utilized four DNA methylation-based EAA estimators; IEAA, EEAA, GrimAA, and PhenoAA. We compared EAA measurements across the 3 HIV/ICC groups using multiple linear regression models. We also compared EAA between 26 tumor tissues and their surrounding normal tissues using paired t -tests. We additionally performed a receiver operating characteristics (ROC) curve analysis to illustrate the area under the curve (AUC) of EAA in ICC., Results: We found the most striking associations between HIV/ICC status and PhenoAge acceleration (PhenoAA). Among HIV-positive women, PhenoAA was on average 13.4 years higher in women with ICC compared to cancer-free women ( P = 0.005). PhenoAA was 20.7 and 7.1 years higher in tumor tissues compared to surrounding normal tissues among HIV-positive women ( P = 0.009) and HIV-negative women ( P = 0.284), respectively. We did not find substantial differences in PhenoAA between HIV-positive and HIV-negative women with ICC., Conclusion: PhenoAA is associated with ICC in HIV-infected women in our study. Our findings suggest that PhenoAA may serve as a potential biomarker for further risk stratification of HIV-associated ICC in Nigeria and similar resource-constrained settings., 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 Musa, Kim, Zheng, Qu, Joyce, Wang, Nannini, Gursel, Silas, Abdulkareem, Imade, Akanmu, Wei, Kocherginsky, Kim, Wehbe, Achenbach, Anorlu, Simon, Sagay, Ogunsola, Murphy and Hou.)

Background: The correlation of ERBB2 copy number gain (CNG) from tissue or circulating tumor DNA (ctDNA) by next-generation sequencing (NGS) with standard HER2 tissue evaluation is not well understood., Materials and Methods: We retrospectively identified patients with ERBB2 CNG on commercial NGS. We described their clinical-pathologic features and calculated the positive predictive value (PPV) of ERBB2 CNG by NGS for HER2-positivity by IHC and FISH testing., Results: 176 patients had NGS revealing an ERBB2 CNG (112 by tumor tissue and 91 by ctDNA). The cancer subtypes with the most cases with ERBB2 CNG by NGS were breast ( n = 67), non-small cell lung ( n = 25), colorectal ( n = 18), gastroesophageal ( n = 17), pancreatic ( n = 11), and uterine ( n = 11). The PPV of ERBB2 CNG in determining HER2 positivity by standard IHC/FISH definitions was 88% for tissue NGS ( n = 57) and 80% for ctDNA ( n = 47). The PPV among breast cancer patients for tissue NGS was 97% ( n = 35) and ctDNA was 93% ( n = 39). However, for non-breast cancer cases, the PPV of ERBB2 amplification by tissue NGS dropped to 76% ( n = 22) and by ctDNA to 44% ( n = 7)., Conclusions: ERBB2 CNG by NGS is detected in numerous malignancies for which HER2 testing is not standard. Detection of ERBB2 CNG by tissue NGS and ctDNA has a high PPV for true HER2-positivity by standard IHC and/or FISH testing in breast cancer., Competing Interests: CONFLICTS OF INTEREST ANS reports honorarium from AstraZeneca. AB reports speaker fees from Lilly, Roche, Thermo fisher scientific, and Foundation Medicine., (Copyright: © 2022 Shah et al.)

Purpose: Circulating tumor DNA (ctDNA) is a promising tool for noninvasive longitudinal monitoring of genomic alterations. We analyzed serial ctDNA to characterize genomic evolution in progressive metastatic breast cancer., Experimental Design: This was a retrospective cohort between 2015 and 2019 obtained under an Institutional Review Board-approved protocol at Northwestern University (Chicago, IL). ctDNA samples were analyzed with Guardant360 next-generation sequencing (NGS) assay. A total of 86 patients had at least two serial ctDNA collections with the second drawn at first post-NGS progression (PN1) by imaging and clinical assessment. A total of 27 participants had ctDNA drawn at second post-NGS clinical progression (PN2). We analyzed alterations, mutant allele frequency (MAF), number of alterations (NOA), and sites of disease on imaging in close proximity to ctDNA evaluation. Matched pairs' variations in MAF, NOA, and alterations at progression were tested through Wilcoxon test. We identified an independent control cohort at Massachusetts General Hospital (Boston, MA) of 63 patients with serial ctDNA sampling and no evidence of progression., Results: We identified 44 hormone receptor-positive, 20 HER2 + , and 22 triple-negative breast cancer cases. The significant alterations observed between baseline and PN1 were TP53 ( P < 0.0075), PIK3CA ( P < 0.0126), AR ( P < 0.0126), FGFR1 ( P < 0.0455), and ESR1 ( P < 0.0143). Paired analyses revealed increased MAF and NOA from baseline to PN1 ( P = 0.0026, and P < 0.0001, respectively). When compared with controls without progression, patients with ctDNA collection at times of progression were associated with increased MAF and NOA ( P = 0.0042 and P < 0.0001, respectively)., Conclusions: Serial ctDNA testing identified resistance alterations and increased NOA and MAF were associated with disease progression. Prospective longitudinal ctDNA evaluation could potentially monitor tumor genomic evolution., (©2020 American Association for Cancer Research.)

Competing Interests: Competing interests: The authors completed the ICMJE Unified Competing Interest form (available upon request from the corresponding author), and declare no conflicts of interest.

Background: We describe the genomic landscape of circulating tumour DNA (ctDNA) across pathological subtypes of metastatic breast cancer., Methods: 255 clinically annotated patients with ctDNA testing by Guardant360 were stratified into HR+, HER2+, and TNBC cohorts. Frequency and heterogeneity of alterations were reported. Paired ctDNA and tissue sequencing were compared for a subset of patients. The association of ctDNA and metastatic sites of disease on imaging was also assessed., Findings: 89% of patients had at least one ctDNA alteration detected. The most common single nucleotide variants (SNVs) for HR+ patients were PIK3CA, ESR1, and TP53. For HER2+, these were TP53, PIK3CA, and ERBB2 with ERBB2 as the most frequent copy number variant (CNV). For TNBC, the most common SNVs were TP53 and PIK3CA, and the most frequent CNVs were MYC, CCNE1, and PIK3CA. TNBC patients had a significantly higher mutant allele frequency (MAF) of the highest variant compared to HR+ or HER2+ patients (P<0.05). Overall, alterations in PIK3CA, ESR1, and ERBB2 were observed in 39.6%, 16.5%, and 21.6% of patients, respectively. Agreement between blood and tissue was 79-91%. MAF and number of alterations were significantly associated with number of metastatic sites on imaging (P<0.0001)., Interpretation: These data demonstrate the genetic heterogeneity of metastatic breast cancer in blood, the high prevalence of clinically actionable alterations, and the potential to utilise ctDNA as a surrogate for tumour burden on imaging., Funding: Lynn Sage Cancer Research Foundation, OncoSET Precision Medicine Program, and REDCap support was funded by the National Institutes of Health UL1TR001422., Competing Interests: Declaration of Competing Interest Andrew A. Davis reports receiving travel support from Menarini Silicon Biosystems, outside the submitted work; Lorenzo Gerratana reports non-financial support from Menarini Silicon Biosystems, personal fees from Lilly, outside the submitted work; Ami N. Shah reports personal fees from Abbvie, personal fees from Taiho, personal fees from Daiichi-Sankyo, outside the submitted work; Amir Behdad reports personal fees from Pfizer, personal fees from Foundation Medicine, personal fees from Bayer, outside the submitted work. Massimo Cristofanilli reports personal fees from Foundation Medicine, personal fees from Lilly, grants and personal fees from Pfizer, personal fees from Cytodyn, personal fees from Sermonix, grants and personal fees from G1Therapeutics, outside the submitted work., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Circulating tumor DNA (ctDNA) is gaining momentum as sensitive diagnostic tool for advanced disease characterization because of its ability both to capture the tumor's heterogeneity and its dynamic adaptations. However, the consistency between all the available platforms is still debated. The aim of the study was to explore the performance of the novel diagnostic NGS platform PredicinePLUS™ and to compare its results with the clinically available Guardant360™ platform for possible analytical inconsistencies. The study suggests that PredicinePLUS™ NGS platform can detect genomic alterations and measure allele frequency in samples of MBC patients and confirmed that different NGS platforms could be potentially compared provided that certain sample management and analytical requirements are met., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Invasive cervical cancer (ICC) is more prevalent in HIV infected women and occurs at younger median age than in HIV negative women. Organized cervical cancer screening (CCS) is presently lacking in Nigeria, and the age at CCS is not known in this population. We sought to examine the age at CCS, the cytology outcomes and whether outcomes differ by HIV infection status in an opportunistic screening setting., Methods: Cross-sectional analysis of data on a sample of women who had received a CCS in an opportunistic screening service in Jos, Nigeria over a 10-year time period (2006-2016). We used logistic regression models to estimate the independent effect of patient-reported HIV and age at CCS and odds ratios for abnormal cytology outcomes adjusting for other covariates. We also assessed the correlation between median age at CCS and severity of abnormal cervical cytology outcomes. Statistical analyses were done on STATA version 14, College Station, Texas, USA., Results: In a sample of 14,088, the median age at CCS was 37 years (IQR; 30-45). For HIV infected women vs. uninfected women, CCS occurred at earlier ages (35.0 ± 7.4 vs 38.2 ± 10.2 years, p  < 0.001). All women, regardless of HIV status, who completed at least 7 or more years of education were 1.27 to 3.51 times more likely to have CCS before age 35 than women with less education. The predictors of an abnormal cervical cytology outcome at CCS were: age at CCS ≥ 35 (aOR = 3.57; 95% CI: 2.74, 4.64), multiparity ≥5 (aOR = 1.27; 95% CI: 1.03, 1.56), and provider-referral (aOR = 1.34; 95% CI: 1.09, 1.64). Irrespective of reported HIV status, we found a positive correlation between median age at CCS and severity of cytology outcome., Discussion: The age at CCS in women who have utilized cervical cancer screening in the study population is relatively late compared to the recommended age by most guidelines from developed settings. Late age at CCS correlates positively with severity of abnormal cytology outcome irrespective of HIV status. More educated women are more likely to have CCS at early age and less likely to have underlying abnormal cytology outcomes., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s). 2019.)

Background: Dysregulation of miRNA and methylation levels are epigenetic hallmarks of cancer, potentially linked via miRNA-processing genes. Studies have found genetic alterations to miRNA-processing genes in cancer cells and human population studies. Our objective was to prospectively examine changes in DNA methylation of miRNA-processing genes and their associations with cancer risk. Methods: We examined cohort data from the Department of Veterans' Affairs Normative Aging Study. Participants were assessed every 3 to 5 years starting in 1999 through 2013 including questionnaires, medical record review, and blood collection. Blood from 686 consenting participants was analyzed using the Illumina 450K BeadChip array to measure methylation at CpG sites throughout the genome. We selected 19 genes based on a literature review, with 519 corresponding CpG sites. We then used Cox proportional hazards models to examine associations with cancer incidence, and generalized estimating equations to examine associations with cancer prevalence. Associations at false discovery rate < 0.05 were considered statistically significant. Results: Methylation of three CpGs ( DROSHA : cg23230564, TNRC6B : cg06751583, and TNRC6B : cg21034183) was prospectively associated with time to cancer development (positively for cg06751583, inversely for cg23230564 and cg21034183), whereas methylation of one CpG site ( DROSHA : cg16131300) was positively associated with cancer prevalence. Conclusions: DNA methylation of DROSHA , a key miRNA-processing gene, and TNRC6B may play a role in early carcinogenesis. Impact: Changes in miRNA processing may exert multiple effects on cancer development, including protecting against it via altered global miRNAs, and may be a useful early detection biomarker of cancer. Cancer Epidemiol Biomarkers Prev; 27(5); 550-7. ©2018 AACR ., (©2018 American Association for Cancer Research.)

The 61 CTSA Consortium sites are home to valuable programs and infrastructure supporting translational science and all are charged with ensuring that such investments translate quickly to improved clinical care. Catalog of Assets for Translational and Clinical Health Research (CATCHR) is the Consortium's effort to collect and make available information on programs and resources to maximize efficiency and facilitate collaborations. By capturing information on a broad range of assets supporting the entire clinical and translational research spectrum, CATCHR aims to provide the necessary infrastructure and processes to establish and maintain an open-access, searchable database of consortium resources to support multisite clinical and translational research studies. Data are collected using rigorous, defined methods, with the resulting information made visible through an integrated, searchable Web-based tool. Additional easy-to-use Web tools assist resource owners in validating and updating resource information over time. In this paper, we discuss the design and scope of the project, data collection methods, current results, and future plans for development and sustainability. With increasing pressure on research programs to avoid redundancy, CATCHR aims to make available information on programs and core facilities to maximize efficient use of resources., (© 2014 Wiley Periodicals, Inc.)

Background: The objective was to examine the short-term risk and predictors of anaemia following initiation of combination antiretroviral therapy (cART) in HIV-infected patients from the Western Africa, Eastern Africa, Southern Africa, Central Africa, Asian-Pacific, and Caribbean and Central and South America regions of the International Epidemiologic Databases to Evaluate AIDS (IeDEA) collaboration., Methods: Anaemia was defined as haemoglobin of < 10 g/dL. Patients were included if they started cART with three or more drugs, had prior haemoglobin of > = 10 g/dL, and had one or more follow-up haemoglobin tests. Factors associated with anaemia up to 12 months were examined using Cox proportional hazards models and stratified by IeDEA region., Results: Between 1998 and 2008, 19,947 patients initiated cART with baseline and follow-up haemoglobin tests (7358, 7289, 2853, 471, 1550 and 426 in the Western Africa, Eastern Africa, Southern Africa, Central Africa, Asian-Pacific, and Caribbean and Central and South America regions, respectively). At initiation, anaemia was found in 45% of Western Africa patients, 29% of Eastern Africa patients, 21% of Southern Africa patients, 36% of Central Africa patients, 15% of patients in Asian-Pacific and 14% of patients in Caribbean and Central and South America. Among patients with haemoglobin of > = 10 g/dL at baseline (13,445), the risks of anaemia were 18.2, 6.6, 9.7, 22.9, 11.8 and 19.5 per 100 person-years in the Western Africa, Eastern Africa, Southern Africa, Central Africa, Asian, and Caribbean and Central and South America regions, respectively. Factors associated with anaemia were female sex, low baseline haemoglobin level, low baseline CD4 count, more advanced disease stage, and initial cART containing zidovudine., Conclusions: In data from 34 cohorts of HIV-infected patients from sub-Saharan Africa, Central and South America, and Asia, the risk of anaemia within 12 months of initiating cART was moderate. Routine haemoglobin monitoring was recommended in patients at risk of developing anaemia following cART initiation.

Background: HIV-infected individuals have heightened cancer risk. With the advent of highly active antiretroviral therapy (HAART), the frequency of some AIDS-defining cancers (ADC) has decreased although certain non-AIDS-defining cancers (NADC) are becoming more frequent. Cancers among HIV-infected individuals in Latin American and the Caribbean have not yet been carefully studied., Methods: Cancer cases among the Caribbean, Central and South American network for HIV Research (CCASAnet) cohort were identified reviewing clinical records and pre-existing databases., Results: There were 406 cancers reported: 331 ADC (224 Kaposi sarcomas and 98 non Hodgkin lymphomas). Most frequent NADC (n = 75) were Hodgkin lymphoma and skin cancers. Seventy-three percent of NADC and 45% of ADC were diagnosed >1 year after HIV diagnosis. Fifty-six percent of ADC occurred before HAART start. Median time from HAART start until cancer diagnosis was 2.5 years for NADC and 0.5 years for ADC (P = <0.001). Within 3372 HAART starters, 158 were diagnosed with 165 cancers (82.4% ADC); 85 cases were previous to or concomitant with HAART initiation. Incidence of cancer after HAART initiation in 8080 person-years of follow-up was 7.2 per 1000 person-years (95% confidence interval = 5.5 to 9.3) for ADC and 2.7 (95% confidence interval = 1.8 to 4.1) for NADC; incidence was higher in the first 2 months, particularly for ADC (47.6). A pre-HAART ADC was a predictor of mortality after adjusting for age, sex, and CD4 at HAART initiation., Conclusions: ADC were the most frequent cancers in this region and were often diagnosed close to HIV diagnosis and HAART start. Incidence of cancer was highest around HAART initiation.

Background: Starting HAART in a very advanced stage of disease is assumed to be the most prevalent form of initiation in HIV-infected subjects in developing countries. Data from Latin America and the Caribbean is still lacking. Our main objective was to determine the frequency, risk factors and trends in time for being late HAART initiator (LHI) in this region., Methodology: Cross-sectional analysis from 9817 HIV-infected treatment-naïve patients initiating HAART at 6 sites (Argentina, Chile, Haiti, Honduras, Peru and Mexico) from October 1999 to July 2010. LHI had CD4(+) count ≤200 cells/mm(3) prior to HAART. Late testers (LT) were those LHI who initiated HAART within 6 months of HIV diagnosis. Late presenters (LP) initiated after 6 months of diagnosis. Prevalence, risk factors and trends over time were analyzed., Principal Findings: Among subjects starting HAART (n = 9817) who had baseline CD4(+) available (n = 8515), 76% were LHI: Argentina (56%[95%CI:52-59]), Chile (80%[95%CI:77-82]), Haiti (76%[95%CI:74-77]), Honduras (91%[95%CI:87-94]), Mexico (79%[95%CI:75-83]), Peru (86%[95%CI:84-88]). The proportion of LHI statistically changed over time (except in Honduras) (p≤0.02; Honduras p = 0.7), with a tendency towards lower rates in recent years. Males had increased risk of LHI in Chile, Haiti, Peru, and in the combined site analyses (CSA). Older patients were more likely LHI in Argentina and Peru (OR 1.21 per +10-year of age, 95%CI:1.02-1.45; OR 1.20, 95%CI:1.02-1.43; respectively), but not in CSA (OR 1.07, 95%CI:0.94-1.21). Higher education was associated with decreased risk for LHI in Chile (OR 0.92 per +1-year of education, 95%CI:0.87-0.98) (similar trends in Mexico, Peru, and CSA). LHI with date of HIV-diagnosis available, 55% were LT and 45% LP., Conclusion: LHI was highly prevalent in CCASAnet sites, mostly due to LT; the main risk factors associated were being male and older age. Earlier HIV-diagnosis and earlier treatment initiation are needed to maximize benefits from HAART in the region.