A longitudinal single-cell atlas of anti-tumour necrosis factor treatment in inflammatory bowel disease.

Precision medicine in immune-mediated inflammatory diseases (IMIDs) requires a cellular understanding of treatment response. We describe a therapeutic atlas for Crohn's disease (CD) and ulcerative colitis (UC) following adalimumab, an anti-tumour necrosis factor (anti-TNF) treatment. We generated ~1 million single-cell transcriptomes, organised into 109 cell states, from 216 gut biopsies (41 subjects), revealing disease-specific differences. A systems biology-spatial analysis identified granuloma signatures in CD and interferon (IFN)-response signatures localising to T cell aggregates and epithelial damage in CD and UC. Pretreatment differences in epithelial and myeloid compartments were associated with remission outcomes in both diseases. Longitudinal comparisons demonstrated disease progression in nonremission: myeloid and T cell perturbations in CD and increased multi-cellular IFN signalling in UC. IFN signalling was also observed in rheumatoid arthritis (RA) synovium with a lymphoid pathotype. Our therapeutic atlas represents the largest cellular census of perturbation with the most common biologic treatment, anti-TNF, across multiple inflammatory diseases.

Robust SARS-CoV-2-specific T cell immunity is maintained at 6 months following primary infection.

The immune response to SARS-CoV-2 is critical in controlling disease, but there is concern that waning immunity may predispose to reinfection. We analyzed the magnitude and phenotype of the SARS-CoV-2-specific T cell response in 100 donors at 6 months following infection. T cell responses were present by ELISPOT and/or intracellular cytokine staining analysis in all donors and characterized by predominant CD4+ T cell responses with strong interleukin (IL)-2 cytokine expression. Median T cell responses were 50% higher in donors who had experienced a symptomatic infection, indicating that the severity of primary infection establishes a 'set point' for cellular immunity. T cell responses to spike and nucleoprotein/membrane proteins were correlated with peak antibody levels. Furthermore, higher levels of nucleoprotein-specific T cells were associated with preservation of nucleoprotein-specific antibody level although no such correlation was observed in relation to spike-specific responses. In conclusion, our data are reassuring that functional SARS-CoV-2-specific T cell responses are retained at 6 months following infection.

Specialized replication mechanisms maintain genome stability at human centromeres.

The high incidence of whole-arm chromosome aneuploidy and translocations in tumors suggests instability of centromeres, unique loci built on repetitive sequences and essential for chromosome separation. The causes behind this fragility and the mechanisms preserving centromere integrity remain elusive. We show that replication stress, hallmark of pre-cancerous lesions, promotes centromeric breakage in mitosis, due to spindle forces and endonuclease activities. Mechanistically, we unveil unique dynamics of the centromeric replisome distinct from the rest of the genome. Locus-specific proteomics identifies specialized DNA replication and repair proteins at centromeres, highlighting them as difficult-to-replicate regions. The translesion synthesis pathway, along with other factors, acts to sustain centromere replication and integrity. Prolonged stress causes centromeric alterations like ruptures and translocations, as observed in ovarian cancer models experiencing replication stress. This study provides unprecedented insights into centromere replication and integrity, proposing mechanistic insights into the origins of centromere alterations leading to abnormal cancerous karyotypes.

Single-cell analysis reveals the continuum of human lympho-myeloid progenitor cells.

The hierarchy of human hemopoietic progenitor cells that produce lymphoid and granulocytic-monocytic (myeloid) lineages is unclear. Multiple progenitor populations produce lymphoid and myeloid cells, but they remain incompletely characterized. Here we demonstrated that lympho-myeloid progenitor populations in cord blood - lymphoid-primed multi-potential progenitors (LMPPs), granulocyte-macrophage progenitors (GMPs) and multi-lymphoid progenitors (MLPs) - were functionally and transcriptionally distinct and heterogeneous at the clonal level, with progenitors of many different functional potentials present. Although most progenitors had the potential to develop into only one mature cell type ('uni-lineage potential'), bi- and rarer multi-lineage progenitors were present among LMPPs, GMPs and MLPs. Those findings, coupled with single-cell expression analyses, suggest that a continuum of progenitors execute lymphoid and myeloid differentiation, rather than only uni-lineage progenitors' being present downstream of stem cells.

RYBP-PRC1 complexes mediate H2A ubiquitylation at polycomb target sites independently of PRC2 and H3K27me3.

Polycomb-repressive complex 1 (PRC1) has a central role in the regulation of heritable gene silencing during differentiation and development. PRC1 recruitment is generally attributed to interaction of the chromodomain of the core protein Polycomb with trimethyl histone H3K27 (H3K27me3), catalyzed by a second complex, PRC2. Unexpectedly we find that RING1B, the catalytic subunit of PRC1, and associated monoubiquitylation of histone H2A are targeted to closely overlapping sites in wild-type and PRC2-deficient mouse embryonic stem cells (mESCs), demonstrating an H3K27me3-independent pathway for recruitment of PRC1 activity. We show that this pathway is mediated by RYBP-PRC1, a complex comprising catalytic subunits of PRC1 and the protein RYBP. RYBP-PRC1 is recruited to target loci in mESCs and is also involved in Xist RNA-mediated silencing, the latter suggesting a wider role in Polycomb silencing. We discuss the implications of these findings for understanding recruitment and function of Polycomb repressors.

Defining genome architecture at base-pair resolution.

In higher eukaryotes, many genes are regulated by enhancers that are 104-106 base pairs (bp) away from the promoter. Enhancers contain transcription-factor-binding sites (which are typically around 7-22 bp), and physical contact between the promoters and enhancers is thought to be required to modulate gene expression. Although chromatin architecture has been mapped extensively at resolutions of 1 kilobase and above; it has not been possible to define physical contacts at the scale of the proteins that determine gene expression. Here we define these interactions in detail using a chromosome conformation capture method (Micro-Capture-C) that enables the physical contacts between different classes of regulatory elements to be determined at base-pair resolution. We find that highly punctate contacts occur between enhancers, promoters and CCCTC-binding factor (CTCF) sites and we show that transcription factors have an important role in the maintenance of the contacts between enhancers and promoters. Our data show that interactions between CTCF sites are increased when active promoters and enhancers are located within the intervening chromatin. This supports a model in which chromatin loop extrusion1 is dependent on cohesin loading at active promoters and enhancers, which explains the formation of tissue-specific chromatin domains without changes in CTCF binding.

Hydrogen bonding heterogeneity correlates with protein folding transition state passage time as revealed by data sonification.

Protein-protein and protein-water hydrogen bonding interactions play essential roles in the way a protein passes through the transition state during folding or unfolding, but the large number of these interactions in molecular dynamics (MD) simulations makes them difficult to analyze. Here, we introduce a state space representation and associated "rarity" measure to identify and quantify transition state passage (transit) events. Applying this representation to a long MD simulation trajectory that captured multiple folding and unfolding events of the GTT WW domain, a small protein often used as a model for the folding process, we identified three transition categories: Highway (faster), Meander (slower), and Ambiguous (intermediate). We developed data sonification and visualization tools to analyze hydrogen bond dynamics before, during, and after these transition events. By means of these tools, we were able to identify characteristic hydrogen bonding patterns associated with "Highway" versus "Meander" versus "Ambiguous" transitions and to design algorithms that can identify these same folding pathways and critical protein-water interactions directly from the data. Highly cooperative hydrogen bonding can either slow down or speed up transit. Furthermore, an analysis of protein-water hydrogen bond dynamics at the surface of WW domain shows an increase in hydrogen bond lifetime from folded to unfolded conformations with Ambiguous transitions as an outlier. In summary, hydrogen bond dynamics provide a direct window into the heterogeneity of transits, which can vary widely in duration (by a factor of 10) due to a complex energy landscape.

ATR-X syndrome protein targets tandem repeats and influences allele-specific expression in a size-dependent manner.

ATRX is an X-linked gene of the SWI/SNF family, mutations in which cause syndromal mental retardation and downregulation of α-globin expression. Here we show that ATRX binds to tandem repeat (TR) sequences in both telomeres and euchromatin. Genes associated with these TRs can be dysregulated when ATRX is mutated, and the change in expression is determined by the size of the TR, producing skewed allelic expression. This reveals the characteristics of the affected genes, explains the variable phenotypes seen with identical ATRX mutations, and illustrates a new mechanism underlying variable penetrance. Many of the TRs are G rich and predicted to form non-B DNA structures (including G-quadruplex) in vivo. We show that ATRX binds G-quadruplex structures in vitro, suggesting a mechanism by which ATRX may play a role in various nuclear processes and how this is perturbed when ATRX is mutated.

Extended panel testing in ovarian cancer reveals BRIP1 as the third most important predisposition gene.

PURPOSE: The prevalence of germline pathogenic variants (PVs) in homologous recombination repair (HRR) and Lynch syndrome (LS) genes in ovarian cancer (OC) is uncertain. METHODS: An observational study reporting the detection rate of germline PVs in HRR and LS genes in all OC cases tested in the North West Genomic Laboratory Hub between September 1996 and May 2024. Effect sizes are reported using odds ratios (ORs) and 95% confidence intervals (95% CI) for unselected cases tested between April 2021 and May 2024 versus 50,703 controls from the Breast Cancer Risk after Diagnostic Gene Sequencing study. RESULTS: 2934 women were tested for BRCA1/2 and 433 (14.8%) had a PV. In up to 1572 women tested for PVs in non-BRCA1/2 HRR genes, detection rates were PALB2 = 0.8%, BRIP1 = 1.1%, RAD51C = 0.4% and RAD51D = 0.4%. In 940 unselected cases, BRIP1 (OR = 8.7, 95% CI 4.6-15.8) was the third most common OC predisposition gene followed by RAD51C (OR = 8.3, 95% CI 3.1-23.1), RAD51D (OR = 6.5, 95% CI 2.1-19.7), and PALB2 (OR = 3.9, 95% CI 1.5-10.3). No PVs in LS genes were detected in unselected cases. CONCLUSION: Panel testing in OC resulted in a detection rate of 2% to 3% for germline PVs in non-BRCA1/2 HRR genes, with the largest contributor being BRIP1. Screening for LS in unselected cases of OC is unnecessary.

Mapping the distance between fire hazard and disaster for communities in Canadian forests.

Communities interspersed throughout the Canadian wildland are threatened by fires that have become bigger and more frequent in some parts of the country in recent decades. Identifying the fireshed (source area) and pathways from which wildland fire may ignite and spread from the landscape to a community is crucial for risk-reduction strategy and planning. We used outputs from a fire simulation model, including fire polygons and rate of spread, to map firesheds, fire pathways and corridors and spread distances for 1980 communities in the forested areas of Canada. We found fireshed sizes are larger in the north, where the mean distances between ecumene and fireshed perimeters were greater than 10 km. The Rayleigh Z test indicated that simulated fires around a large proportion of communities show significant directional trends, and these trends are stronger in the Boreal Plains and Shields than in the Rocky Mountain area. The average distance from which fire, when spreading at the maximum simulated rate, could reach the community perimeter was approximately 5, 12 and 18 km in 1, 2 and 3 days, respectively. The average daily spread distances increased latitudinally, from south to north. Spread distances were the shortest in the Pacific Maritime, Atlantic Maritime and Boreal Plains Ecozones, implying lower rates of spread compared to the rest of the country. The fire corridors generated from random ignitions and from ignitions predicted from local fire history differ, indicating that factors other than fuel (e.g. fire weather, ignition pattern) play a significant role in determining the direction that fires burn into a community.

Fast Parameter Inference on Pulsar Timing Arrays with Normalizing Flows.

Pulsar timing arrays perform Bayesian posterior inference with expensive Markov chain Monte Carlo (MCMC) methods. Given a dataset of ∼10-100 pulsars and O(10^{3}) timing residuals each, producing a posterior distribution for the stochastic gravitational wave background (SGWB) can take days to a week. The computational bottleneck arises because the likelihood evaluation required for MCMC is extremely costly when considering the dimensionality of the search space. Fortunately, generating simulated data is fast, so modern simulation-based inference techniques can be brought to bear on the problem. In this Letter, we demonstrate how conditional normalizing flows trained on simulated data can be used for extremely fast and accurate estimation of the SGWB posteriors, reducing the sampling time from weeks to a matter of seconds.

Efficient Large-Scale, Targeted Gravitational-Wave Probes of Supermassive Black-Hole Binaries.

Binary systems of supermassive black holes are promising sources of low-frequency gravitational waves (GWs) and bright electromagnetic emission. Pulsar timing array GW searches for individual binaries have been limited to only a few candidate systems due to computational demands, which get worse as more pulsars are added. By modeling the GW signal using only components from when the GW passes Earth (rather than also each pulsar), we find constraints on the binary's total mass and GW frequency that are similar to a full signal analysis, yet ∼70 times more efficient.

Exploiting a living biobank to delineate mechanisms underlying disease-specific chromosome instability.

Chromosome instability (CIN) is a cancer hallmark that drives tumour heterogeneity, phenotypic adaptation, drug resistance and poor prognosis. High-grade serous ovarian cancer (HGSOC), one of the most chromosomally unstable tumour types, has a 5-year survival rate of only ~30% - largely due to late diagnosis and rapid development of drug resistance, e.g., via CIN-driven ABCB1 translocations. However, CIN is also a cell cycle vulnerability that can be exploited to specifically target tumour cells, illustrated by the success of PARP inhibitors to target homologous recombination deficiency (HRD). However, a lack of appropriate models with ongoing CIN has been a barrier to fully exploiting disease-specific CIN mechanisms. This barrier is now being overcome with the development of patient-derived cell cultures and organoids. In this review, we describe our progress building a Living Biobank of over 120 patient-derived ovarian cancer models (OCMs), predominantly from HGSOC. OCMs are highly purified tumour fractions with extensive proliferative potential that can be analysed at early passage. OCMs have diverse karyotypes, display intra- and inter-patient heterogeneity and mitotic abnormality rates far higher than established cell lines. OCMs encompass a broad-spectrum of HGSOC hallmarks, including a range of p53 alterations and BRCA1/2 mutations, and display drug resistance mechanisms seen in the clinic, e.g., ABCB1 translocations and BRCA2 reversion. OCMs are amenable to functional analysis, drug-sensitivity profiling, and multi-omics, including single-cell next-generation sequencing, and thus represent a platform for delineating HGSOC-specific CIN mechanisms. In turn, our vision is that this understanding will inform the design of new therapeutic strategies.

Influence of Patient Weight on Prehospital Advanced Airway Procedure Success Rates.

OBJECTIVE: Previous investigations of the relationship between obesity and difficult airway management have provided mixed results. Almost universally, these studies were conducted in the hospital setting, and the influence of patient body weight on successful prehospital airway management remains unclear. Because patient weight could be one readily identifiable risk factor for problematic airway interventions, we sought to evaluate this relationship. METHODS: We conducted a retrospective analysis using the 2020 ESO Data Collaborative dataset. The inclusion criteria consisted of adult patients weighing >30kg with an attempted orotracheal intubation (OTI) and/or blind insertion airway device (BIAD) placement. Separate logistic regression models were developed to determine the influence of weight (dichotomized at 100 kg) on cumulative procedure success for OTI and BIAD, and linear regression models were used to identify trends for each across weight strata. RESULTS: A total of 45,344 patients met inclusionary criteria, among which 40,668(89.7%) suffered from a medical emergency, followed by 3,130(6.9%) with traumatic injuries, and 1,546(3.4%) attributable to a combined medical-trauma etiology. Cardiac arrest occurred either prior to EMS arrival or at some point during EMS care in 38,210(84.3%) patients. OTI was attempted in 18,153(40.0%) patients, while 21,597(47.6%) had a BIAD attempt and 5,594(12.3%) had both airway types attempted. The overall cumulative insertion success rates for OTI and BIAD were 79.5% and 92.7%, respectively. Altogether, 2,711(6.0%) had no advanced airway of any type successfully placed, which represents the overall failed advanced airway rate. After controlling for patient age, sex, minority status, and call type (medical vs. trauma), weight >100kg was associated with decreased likelihood of cumulative OTI success (OR = 0.64, p < 0.001), but higher likelihood of cumulative BIAD success (OR = 1.31, p < 0.001). Cumulative OTI success was associated with a negative 0.6% linear trend per 5 kg of body weight (p < 0.001) while cumulative BIAD success had a 0.2% positive trend (p < 0.001). CONCLUSION: This retrospective analysis of a national EMS database revealed that increasing patient weight was negatively associated with intubation success. A positive, but smaller, linear trend was observed for BIAD placement. Patient weight may be an easily identifiable predictor of difficult oral intubation and may be a consideration when selecting an airway management strategy.

The Route to ROSC: Evaluating the Impact of Route and Timing of Epinephrine Administration in Out-of-Hospital Cardiac Arrest Outcomes.

OBJECTIVES: Previous investigations comparing intraosseous (IO) and intravenous (IV) epinephrine delivery in out-of-hospital cardiac arrest (OHCA) suggest that epinephrine is oftentimes more expeditiously administered via the IO route, but this temporal benefit doesn't always translate to clinical benefit. However, very few studies adequately controlled for indication and resuscitation time biases, making the influence of first epinephrine route on OHCA outcomes unclear. To determine the association between first epinephrine route and return of spontaneous circulation (ROSC) while controlling for resuscitation time bias and other potential confounders. METHODS: We conducted a retrospective analysis using the 2020 ESO Data Collaborative dataset. Adult patients with a witnessed, non-traumatic OHCA prior to EMS arrival were included. Logistic regression was used to determine the association between medication route and ROSC. Linear regression was then used to calculate the probability of ROSC for each route across all call receipt-to-drug delivery intervals. Using these linear equations, the call receipt-to-drug delivery intervals were calculated that would yield equivalent probabilities of ROSC between the IV and IO routes. RESULTS: Data were available for 10,350 patients, of which 27.4% presented with a shockable rhythm, 29.7% received bystander CPR, and 39.6% experienced ROSC. After controlling for confounders, IO epinephrine was associated with decreased likelihood of ROSC (OR = 0.77, p < 0.001). The linear regression models provided differing slope coefficients for ROSC between each route, with the IV route associated with a higher likelihood of ROSC for any given call receipt-to-drug-delivery interval. From these equations, the additional time allowed to establish an IV and administer epinephrine intravenously beyond the time required for IO delivery, yet with an equivalent predicted probability of ROSC via the IO route, was calculated. This additional time interval for intravenous administration declined linearly from 9 min at a call receipt-to-intraosseous epinephrine interval of 4 min to no additional time at a call receipt-to-intraosseous epinephrine interval of 29 min. CONCLUSIONS: This retrospective analysis of a national EMS database revealed that IO epinephrine was negatively associated with ROSC. Additionally, there appears to be a finite time window during which intravenous epinephrine remains superior to the intraosseous route even if there are brief initial delays in IV drug delivery.

Towards a core outcome set for dysarthria after stroke: What should we measure?

OBJECTIVE: To identify and agree on what outcome domains should be measured in research and clinical practice when working with stroke survivors who have dysarthria. DESIGN: Delphi process, two rounds of an online survey followed by two online consensus meetings. SETTING: UK and Australia. PARTICIPANTS: Stroke survivors with experience of dysarthria, speech and language therapists/pathologists working in stroke and communication researchers. METHODS: Initial list of outcome domains generated from existing literature and with our patient and public involvement group to develop the survey. Participants completed two rounds of this survey to rate importance. Outcomes were identified as 'in', 'unclear' or 'out' from the second survey. All participants were invited to two consensus meetings to discuss these results followed by voting to identify critically important outcome domains for a future Core Outcome Set. All outcomes were voted on in the consensus meetings and included if 70% of meeting participants voted 'yes' for critically important. RESULTS: In total, 148 surveys were fully completed, and 28 participants attended the consensus meetings. A core outcome set for dysarthria after stroke should include four outcome domains: (a) intelligibility of speech, (b) ability to participate in conversations, (c) living well with dysarthria, (d) skills and knowledge of communication partners (where relevant). CONCLUSIONS: We describe the consensus of 'what' speech outcomes after stroke are valued by all stakeholders including those with lived experience. We share these findings to encourage the measurement of these domains in clinical practice and research and for future research to identify 'how' best to measure these outcomes.

Efficacy and Safety of Switching to the 2-Drug Regimen Dolutegravir/Lamivudine Versus Continuing a 3- or 4-Drug Regimen for Maintaining Virologic Suppression in Adults Living With Human Immunodeficiency Virus 1 (HIV-1): Week 48 Results From the Phase 3, Noninferiority SALSA Randomized Trial.

BACKGROUND: In TANGO, switching to dolutegravir/lamivudine (DTG/3TC) demonstrated long-term noninferior efficacy vs continuing tenofovir alafenamide-based regimens in treatment-experienced adults with HIV-1. The phase 3 SALSA study evaluated efficacy and safety of switching to DTG/3TC compared with continuing various 3-/4-drug current antiretroviral regimens (CARs). METHODS: Adults with HIV-1 RNA <50 copies/mL and no previous virologic failure were randomized (1:1, stratified by baseline third agent class) to switch to once-daily fixed-dose combination DTG/3TC or continue CAR (primary endpoint: proportion of participants with HIV-1 RNA ≥50 copies/mL at week 48; Snapshot, intention-to-treat-exposed population, 5% noninferiority margin). RESULTS: Overall, 493 adults (39% women; 39% aged ≥50 years; 19% African American/African heritage; 14% Asian) were randomized to switch to DTG/3TC (n = 246) or continue CAR (n = 247). At week 48, 1 (0.4%) participant in the DTG/3TC group and 3 (1.2%) in the CAR group had HIV-1 RNA ≥50 copies/mL (Snapshot), demonstrating noninferiority (adjusted difference, -0.8%; 95% CI, -2.4%, .8%). Zero participants met confirmed virologic withdrawal criteria; therefore, no resistance testing was performed. Drug-related adverse events were more frequent with DTG/3TC (20%) than CAR (6%) through week 48 but comparable post-week 24 (5% vs 2%, respectively). Proximal tubular renal function and bone turnover biomarkers improved with DTG/3TC. Both groups had generally minimal changes in lipids and inflammatory biomarkers. CONCLUSIONS: Switching to DTG/3TC was noninferior to continuing CAR for maintaining virologic suppression at week 48 with no observed resistance, supporting the efficacy, good safety, and high barrier to resistance of DTG/3TC. CLINICAL TRIALS REGISTRATION: www.clinicaltrials.gov, NCT04021290.

LanceOtron: a deep learning peak caller for genome sequencing experiments.

MOTIVATION: Genome sequencing experiments have revolutionized molecular biology by allowing researchers to identify important DNA-encoded elements genome wide. Regions where these elements are found appear as peaks in the analog signal of an assay's coverage track, and despite the ease with which humans can visually categorize these patterns, the size of many genomes necessitates algorithmic implementations. Commonly used methods focus on statistical tests to classify peaks, discounting that the background signal does not completely follow any known probability distribution and reducing the information-dense peak shapes to simply maximum height. Deep learning has been shown to be highly accurate for many pattern recognition tasks, on par or even exceeding human capabilities, providing an opportunity to reimagine and improve peak calling. RESULTS: We present the peak calling framework LanceOtron, which combines deep learning for recognizing peak shape with multifaceted enrichment calculations for assessing significance. In benchmarking ATAC-seq, ChIP-seq and DNase-seq, LanceOtron outperforms long-standing, gold-standard peak callers through its improved selectivity and near-perfect sensitivity. AVAILABILITY AND IMPLEMENTATION: A fully featured web application is freely available from LanceOtron.molbiol.ox.ac.uk, command line interface via python is pip installable from PyPI at https://pypi.org/project/lanceotron/, and source code and benchmarking tests are available at https://github.com/LHentges/LanceOtron. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

A matched cohort study investigating premature, accentuated, and accelerated aging in people living with HIV.

INTRODUCTION: The impact of HIV infection on the aging process is disputed and largely unknown. We aimed to identify whether people living with HIV experience premature, accelerated, and/or accentuated aging by investigating the development of four age-related non-communicable diseases in people living with versus without HIV. METHODS: This population-based matched cohort study design used UK-based primary care electronic health records from the IQVIA Medical Research Database. Between January 2000 and January 2020, all people living with and without HIV aged ≥18 years were eligible. Outcomes included cardiovascular disease (CVD), hypertension, type 2 diabetes mellitus (T2DM), and chronic kidney disease (CKD), which were identified by Read codes. We used age at diagnosis to investigate premature aging and age at exit date to investigate accentuation and acceleration. For each outcome, people with and without HIV were excluded if they had the outcome of interest at baseline. Participants were matched based on propensity scores (1:1 ratio). Linear regression was used to report any difference in age at diagnosis between the two groups and to report the prevalence trends for age at exit date. RESULTS: In total, 8880 people living with HIV were matched with 8880 people without HIV and were found to have an earlier onset of CVD (54.5 vs. 56.8; p = 0.002). Similarly, people living with HIV had an earlier onset of hypertension (49.7 vs. 51.4; p = 0.002). No difference was found for T2DM or CKD (53.4 vs. 52.6; p = 0.368 and 57.6 vs. 58.1; p = 0.483, respectively). The burden of CKD increased over time, whereas no difference in the burden was found for the other conditions. CONCLUSION: The earlier development of CVD and hypertension in people living with HIV than in those without HIV indicates premature aging, whereas the increased burden of CKD indicates accelerated aging.