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In secondary lymphoid tissues, human immunodeficiency virus (HIV) can replicate in both the follicular and extrafollicular compartments. Yet, virus is concentrated in the follicular compartment in the absence of antiretroviral therapy, in part due to the lack of cytotoxic T lymphocyte (CTL)-mediated activity there. CTLs home to the extrafollicular compartment, where they can suppress virus load to relatively low levels. We use mathematical models to show that this compartmentalization can explain seemingly counter-intuitive observations. First, it can explain the observed constancy of the viral decline slope during antiviral therapy in the peripheral blood, irrespective of the presence of CTL in Simian Immunodeficiency Virus (SIV)-infected macaques, under the assumption that CTL-mediated lysis significantly contributes to virus suppression. Second, it can account for the relatively long times it takes for CTL escape mutants to emerge during chronic infection even if CTL-mediated lysis is responsible for virus suppression. The reason is the heterogeneity in CTL activity and the consequent heterogeneity in selection pressure between the follicular and extrafollicular compartments. Hence, to understand HIV dynamics more thoroughly, this analysis highlights the importance of measuring virus populations separately in the extrafollicular and follicular compartments rather than using virus load in peripheral blood as an observable; this hides the heterogeneity between compartments that might be responsible for the particular patterns seen in the dynamics and evolution of the HIV in vivo.

Early initiation of antiretroviral therapy (ART) alters viral rebound kinetics after analytic treatment interruption (ATI) and may play a role in promoting HIV-1 remission. Autologous neutralizing antibodies (aNAbs) represent a key adaptive immune response in people living with HIV-1. We aimed to investigate the role of aNAbs in shaping post-ATI HIV-1 rebound variants. We performed single-genome amplification of HIV-1 env from pre-ART and post-ATI plasma samples of 12 individuals who initiated ART early after infection. aNAb activity was quantified using pseudoviruses derived from the most common plasma variant, and the serum dilution that inhibited 50% of viral infections was determined. aNAb responses matured while participants were on suppressive ART, because on-ART plasma and purified immunoglobulin G (IgG) demonstrated improved neutralizing activity against pre-ART HIV-1 strains when compared with pre-ART plasma or purified IgG. Post-ATI aNAb responses exerted selective pressure on the rebounding viruses, because the post-ATI HIV-1 strains were more resistant to post-ATI plasma neutralization compared with the pre-ART virus. Several pre-ATI features distinguished post-treatment controllers from noncontrollers, including an infecting HIV-1 sequence that was more similar to consensus HIV-1 subtype B, more restricted proviral diversity, and a stronger aNAb response. Post-treatment control was also associated with the evolution of distinct N-glycosylation profiles in the HIV-1 envelope. In summary, aNAb responses appeared to mature after early initiation of ART and applied selective pressure on rebounding viruses. The combination of aNAb activity with select HIV-1 sequence and reservoir features identified individuals with a greater chance of post-treatment control.

HIV post-treatment controllers (PTCs) are rare individuals who maintain low levels of viremia after stopping antiretroviral therapy (ART). Understanding the mechanisms of HIV post-treatment control will inform development of strategies aiming at achieving HIV functional cure. In this study, we evaluated 22 PTCs from 8 AIDS Clinical Trials Group (ACTG) analytical treatment interruption (ATI) studies who maintained viral loads ≤400 copies/mL for ≥24 wk. There were no significant differences in demographics or frequency of protective and susceptible human leukocyte antigen (HLA) alleles between PTCs and post-treatment noncontrollers (NCs, n = 37). Unlike NCs, PTCs demonstrated a stable HIV reservoir measured by cell-associated RNA (CA-RNA) and intact proviral DNA assay (IPDA) during analytical treatment interruption (ATI). Immunologically, PTCs demonstrated significantly lower CD4+ and CD8+ T cell activation, lower CD4+ T cell exhaustion, and more robust Gag-specific CD4+ T cell responses and natural killer (NK) cell responses. Sparse partial least squares discriminant analysis (sPLS-DA) identified a set of features enriched in PTCs, including a higher CD4+ T cell% and CD4+/CD8+ ratio, more functional NK cells, and a lower CD4+ T cell exhaustion level. These results provide insights into the key viral reservoir features and immunological profiles for HIV PTCs and have implications for future studies evaluating interventions to achieve an HIV functional cure.

Posttreatment controllers (PTCs) are rare HIV-infected individuals who can limit viral rebound after antiretroviral therapy interruption (ATI), but the mechanisms of this remain unclear. To investigate these mechanisms, we quantified various HIV RNA transcripts (via reverse transcription droplet digital PCR [RT-ddPCR]) and cellular transcriptomes (via RNA-seq) in blood cells from PTCs and noncontrollers (NCs) before and two time points after ATI. HIV transcription initiation did not significantly increase after ATI in PTCs or in NCs, whereas completed HIV transcripts increased at early ATI in both groups and multiply-spliced HIV transcripts increased only in NCs. Compared to NCs, PTCs showed lower levels of HIV DNA, more cell-associated HIV transcripts per total RNA at all times, no increase in multiply-spliced HIV RNA at early or late ATI, and a reduction in the ratio of completed/elongated HIV RNA after early ATI. NCs expressed higher levels of the IL-7 pathway before ATI and expressed higher levels of multiple cytokine, inflammation, HIV transcription, and cell death pathways after ATI. Compared to the baseline, the NCs upregulated interferon and cytokine (especially TNF) pathways during early and late ATI, whereas PTCs upregulated interferon and p53 pathways only at early ATI and downregulated gene translation during early and late ATI. In NCs, viral rebound after ATI is associated with increases in HIV transcriptional completion and splicing, rather than initiation. Differences in HIV and cellular transcription may contribute to posttreatment control, including an early limitation of spliced HIV RNA, a delayed reduction in completed HIV transcripts, and the differential expression of the IL-7, p53, and TNF pathways. IMPORTANCE The findings presented here provide new insights into how HIV and cellular gene expression change after stopping ART in both noncontrollers and posttreatment controllers. Posttreatment control is associated with an early ability to limit increases in multiply-spliced HIV RNA, a delayed (and presumably immune-mediated) ability to reverse an initial rise in processive/completed HIV transcripts, and multiple differences in cellular gene expression pathways. These differences may represent correlates or mechanisms of posttreatment control and may provide insight into the development and/or monitoring of therapeutic strategies that are aimed at a functional HIV cure.

Background The brain reserve hypothesis posits that larger maximal lifetime brain growth (MLBG) may confer protection against physical disability in multiple sclerosis (MS). Larger MLBG as a proxy for brain reserve, has been associated with reduced progression of physical disability in patients with early MS; however, it is unknown whether this association remains once in the secondary progressive phase of MS (SPMS). Our aim was to assess whether larger MLBG is associated with decreased physical disability progression in SPMS.Methods We conducted a post hoc analysis of participants in the MS-Secondary Progressive Multi-Arm Randomisation Trial (NCT01910259), a multicentre randomised placebo-controlled trial of the neuroprotective potential of three agents in SPMS. Physical disability was measured by Expanded Disability Status Scale (EDSS), 9-hole peg test (9HPT) and 25-foot timed walk test (T25FW) at baseline, 48 and 96 weeks. MLBG was estimated by baseline intracranial volume (ICV). Multivariable time-varying Cox regression models were used to investigate the association between MLBG and physical disability progression.Results 383 participants (mean age 54.5 years, 298 female) were followed up over 96 weeks. Median baseline EDSS was 6.0 (range 4.0–6.5). Adjusted for covariates, larger MLBG was associated with a reduced risk of EDSS progression (HR 0.84,95% CI:0.72 to 0.99;p=0.04). MLBG was not independently associated with time to progression as measured by 9HPT or T25FW.Conclusion Larger MLBG is independently associated with physical disability progression over 96 weeks as measured by EDSS in SPMS. This suggests that MLBG as a proxy for brain reserve may continue to confer protection against disability when in the secondary progression phase of MS.Trail registration number NCT01910259.

PurposeMultiple sclerosis (MS) is an immune-mediated, neuroinflammatory disease of the central nervous system and in industrialised countries is the most common cause of progressive neurological disability in working age persons. While treatable, there is substantial interindividual heterogeneity in disease activity and response to treatment. Currently, the ability to predict at diagnosis who will have a benign, intermediate or aggressive disease course is very limited. There is, therefore, a need for integrated predictive tools to inform individualised treatment decision making.ParticipantsEstablished with the aim of addressing this need for individualised predictive tools, FutureMS is a nationally representative, prospective observational cohort study of 440 adults with a new diagnosis of relapsing-remitting MS living in Scotland at the time of diagnosis between May 2016 and March 2019.Findings to dateThe study aims to explore the pathobiology and determinants of disease heterogeneity in MS and combines detailed clinical phenotyping with imaging, genetic and biomarker metrics of disease activity and progression. Recruitment, baseline assessment and follow-up at year 1 is complete. Here, we describe the cohort design and present a profile of the participants at baseline and 1 year of follow-up.Future plansA third follow-up wave for the cohort has recently begun at 5 years after first visit and a further wave of follow-up is funded for year 10. Longer-term follow-up is anticipated thereafter.

Clinical trials including an analytical treatment interruption (ATI) are vital for evaluating the efficacy of novel strategies for HIV remissions. We briefly describe an interactive tool for predicting viral rebound timing in ATI trials and the impact of posttreatment controller (PTC) definitions on PTC frequency estimates. A 4-week viral load threshold of 1000 cps/ml provides both high specificity and sensitivity for PTC detection. PTC frequency varies greatly based on the definition of a PTC.

Myelin loss is associated with axonal damage in established multiple sclerosis. This relationship is challenging to study in vivo in early disease. Here, we ask whether myelin loss is associated with axonal damage at diagnosis by combining non-invasive neuroimaging and blood biomarkers. We performed quantitative microstructural MRI and single-molecule ELISA plasma neurofilament measurement in 73 patients with newly diagnosed, immunotherapy naïve relapsing-remitting multiple sclerosis. Myelin integrity was evaluated using aggregate g-ratios, derived from magnetization transfer saturation and neurite orientation dispersion and density imaging diffusion data. We found significantly higher g-ratios within cerebral white matter lesions (suggesting myelin loss) compared with normal-appearing white matter (0.61 versus 0.57, difference 0.036, 95% CI: 0.029-0.043, P < 0.001). Lesion volume (Spearman's rho rs= 0.38, P < 0.001) and g-ratio (rs= 0.24, P < 0.05) correlated independently with plasma neurofilament. In patients with substantial lesion load (n = 38), those with higher g-ratio (defined as greater than median) were more likely to have abnormally elevated plasma neurofilament than those with normal g-ratio (defined as less than median) [11/23 (48%) versus 2/15 (13%), P < 0.05]. These data suggest that, even at multiple sclerosis diagnosis, reduced myelin integrity is associated with axonal damage. MRI-derived g-ratio may provide useful additional information regarding lesion severity and help to identify individuals with a high degree of axonal damage at disease onset.

In this research note, I track the reflective process of creating and facilitating a workshop series in Amman, Jordan, as a way in which to explore the (re)creation, (re)construction, and (re)negotiation of understandings of Palestinian cultural heritage and identity. The workshop centers around the idea of materiality from the Palestinian homes in Amman being framed as a “material witness” of exile. These material witnesses become an access point into the individual versus the larger transnational exilic experience. I introduce the idea of playing within a participatory heritage framework and how, by starting with the material witnesses from houses in Amman today, it enables a discussion on the modalities of exile, local identity formation, and the performativity of memory as part of an ongoing creative process of meaning-making. I also draw out discussions of playing with my own methodology practice and what it means for future research.

Abstract Background Medical doctors routinely undertake a number of practical procedures and these should be performed competently. The UK Postgraduate Medical Education and Training Board (PMETB) curriculum lists the procedures trainees should be competent in. We aimed to describe medical practitioner's confidence in their procedural skills, and to define which practical procedures are important in current medical practice. Methods A cross sectional observational study was performed measuring procedural confidence in 181 hospital practitioners at all grades from 2 centres in East Anglia, England. Results Both trainees and consultants provide significant service provision. SpR level doctors perform the widest range and the highest median number of procedures per year. Most consultants perform few if any procedures, however some perform a narrow range at high volume. Cumulative confidence for the procedures tested peaks in the SpR grade. Five key procedures (central line insertion, lumbar puncture, pleural aspiration, ascitic aspiration, and intercostal drain insertion) are the most commonly performed, are seen as important generic skills, and correspond to the total number of procedures for which confidence can be maintained. Key determinants of confidence are gender, number of procedures performed in the previous year and total number of procedures performed. Conclusion The highest volume of service requirement is for six procedures. The procedural confidence is dependent upon gender, number of procedures performed in the previous year and total number of procedures performed. This has implications for those designing the training curriculum and with regards the move to shorten the duration of training.

Abstract Background No treatments are currently available that slow, stop, or reverse disease progression in established multiple sclerosis (MS). The Mesenchymal Stem Cells in Multiple Sclerosis (MSCIMS) trial tests the safety and feasibility of treatment with a candidate cell-based therapy, and will inform the wider challenge of designing early phase clinical trials to evaluate putative neuroprotective therapies in progressive MS. Illustrated by the MSCIMS trial protocol, we describe a novel methodology based on detailed assessment of the anterior visual pathway as a model of wider disease processes - the "sentinel lesion approach". Methods/design MSCIMS is a phase IIA study of autologous mesenchymal stem cells (MSCs) in secondary progressive MS. A pre-test : post-test design is used with healthy controls providing normative data for inter-session variability. Complementary eligibility criteria and outcomes are used to select participants with disease affecting the anterior visual pathway. Results Ten participants with MS and eight healthy controls were recruited between October 2008 and March 2009. Mesenchymal stem cells were successfully isolated, expanded and characterised in vitro for all participants in the treatment arm. Conclusions In addition to determining the safety and feasibility of the intervention and informing design of future studies to address efficacy, MSCIMS adopts a novel strategy for testing neuroprotective agents in MS - the sentinel lesion approach - serving as proof of principle for its future wider applicability. Trial registration ClinicalTrials.gov (NCT00395200).

Cryptosporidium parvum is an opportunistic intracellular parasite that causes disease in animal populations such as calves and goats. It is also a significant zoonotic disease globally, causing mild to severe human diarrhea. In immunocompromised animals, calves and lambs, and immunocompromised humans such as AIDS patients, an infection can be life-threatening as no effective treatments are currently available to control infection. The effects of Cryptosporidium parvum antigen (CPA) on dendritic cells (DCs) were investigated. This study examined cytokine secretion and cell surface marker expression on DCs exposed to CPA. Cytokine production in CD4+ cells co-cultured with CPA primed DCs in the presence of anti-CD3 was also measured. CPA induced a significant increase in the production of interleukin (IL)-12p40, IL-10, IL-6, and TNF-α by DCs and enhanced the expression of the cell surface markers TLR4, CD80, CD86, and MHC11. CPA primed DC co-cultured in the presence of anti-CD3 with CD4+ T-cells inhibited the secretion of Th2-associated cytokines, notably IL-5 and IL-13, with no effects on the secretions of interferon (IFN)-γ, IL-2, IL-17, and IL-10. These findings support studies in the literature that CPA can induce the full maturation of DCs that subsequently initiate Th1 immune responses critical to the resolution of C. parvum infection.

The vapochromic properties of [Pt(tpy)Cl](PF6) crystals in the presence of acetonitrile and its effect on the crystal structure as well as the fluorescence spectrum of this complex have already been studied in the past. We synthesized nanocrystals of this compound for the first time, and discussed different parameters and methods that affect nanocrystal structure modulation. The study demonstrates the vapochromic properties of the nanocrystals toward acetonitrile vapor by investigating the morphology and fluorescence spectra of the nanocrystals. Vapochromic studies were conducted on [Pt(tpy)Cl](PF6) nanocrystals for five cycles of absorption and desorption of acetonitrile, demonstrating shorter response times compared to regular bulk crystals.

BackgroundPatterns of antiretroviral therapy (ART) use and immunologic correlates vary globally, and contemporary trends are not well described.MethodsThe REPRIEVE trial (Randomized Trial to Prevent Vascular Events in HIV) enrolled persons with human immunodeficiency virus (HIV) who were aged 40-75 years, receiving ART, and had low-to-moderate cardiovascular disease risk. ART use was summarized within Global Burden of Disease (GBD) super-regions, with adjusted linear and logistic regression analyses examining associations with immune parameters and key demographics.ResultsA total of 7770 participants were enrolled, with a median age of 50 years (interquartile range, 45-55 years); 31% were female, 43% were black or African American, 15% were Asian, 56% had a body mass index >25 (calculated as weight in kilograms divided by height in meters squared), and 49% were current or former smokers. The median CD4 T-cell count was 620/µL (interquartile range, 447-826/ µ L), and the median duration of prior ART use, 9.5 years (5.3-14.8) years. The most common ART regimens were nucleoside/nucleotide reverse-transcriptase inhibitor (NRTI) plus nonnucleoside reverse-transcriptase inhibitor (43%), NRTI plus integrase strand transfer inhibitor (25%), and NRTI plus protease inhibitor (19%). Entry ART varied by GBD region, with shifts during the trial enrollment period. In adjusted analyses, entry CD4 cell count and CD4/CD8 ratio were associated with GBD region, sex, entry regimen, duration of ART, and nadir CD4 cell count; CD4 and CD8 cell counts were also associated with body mass index and smoking status.ConclusionsThere were substantial variations in ART use by geographic region and over time, likely reflecting the local availability of specific medications, changes in treatment guidelines and provider/patient preferences. The analyses of CD4 cell counts and CD4/CD8 ratios may provide valuable insights regarding immune correlates and outcomes in people living with HIV.Clinical trials registrationNCT02344290.

In this follow-up article, we investigate the use of convolutional neural network for deriving stellar parameters from observed spectra. Using hyperparameters determined previously, we have constructed a Neural Network architecture suitable for the derivation of Teff{T}_{{\rm{eff}}}, logg\log g, [M/H]\left[M\hspace{0.1em}\text{/}\hspace{0.1em}H], and vesini{v}_{e}\sin i. The network was constrained by applying it to databases of AFGK synthetic spectra at different resolutions. Then, parameters of A stars from Polarbase, SOPHIE, and ELODIE databases are derived, as well as those of FGK stars from the spectroscopic survey of stars in the solar neighbourhood. The network model’s average accuracy on the stellar parameters is found to be as low as 80 K for Teff{T}_{{\rm{eff}}}, 0.06 dex for logg\log g, 0.08 dex for [M/H]\left[M\hspace{0.1em}\text{/}\hspace{0.1em}H], and 3 km/s for vesini{v}_{e}\sin i for AFGK stars.

Abstract Background: Depression has a point prevalence of 25% and lifetime prevalence of 50% in people with multiple sclerosis (pwMS). Due to accessibility and brevity, the 9-item Patient Health Questionnaire (PHQ-9) may be a useful tool in clinical practice for screening and monitoring of depressive symptoms in people with MS (pwMS). Methods: The objective of this study was to evaluate the reliability, validity and acceptability of the PHQ-9 as a screening tool for depressive symptoms in pwMS. PwMS completed online questionnaires at 3 time-points over 4-weeks. The PHQ-9, Multiple Sclerosis Impact Scale (MSIS-29), Centre for Disease Control Health-Related Quality of Life Measure (CDC-HQOL-4) and clinical history. Results: 103 participants completed the PHQ-9 at three time points, 43% were categorised as depressed on at least one response. The PHQ-9 exhibited high internal reliability (Cronbach’s α = 0.89), and test-re-test agreement (ICC 0.89, 95% CI 0.85–0.91). Convergent validity was indicated through positive correlation with the mental health items on the MSIS-29 (r = 0.46 and r = 0.50) and CDC-HQOL-4 (r = 0.79 and r = 0.73) at both assessment points. Positive correlations between the PHQ-9 and the MSIS-29 (r = 0.86 and r = 0.84) and CDC-HQOL-4 (r = 0.55 and r = 0.37) physical symptom sub-scores did not indicate divergent validity. 93% of ratings evaluated the PHQ-9 as “Very” or “Completely” acceptable. Conclusion: The PHQ-9 is a reliable and valid measure of depressive symptoms in people with MS. Given its accessibility, ease of administration, and acceptability, we recommend the PHQ-9 as a tool to screen for depressive symptoms in people with MS.

Abstract Objective In multiple sclerosis chronic demyelination is associated with axonal loss, and ultimately contributes to irreversible progressive disability. Enhancing remyelination may slow, or even reverse, disability. We recently trialled bexarotene versus placebo in 49 people with multiple sclerosis. While the primary MRI outcome was negative, there was converging neurophysiological and MRI evidence of efficacy. Multiple factors influence lesion remyelination. In this study we undertook a systematic exploratory analysis to determine whether treatment response – measured by change in magnetisation transfer ratio – is influenced by location (tissue type and proximity to CSF) or the degree of abnormality (using baseline magnetisation transfer ratio and T1 values). Methods We examined treatment effects at the whole lesion level, the lesion component level (core, rim and perilesional tissues) and at the individual lesion voxel level. Results At the whole lesion level, significant treatment effects were seen in GM but not WM lesions. Voxel‐level analyses detected significant treatment effects in WM lesion voxels with the lowest baseline MTR, and uncovered gradients of treatment effect in both WM and CGM lesional voxels, suggesting that treatment effects were lower near CSF spaces. Finally, larger treatment effects were seen in the outer and surrounding components of GM lesions compared to inner cores. Interpretation Remyelination varies markedly within and between lesions. The greater remyelinating effect in GM lesions is congruent with neuropathological observations. For future remyelination trials, whole GM lesion measures require less complex post‐processing compared to WM lesions (which require voxel level analyses) and markedly reduce sample sizes.

Since publication of this paper (Royal Society open science, 2022. 9(1): p. 211799), the authors have published a correction clarifying that the paper presents a case study that ‘… did not meet the definition for research with regard to human subjects'. The data are incorrectly referred to as experimental because the study has no experimental control. Furthermore, the paper has been presented previously but the version presented here selectively omits several analyses, posing a significant risk of bias. Of the prosthetic-related disadvantages identified by the authors, the most substantive was a 40% increase in time to 20 m (59.5 s.d. below the mean for NA sprinters). However the analysis was incomplete: acceleration modelling for NA sprinters continued up to 98% of maximum velocity, while Fastest BA was truncated at approximately 80%. We extrapolated the model, revealing the duration of maximum acceleration for Fastest BA is approximately 100% longer than NA sprinters. Important differences in Fastest BA contact lengths (0.10–0.15 m) were also identified. We posit that together, these large and important differences in sprint biomechanics and their likely physiological consequences suggest that running with and without prosthetics are so different that, although running times may be similar, the precautionary principle should apply and, in the interests of athletic competition integrity, runners with and without prosthetics should continue to compete separately.

Machine learning is an efficient method for analysing and interpreting the increasing amount of astronomical data that are available. In this study, we show a pedagogical approach that should benefit anyone willing to experiment with deep learning techniques in the context of stellar parameter determination. Using the convolutional neural network architecture, we give a step-by-step overview of how to select the optimal parameters for deriving the most accurate values for the stellar parameters of stars: Teff{T}_{{\rm{eff}}}, logg\log g, [M/H], and vesini{v}_{e}\sin i. Synthetic spectra with random noise were used to constrain this method and to mimic the observations. We found that each stellar parameter requires a different combination of network hyperparameters and the maximum accuracy reached depends on this combination as well as the signal-to-noise ratio of the observations, and the architecture of the network. We also show that this technique can be applied to other spectral-types in different wavelength ranges after the technique has been optimized.

The reactive strength index (RSI) measures the stretch shortening cycle (SSC), an important neuromuscular property for running performance, and critical for the game of Australian Football (AF). The 10/5 Repeated Jump test (RJ) is used to measure RSI, thus, the aims of the study were to determine if this test was reliable and could determine worthwhile change. Twenty-three male participants from an elite AF club completed RJ testing on two separate days of the week during the start of the preseason to determine interday and intraday reliability and determine whether smallest worthwhile change could be detected. All variables measured, (RSI, ground contact time, flight time, mean impulse and mean active stiffness) all had “excellent” ICC ratings >0.90 for both interday and intraday reliability. Mean landing RFD had “good” (ICC: 0.88) ratings for interday and “excellent” ratings for intraday reliability. Coefficient of variation ranged between 1.36-5.56% for all variables. All variables had a usefulness rating of “good”, indicating ability to detect smallest worthwhile change. The RJ test, is a reliable and sensitive measure to assess reactive strength index in AF athletes.

Objectives Motor neuron disease (MND) is an incurable progressive neurodegenerative disease with limited treatment options. There is a pressing need for innovation in identifying therapies to take to clinical trial. Here, we detail a systematic and structured evidence-based approach to inform consensus decision making to select the first two drugs for evaluation in Motor Neuron Disease-Systematic Multi-arm Adaptive Randomised Trial (MND-SMART: NCT04302870), an adaptive platform trial. We aim to identify and prioritise candidate drugs which have the best available evidence for efficacy, acceptable safety profiles and are feasible for evaluation within the trial protocol.Methods We conducted a two-stage systematic review to identify potential neuroprotective interventions. First, we reviewed clinical studies in MND, Alzheimer’s disease, Huntington’s disease, Parkinson’s disease and multiple sclerosis, identifying drugs described in at least one MND publication or publications in two or more other diseases. We scored and ranked drugs using a metric evaluating safety, efficacy, study size and study quality. In stage two, we reviewed efficacy of drugs in MND animal models, multicellular eukaryotic models and human induced pluripotent stem cell (iPSC) studies. An expert panel reviewed candidate drugs over two shortlisting rounds and a final selection round, considering the systematic review findings, late breaking evidence, mechanistic plausibility, safety, tolerability and feasibility of evaluation in MND-SMART.Results From the clinical review, we identified 595 interventions. 66 drugs met our drug/disease logic. Of these, 22 drugs with supportive clinical and preclinical evidence were shortlisted at round 1. Seven drugs proceeded to round 2. The panel reached a consensus to evaluate memantine and trazodone as the first two arms of MND-SMART.Discussion For future drug selection, we will incorporate automation tools, text-mining and machine learning techniques to the systematic reviews and consider data generated from other domains, including high-throughput phenotypic screening of human iPSCs.

Recurrent neuroinflammation in relapsing-remitting MS (RRMS) is thought to lead to neurodegeneration, resulting in progressive disability. Repeated magnetic resonance imaging (MRI) of the brain provides non-invasive measures of atrophy over time, a key marker of neurodegeneration. This study investigates regional neurodegeneration of the brain in recently-diagnosed RRMS using volumetry and voxel-based morphometry (VBM). RRMS patients (N = 354) underwent 3T structural MRI

BackgroundHIV posttreatment controllers are rare individuals who start antiretroviral therapy (ART), but maintain HIV suppression after treatment interruption. The frequency of posttreatment control and posttreatment interruption viral dynamics have not been well characterized.MethodsPosttreatment controllers were identified from 14 studies and defined as individuals who underwent treatment interruption with viral loads ≤400 copies/mL at two-thirds or more of time points for ≥24 weeks. Viral load and CD4+ cell dynamics were compared between posttreatment controllers and noncontrollers.ResultsOf the 67 posttreatment controllers identified, 38 initiated ART during early HIV infection. Posttreatment controllers were more frequently identified in those treated during early versus chronic infection (13% vs 4%, P < .001). In posttreatment controllers with weekly viral load monitoring, 45% had a peak posttreatment interruption viral load of ≥1000 copies/mL and 33% had a peak viral load ≥10000 copies/mL. Of posttreatment controllers, 55% maintained HIV control for 2 years, with approximately 20% maintaining control for ≥5 years.ConclusionsPosttreatment control was more commonly identified amongst early treated individuals, frequently characterized by early transient viral rebound and heterogeneous durability of HIV remission. These results may provide mechanistic insights and have implications for the design of trials aimed at achieving HIV remission.

HIV posttreatment controllers (PTCs) represent a natural model of sustained HIV remission, but they are rare and little is known about their viral reservoir. We obtained 1,450 proviral sequences after near-full-length amplification for 10 PTCs and 16 posttreatment noncontrollers (NCs). Before treatment interruption, the median intact and total reservoir size in PTCs was 7-fold lower than in NCs, but the proportion of intact, defective, and total clonally expanded proviral genomes was not significantly different between the 2 groups. Quantification of total but not intact proviral genome copies predicted sustained HIV remission as 81% of NCs, but none of the PTCs had a total proviral genome greater than 4 copies per million peripheral blood mononuclear cells (PBMCs). The results highlight the restricted intact and defective HIV reservoir in PTCs and suggest that total proviral genome burden could act as the first biomarker for identifying PTCs. Total and defective but not intact proviral copy numbers correlated with levels of cell-associated HIV RNA, activated NK cell percentages, and both HIV-specific CD4+ and CD8+ responses. These results support the concept that defective HIV genomes can lead to viral antigen production and interact with both the innate and adaptive immune systems.

Analytic treatment interruption (ATI) studies are required to evaluate strategies aimed at achieving ART-free HIV remission, but the impact of ATI on the viral reservoir remains unclear. We validated a DNA size selection-based assay for measuring levels of integrated HIV DNA and applied it to assess the effects of short-term ATI on the HIV reservoir. Samples from participants from four AIDS Clinical Trials Group ATI studies were assayed for integrated HIV DNA levels. Cryopreserved peripheral blood mononuclear cells (PBMCs) were obtained for 12 participants with available samples pre-ATI and approximately 6 months after ART resumption. Four participants also had samples available during the ATI. The median duration of ATI was 12 weeks. Validation of the HIV integrated DNA size-exclusion (HIDE) assay was performed using samples spiked with unintegrated HIV DNA, HIV-infected cell lines, and participant PBMCs. The HIDE assay eliminated 99% of unintegrated HIV DNA species and strongly correlated with the established Alu-gag assay. For the majority of individuals, integrated DNA levels increased during ATI and subsequently declined upon ART resumption. There was no significant difference in the levels of integrated HIV DNA between the pre- and post-ATI time points, with a median ratio of post- to pre-ATI HIV DNA levels of 0.95. Using a new integrated HIV DNA assay, we found minimal change in the levels of integrated HIV DNA in participants who underwent an ATI, followed by 6 months of ART. This suggests that short-term ATI can be conducted without a significant impact on the levels of integrated proviral DNA in the peripheral blood.IMPORTANCE Interventions aimed at achieving sustained antiretroviral therapy (ART)-free HIV remission require treatment interruption trials to assess their efficacy. However, these trials are accompanied by safety concerns related to the expansion of the viral reservoir. We validated an assay that uses an automated DNA size-selection platform for quantifying levels of integrated HIV DNA and is less sample- and labor-intensive than current assays. Using stored samples from AIDS Clinical Trials Group studies, we found that short-term ART discontinuation had minimal impact on integrated HIV DNA levels after ART resumption, providing reassurance about the reservoir effects of short-term treatment interruption trials.

Fatal pulmonary arterial hypertension (PAH) affects HIV-infected individuals at significantly higher frequencies. We previously showed plexiform-like lesions characterized by recanalized lumenal obliteration, intimal disruption, medial hypertrophy, and thrombosis consistent with PAH in rhesus macaques infected with chimeric SHIVnef but not with the parental SIVmac239, suggesting that Nef is implicated in the pathophysiology of HIV-PAH. However, the current literature on non-human primates as animal models for SIV(HIV)-associated pulmonary disease reports the ultimate pathogenic pulmonary outcomes of the research efforts; however, the variability and features in the actual disease progression remain poorly described, particularly when using different viral sources for infection. We analyzed lung histopathology, performed immunophenotyping of cells in plexogenic lesions pathognomonic of PAH, and measured cardiac hypertrophy biomarkers and cytokine expression in plasma and lung of juvenile SHIVnef-infected macaques. Here, we report significant hematopathologies, changes in cardiac biomarkers consistent with ventricular hypertrophy, significantly increased levels of interleukin-12 and GM-CSF and significantly decreased sCD40 L, CCL-2, and CXCL-1 in plasma of the SHIVnef group. Pathway analysis of inflammatory gene expression predicted activation of NF-κB transcription factor RelB and inhibition of bone morphogenetic protein type-2 in the setting of SHIVnef infection. Our findings highlight the utility of SHIVnef-infected macaques as suitable models of HIV-associated pulmonary vascular remodeling as pathogenetic changes are concordant with features of idiopathic, familial, scleroderma, and HIV-PAH.

A major barrier in the use of humanized mice as models of HIV-1 (HIV) infection is the inadequate generation of virus-specific antibody responses. Humanized DRAGA (hDRAGA) mice generate antigen-specific class switched antibodies to several pathogens, but whether they do so in HIV infection and the extent to which their secondary lymphoid tissues (sLT) support germinal center responses is unknown. hDRAGA mice were evaluated for their ability to support HIV replication, generate virus-specific antibody responses, develop splenocyte subsets, and organize sLT architecture. hDRAGA mice supported persistent HIV replication and developed modest levels of gp41-specific human IgM and IgG. Spleens from uninfected and HIV infected hDRAGA mice contained differentiated B and CD4+ T cell subsets including germinal center (GC) B cells and T follicular helper cells (TFH); relative expansions of TFH and CD8+ T cells, but not GC B cells, occurred in HIV-infected hDRAGA mice compared to uninfected animals. Immunofluorescent staining of spleen and mesenteric lymph node sections demonstrated atypical morphology. Most CD4+ and CD8+ T cells resided within CD20hi areas. CD20hi areas lacked canonical germinal centers, as defined by staining for IgD-Ki67+cells. No human follicular dendritic cells (FDC) were detected. Mouse FDC were distributed broadly throughout both CD20hi and CD20lo regions of sLT. HIV RNA particles were detected by in situ hybridization within CD20+ areas and some co-localized with mouse FDC. Viral RNA+ cells were more concentrated within CD20hi compared to CD20lo areas of sLT, but differences were diminished in spleen and eliminated in mesenteric lymph nodes when adjusted for CD4+ cell frequency. Thus, hDRAGA mice recapitulated multiple aspects of HIV pathogenesis including HIV replication, relative expansions in TFH and CD8+ T cells, and modest HIV-specific antibody production. Nevertheless, classical germinal center morphology in sLT was not observed, which may account for the inefficient expansion of GC B cells and generation of low titer human antibody responses to HIV-1 in this model.

Follicular helper CD4+ T cells (TFH) are highly permissive to HIV and major foci of virus expression in both untreated and treated infection. Follicular regulatory CD4+ T cells (TFR) limit TFH numbers and function in vitro and in vivo. We evaluated the hypothesis that TFR suppress HIV replication in TFH using a well-established model of ex vivo HIV infection that employs tonsil cells from HIV uninfected individuals spinoculated with CXCR4- and CCR5-tropic HIV-GFP reporter viruses. Both CXCR4 and CCR5-tropic HIV replication were reduced in TFH cultured with TFR as compared to controls. Blocking antibodies to CD39, CTLA-4, IL-10, and TGF-beta failed to reverse suppression of HIV replication by TFR, and there were no sex differences in TFR suppressive activity. TFR reduced viability of TFH and even more so reduced HIV infected TFH as assessed by total and integrated HIV DNA. Exogenous IL-2 enhanced TFH viability and particularly numbers of GFP+ TFH in a concentration dependent manner. TFR reduced productively infected TFH at low and moderate IL-2 concentrations, and this was associated with decreases in extracellular IL-2. Both IL-2 expressing cells and larger numbers of FoxP3+CD4+ cells were detected in follicles and germinal centers of lymph nodes of people living with HIV. TFR may deplete TFH in vivo through restriction of IL-2 and thereby contribute to decay of HIV expressing cells in B cell follicles during HIV infection.

Objective Multiple sclerosis (MS) is an inflammatory degenerative condition of central nervous system. The disease course and presentation of MS is highly heterogeneous. Advanced retinal imaging techniques such as optic coherence tomography (OCT) can capture abnormalities of anterior visual pathway with high resolution, which may contribute greater insights into the pathophysiology of MS.Methods People with newly diagnosed relapsing-remitting MS were recruited for FutureMS retinal imaging study from two study centres in Scotland. The baseline visit was completed within 6 months of diagnosis with initial follow-up 12 months after the baseline visit. The assessments included in FutureMS retinal imaging study were visual acuity test, self-reported eye questionnaire and OCT scan.Results A total of 196 FutureMS participants completed the retinal imaging study of FutureMS with 185 participants at M0 and 155 at M12. A total of 144 participants completed both M0 and M12 visits. At the whole cohort level, the distribution of retinal measures is generally consistent between baseline and follow-up.Conclusion The FutureMS retinal imaging study aims to demonstrate that patient with MS present with different extent of retinal abnormalities that can be captured by retinal imaging modalities such as OCT soon after diagnosis. These changes may sensitively mirror the brain atrophy or serve as predictors for disease activity. By developing sensitive, quantifiable and objective retinal biomarkers, FutureMS retinal imaging study will provide an opportunity to stratify patient with MS at an early stage and support future therapeutic strategies for a better outcome.

A five-day discovery-based summer workshop for incoming ninth graders was designed and conducted at the University of Cincinnati (UC). The idea was to have an inquiry-based, research-driven laboratory experience where students were provided with a mentor who encouraged creativity and inquisitiveness. Over a period of three years, 33 students participated in this UC workshop. The students performed a series of experiments and toured and utilized the analytical instrumentation facilities at UC. During the first year, the goal of the workshop was to have the students design their own chemical sensor for anions in water. In subsequent years, the students were given the opportunity to investigate a research question arising from any of the experiments they performed throughout the week. Students were not given explicit instructions for activities. For example, a typical question could have been "Which anion shows luminescence?", but they were not told how to discover this. On the last two days the students were tasked with proposing a question they wished to have answered and developed an experiment to test the hypothesis. At the conclusion of the workshop, each group or individual student presented their results and showed confidence in their work.

Introduction: Multiple sclerosis (MS) is a chronic neuroinflammatory and neurodegenerative disease. MS prevalence varies geographically and is notably high in Scotland. Disease trajectory varies significantly between individuals and the causes for this are largely unclear. Biomarkers predictive of disease course are urgently needed to allow improved stratification for current disease modifying therapies and future targeted treatments aimed at neuroprotection and remyelination. Magnetic resonance imaging (MRI) can detect disease activity and underlying damage non-invasively in vivo at the micro and macrostructural level. FutureMS is a prospective Scottish longitudinal multi-centre cohort study, which focuses on deeply phenotyping patients with recently diagnosed relapsing-remitting MS (RRMS). Neuroimaging is a central component of the study and provides two main primary endpoints for disease activity and neurodegeneration. This paper provides an overview of MRI data acquisition, management and processing in FutureMS. FutureMS is registered with the Integrated Research Application System (IRAS, UK) under reference number 169955. Methods and analysis: MRI is performed at baseline (N=431) and 1-year follow-up, in Dundee, Glasgow and Edinburgh (3T Siemens) and in Aberdeen (3T Philips), and managed and processed in Edinburgh. The core structural MRI protocol comprises T1-weighted, T2-weighted, FLAIR and proton density images. Primary imaging outcome measures are new/enlarging white matter lesions (WML) and reduction in brain volume over one year. Secondary imaging outcome measures comprise WML volume as an additional quantitative structural MRI measure, rim lesions on susceptibility-weighted imaging, and microstructural MRI measures, including diffusion tensor imaging and neurite orientation dispersion and density imaging metrics, relaxometry, magnetisation transfer (MT) ratio, MT saturation and derived g-ratio measures. Conclusions: FutureMS aims to reduce uncertainty around disease course and allow for targeted treatment in RRMS by exploring the role of conventional and advanced MRI measures as biomarkers of disease severity and progression in a large population of RRMS patients in Scotland.

During chronic human immunodeficiency virus (HIV) or simian immunodeficiency virus (SIV) infection prior to AIDS progression, the vast majority of viral replication is concentrated within B cell follicles of secondary lymphoid tissues. We investigated whether infusion of T cells expressing an SIV-specific chimeric antigen receptor (CAR) and the follicular homing receptor, CXCR5, could successfully kill viral-RNA+ cells in targeted lymphoid follicles in SIV-infected rhesus macaques. In this study, CD4 and CD8 T cells from rhesus macaques were genetically modified to express antiviral CAR and CXCR5 moieties (generating CAR/CXCR5-T cells) and autologously infused into a chronically infected animal. At 2 days post-treatment, the CAR/CXCR5-T cells were located primarily in spleen and lymph nodes both inside and outside of lymphoid follicles. Few CAR/CXCR5-T cells were detected in the ileum, rectum, and lung, and no cells were detected in the bone marrow, liver, or brain. Within follicles, CAR/CXCR5-T cells were found in direct contact with SIV-viral RNA+ cells. We next infused CAR/CXCR5-T cells into ART-suppressed SIV-infected rhesus macaques, in which the animals were released from ART at the time of infusion. These CAR/CXCR5-T cells replicated in vivo within both the extrafollicular and follicular regions of lymph nodes and accumulated within lymphoid follicles. CAR/CXR5-T cell concentrations in follicles peaked during the first week post-infusion but declined to undetectable levels after 2 to 4 weeks. Overall, CAR/CXCR5-T cell-treated animals maintained lower viral loads and follicular viral RNA levels than untreated control animals, and no outstanding adverse reactions were noted. These findings indicate that CAR/CXCR5-T cell treatment is safe and holds promise as a future treatment for the durable remission of HIV.

UnlabelledHost and viral factors influence the HIV-1 infection course. Reduced Nef function has been observed in HIV-1 controllers during the chronic phase, but the kinetics and mechanisms of Nef attenuation in such individuals remain unclear. We examined plasma RNA-derived Nef clones from 10 recently infected individuals who subsequently suppressed viremia to less than 2,000 RNA copies/ml within 1 year postinfection (acute controllers) and 50 recently infected individuals who did not control viremia (acute progressors). Nef clones from acute controllers displayed a lesser ability to downregulate CD4 and HLA class I from the cell surface and a reduced ability to enhance virion infectivity compared to those from acute progressors (all P

Coccidioidomycosis is a fungal infection endemic to the Southwestern United States which is associated with high morbidity and mortality in immunocompromised hosts. Serology is the main diagnostic tool, although less sensitive among immunocompromised hosts. (1→3)-β-D-glucan (BDG) is a non-specific fungal diagnostic test that may identify suspected coccidioidomycosis and other invasive fungal infections. We retrospectively investigated the utility of BDG between 2017 and 2021 in immunocompromised hosts with positive Coccidioides spp. cultures at our institutions. During the study period, there were 368 patients with positive cultures for Coccidioides spp.; among those, 28 patients were immunocompromised hosts, had both Coccidioides serology and BDG results available, and met other inclusion and exclusion criteria. Half of the patients had positive Coccidioides serology, and 57% had a positive BDG ≥ 80 pg/mL. Twenty-three (82%) had at least one positive test during their hospitalization. Among immunocompromised hosts with suspicion for coccidioidomycosis, the combination of Coccidioides serology and BDG can be useful in the initial work up and the timely administration of appropriate antifungal therapy. However, both tests failed to diagnose many cases, underscoring the need for better diagnostic techniques for identifying coccidioidomycosis in this population.

A patient with morbid obesity and several psychiatric comorbidities underwent laparoscopic sleeve gastrectomy and experienced success with weight loss. However, she experienced lightheadedness, nausea, and a fall and was admitted to the hospital for encephalopathy due to lithium toxicity. The pharmacokinetics of lithium is altered following bariatric surgery. Due to these factors, adjustments were made to the patient’s lithium therapy, her levels were subsequently reduced into the therapeutic range, and she continued with no further issues. Mechanisms of lithium toxicity following bariatric surgery and a monitoring protocol to prevent toxicity are discussed.

Background: Neuroprotective drugs are needed to slow or prevent neurodegeneration and disability accrual in secondary progressive multiple sclerosis. Amiloride, fluoxetine and riluzole are repurposed drugs with potential neuroprotective effects. Objectives: To assess whether or not amiloride, fluoxetine and riluzole can reduce the rate of brain volume loss in people with secondary progressive multiple sclerosis over 96 weeks. The secondary objectives that were assessed were feasibility of a multiarm trial design approach, evaluation of anti-inflammatory effects, clinician- and patient-reported efficacy and three mechanistic substudies. Design: A multicentre, multiarm, randomised, double-blind, placebo-controlled, parallel-group Phase IIb trial with follow-up at 4, 8, 12, 24, 36, 48, 72 and 96 weeks. Patients, investigators (including magnetic resonance imaging analysts), and treating and independent assessing neurologists were blinded to the treatment allocation. The target sample size was 440 patients. Setting: Thirteen UK clinical neuroscience centres. Participants: Participants were aged 25–65 years, had secondary progressive multiple sclerosis with evidence of disease progression independent of relapses in the previous 2 years, and had an Expanded Disability Status Scale score of 4.0–6.5. Patients were ineligible if they could not have a magnetic resonance imaging scan; had a relapse or steroids in the previous 3 months; or had epilepsy, depression, bipolar disorder, glaucoma, bleeding disorders or significant organ comorbidities. Exclusion criteria were concurrent disease-modified treatments, immunosuppressants or selective serotonin reuptake inhibitors. Interventions: Participants received amiloride (5 mg), fluoxetine (20 mg), riluzole (50 mg) or placebo (randomised 1 : 1 : 1 : 1) twice daily. Main outcome measures: The primary end point was magnetic resonance imaging-derived percentage brain volume change at 96 weeks. Secondary end points were new/enlarging T2 lesions, pseudoatrophy, and clinician- and patient-reported measures (including the Expanded Disability Status Scale, Multiple Sclerosis Functional Composite, Symbol Digit Modalities Test, low-contrast letter visual acuity, Multiple Sclerosis Impact Scale 29 items, version 2, Multiple Sclerosis Walking Scale, version 2, and questionnaires addressing pain and fatigue). The exploratory end points included measures of persistent new T1 hypointensities and grey matter volume changes. The substudies were advanced magnetic resonance imaging, optical coherence tomography and cerebrospinal fluid analyses. Results: Between December 2014 and June 2016, 445 patients were randomised (analysed) to amiloride [n = 111 (99)], fluoxetine [n = 111 (96)], riluzole [n = 111 (99)] or placebo [n = 112 (99)]. A total of 206 randomised patients consented to the advanced magnetic resonance imaging substudy, 260 consented to the optical coherence tomography substudy and 70 consented to the cerebrospinal fluid substudy. No significant difference was seen between the active drugs and placebo in percentage brain volume change at week 96 as follows (where negative values mean more atrophy than placebo): amiloride minus placebo 0.0% (Dunnett-adjusted 95% confidence interval –0.4% to 0.5%), fluoxetine minus placebo –0.1% (Dunnett-adjusted 95% confidence interval –0.5% to 0.3%); riluzole minus placebo –0.1% (Dunnett-adjusted 95% confidence interval –0.6% to 0.3%). There was good adherence to study drugs. The proportion of patients experiencing adverse events was similar in the treatment and placebo groups. There were no emergent safety issues. Limitations: There was a lower than expected uptake in the cerebrospinal fluid substudy. Conclusions: A multiarm Phase II paradigm is efficient in determining which neuroprotective agents to take through to Phase III trials. Amiloride, fluoxetine and riluzole were not effective in reducing the brain atrophy rate in people with secondary progressive multiple sclerosis. Mechanistic pathobiological insight was gained. Future work: To use the information gained from the Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial (MS-SMART) to inform future trial design as new candidate agents are identified. Trial registration: Current Controlled Trials ISRCTN28440672, NCT01910259 and EudraCT 2012-005394-31. Funding: This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 7, No. 3. See the NIHR Journals Library website for further project information. This trial also received funding from the UK MS Society and the US National Multiple Sclerosis Society.

The natural history of relapsing remitting multiple sclerosis (RRMS) is variable and prediction of individual prognosis challenging. The inability to reliably predict prognosis at diagnosis has important implications for informed decision making especially in relation to disease modifying therapies. We conducted a systematic review in order to collate, describe and assess the methodological quality of published prediction models in RRMS. We searched Medline, Embase and Web of Science. Two reviewers independently screened abstracts and full text for eligibility and assessed risk of bias. Studies reporting development or validation of prediction models for RRMS in adults were included. Data collection was guided by the checklist for critical appraisal and data extraction for systematic reviews (CHARMS) and applicability and methodological quality assessment by the prediction model risk of bias assessment tool (PROBAST). 30 studies were included in the review. Applicability was assessed as high risk of concern in 27 studies. Risk of bias was assessed as high for all studies. The single most frequently included predictor was baseline EDSS (n = 11). T2 Lesion volume or number and brain atrophy were each retained in seven studies. Five studies included external validation and none included impact analysis. Although a number of prediction models for RRMS have been reported, most are at high risk of bias and lack external validation and impact analysis, restricting their application to routine clinical practice.

Titanium is essentially absent from biological systems yet reliably integrates into bone. To achieve osseointegration, titanium must activate biological processes without entering cells, defining it as a bio-activating material. Nanostructuring bulk titanium reduces grain size, increases strength, and improves other quantifiable physical properties, including cytocompatibility. The biological processes activated by increasing grain boundary availability were detected with total RNA-sequencing in mouse pre-osteoblasts grown for 72 hours on nanometrically smooth substrates of either coarse grain or nanostructured ultrafine grain titanium. The average grain boundary length under cells on the conventional coarse grain substrates is 273.0 μm, compared to 70,881.5 μm for cells adhered to the nanostructured ultrafine grain substrates; a 260-fold difference. Cells on both substrates exhibit similar expression profiles for genes whose products are critical for mechanosensation and transduction of cues that trigger osteoconduction. Biological process Gene Ontology term enrichment analysis of differentially expressed genes reveals that cell cycle, chromatin modification, telomere maintenance, and RNA metabolism processes are upregulated on ultrafine grain titanium. Processes related to immune response, including apoptosis, are downregulated. Tumor-suppressor genes are upregulated while tumor-promoting genes are downregulated. Upregulation of genes involved in chromatin remodeling and downregulation of genes under the control of the peripheral circadian clock implicate both processes in the transduction of mechanosensory information. Non-coding RNAs may also play a role in the response. Merging transcriptomics with well-established mechanobiology principles generates a unified model to explain the bio-activating properties of titanium. The modulation of processes is accomplished through chromatin remodeling in which the nucleus responds like a rheostat to grain boundary concentration. This convergence of biological and materials science reveals a pathway toward understanding the biotic-abiotic interface and will inform the development of effective bio-activating and bio-inactivating materials.