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Disease-modifying therapies are standard of care (SOC) for sickle cell disease (SCD), but hematopoietic cell transplantation (HCT) has curative potential. We compared outcomes prospectively through 2-years after biologic assignment to a Donor or No Donor (SOC) Arm based on the availability of an HLA-matched sibling or unrelated donor (BMTCTN 1503; NCT02766465). A donor search was commenced after eligibility confirmation. The primary endpoint was the comparison of survival 2 years after biologic assignment between treatment arms. Power calculations required 60 participants on the Donor Arm and 140 on the No Donor Arm to determine if early transplant-related mortality might be balanced by disease-related mortality over a longer period of follow-up. Secondary objectives compared changes in SCD-related events, functional outcomes, and organ function. Data were analyzed by the intent-to-treat principle. A total of 113 participants were enrolled, 28 on the Donor and 85 on the No Donor Arm The 2-year probabilities of survival were 89% and 93%, on the Donor and No Donor Arms, respectively. Vaso-occlusive pain (VOC) was less frequent on the Donor Arm in the second year after biologic assignment (p < 0.001). On PROMIS-57 surveys there was decreased fatigue (p=0.003) and an increased ability to participate in social roles and activities (p=0.003) on the Donor Arm 2-years after biologic assignment. Differences in other secondary outcomes did not reach statistical significance. Barriers to accrual prevented an objective comparison of survival. Assignment to the Donor Arm led to improvements in VOC, fatigue, and social function., (Copyright © 2024 American Society of Hematology.)

Objective: In the randomized Scleroderma: Cyclophosphamide or Transplantation (SCOT) trial, myeloablation, followed by hematopoietic stem cell transplantation (HSCT), led to the normalization of systemic sclerosis (SSc) peripheral blood cell (PBC) gene expression signature at the 26-month visit. Herein, we examined long-term molecular changes ensuing 54 months after randomization for individuals receiving an HSCT or 12 months of intravenous cyclophosphamide (CYC)., Methods: Global PBC transcript studies were performed in study participants at pretreatment baseline and at 38 months and 54 months after randomization, as well as in healthy controls using Illumina HT-12 arrays., Results: Thirty (HSCT = 19 and CYC = 11) participants had 38-month samples available, and 26 (HSCT = 16 and CYC = 11) had 54-month samples available. In the paired comparison to baseline, a significant down-regulation of interferon modules and an up-regulation of cytotoxic/natural killer module were observed at the 38-month and 54-month visits in the HSCT arm, indicating a long-term normalization of baseline SSc gene expression signature. No differentially expressed modules were detected in the CYC arm. In comparison to samples from healthy controls, 38-month visit samples in the HSCT arm showed an up-regulation of B cell and plasmablast modules and a down-regulation of myeloid and inflammation modules. Importantly, 54-month HSCT samples did not show any differentially expressed modules compared to healthy control samples, suggesting completion of immune reconstitution. Participants in the CYC arm continued to show an SSc transcript signature in comparison to controls at both time points., Conclusion: Paralleling the observed clinical benefit, HSCT leads to durable long-term normalization of the molecular signature in SSc, with completion of immune resetting to 54 months after HSCT., (© 2024 American College of Rheumatology. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

With the increasing use of infotainment systems in vehicles, secondary tasks requiring executive demand may increase crash risk, especially for young drivers. Naturalistic driving data were examined to determine if secondary tasks with increasing executive demand would result in increasing crash risk. Data were extracted from the Second Strategic Highway Research Program Naturalistic Driving Study, where vehicles were instrumented to record driving behavior and crash/near-crash data. executive and visual-manual tasks paired with a second executive task (also referred to as dual executive tasks) were compared to the executive and visual-manual tasks performed alone. Crash/near-crash odds ratios were computed by comparing each task condition to driving without the presence of any secondary task. Dual executive tasks resulted in greater odds ratios than those for single executive tasks. The dual visual-manual task odds ratios did not increase from single task odds ratios. These effects were only found in young drivers. The study shows that dual executive secondary task load increases crash/near-crash risk in dual task situations for young drivers. Future research should be conducted to minimize task load associated with vehicle infotainment systems that use such technologies as voice commands., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Background and objective It is crucial to make early differentiation between coronavirus disease 2019 (COVID-19) and seasonal influenza infections at the time of a patient's presentation to the emergency department (ED). In light of this, this study aimed to identify key epidemiological, initial laboratory, and radiological differences that would enable early recognition during co-circulation. Methods This was a retrospective, observational cohort study. All adult patients presenting to our ED at the Watford General Hospital, UK, with a laboratory-confirmed diagnosis of COVID-19 (2019/20) or influenza (2018/19) infection were included in this study. Demographic, laboratory, and radiological data were collected. Binary logistic regression was employed to determine features associated with COVID-19 infection rather than influenza. Results Chest radiographs suggestive of viral pneumonitis and older age (≥80 years) were associated with increased odds of having COVID-19 [odds ratio (OR): 47.00, 95% confidence interval (CI): 21.63-102.13 and OR: 64.85, 95% CI: 19.96-210.69 respectively]. Low eosinophils (<0.02 x 10 9 /L) were found to increase the odds of COVID-19 (OR: 2.12, 95% CI: 1.44-3.10, p<0.001). Conclusions Gaining awareness about the epidemiological, biological, and radiologic presentation of influenza-like illness can be useful for clinicians in ED to differentiate between COVID-19 and influenza. This study showed that older age, eosinopenia, and radiographic evidence of viral pneumonitis significantly increase the odds of having COVID-19 compared to influenza. Further research is needed to determine if these findings are affected by acquired or natural immunity., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Naji et al.)

The Adult Autism Quotient (AQ), the Empathy Quotient (EQ) and the Relative's Questionnaire (RQ) were used as part of the Adult Asperger's Assessment (AAA) by a diagnostic service for adults without an intellectual disability with suspected autism spectrum disorder (ASD). This service is part of the National Health Service (NHS) in England. Little is known about the utility of these structured questionnaires despite wide use in clinical practice. It was investigated whether the questionnaires could discriminate between individuals with and without a diagnosis of ASD. Receiver Operating Curve analysis showed good levels of sensitivity to detect a positive diagnosis, but the specificity to exclude those without a diagnosis was poor. A binary logistic regression showed that a combination of the questionnaires also showed limited diagnostic validity. These findings have clinical implications in reviewing the efficiency of the assessment process., (© 2022. Crown.)

Scleroderma is a rare, potentially fatal, clinically heterogeneous, systemic autoimmune connective tissue disorder that is characterized by progressive fibrosis of the skin and visceral organs, vasculopathy and immune dysregulation. The more severe form of the disease, diffuse cutaneous scleroderma (dcSSc), has no cure and limited treatment options. Haematopoietic stem cell transplantation has emerged as a potentially disease-modifying treatment but faces challenges such as toxicity associated with fully myeloablative conditioning and recurrence of autoimmunity. Novel cell therapies-such as mesenchymal stem cells, chimeric antigen receptor-based therapy, tolerogenic dendritic cells and facilitating cells-that may restore self-tolerance with more favourable safety and tolerability profiles are being explored for the treatment of dcSSc and other autoimmune diseases. This narrative review examines these evolving cell therapies., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objectives: Results from the SCOT (Scleroderma: Cyclophosphamide Or Transplantation) clinical trial demonstrated significant benefits of haematopoietic stem cell transplant (HSCT) versus cyclophosphamide (CTX) in patients with systemic sclerosis. The objective of this study was to test the hypothesis that transplantation stabilises the autoantibody repertoire in patients with favourable clinical outcomes., Methods: We used a bead-based array containing 221 protein antigens to profile serum IgG autoantibodies in participants of the SCOT trial., Results: Comparison of autoantibody profiles at month 26 (n=23 HSCT; n=22 CTX) revealed antibodies against two viral antigens and six self-proteins (SSB/La, CX3CL1, glycyl-tRNA synthetase (EJ), parietal cell antigen, bactericidal permeability-increasing protein and epidermal growth factor receptor (EGFR)) that were significantly different between treatment groups. Linear mixed model analysis identified temporal increases in antibody levels for hepatitis B surface antigen, CCL3 and EGFR in HSCT-treated patients. Eight of 32 HSCT-treated participants and one of 31 CTX-treated participants had temporally varying serum antibody profiles for one or more of 14 antigens. Baseline autoantibody levels against 20 unique antigens, including 9 secreted proteins (interleukins, IL-18, IL-22, IL-23 and IL-27), interferon-α2A, stem cell factor, transforming growth factor-β, macrophage colony-stimulating factor and macrophage migration inhibitory factor were significantly higher in patients who survived event-free to month 54., Conclusions: Our results suggest that HSCT favourably alters the autoantibody repertoire, which remains virtually unchanged in CTX-treated patients. Although antibodies recognising secreted proteins are generally thought to be pathogenic, our results suggest a subset could potentially modulate HSCT in scleroderma., Competing Interests: Competing interests: LC serves on the advisory board or received consulting fees from Mitsubishi Tanabe, Jannsen, Genentech, Kyverna, and Eicos Sciences., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Abstract: Herpes zoster (HZ) and HZ-associated pain greatly affect patients' quality of life, particularly in older and immunocompromised adults, for whom comorbidities and polypharmacy are often reported. Three phase III, randomized, placebo-controlled clinical trials have reported the adjuvanted recombinant zoster vaccine (RZV) as highly efficacious in preventing HZ and reducing pain severity in healthy adults ≥50 years old (Zoster Efficacy Study [ZOE]-50 study, NCT01165177) and ≥70 years old (ZOE-70; NCT01165229) and in immunocompromised adults ≥18 years old undergoing autologous hematopoietic stem cell transplantation (ZOE-HSCT; NCT01610414). Here, we investigated efficacy of RZV in reducing (i) the duration of clinically significant pain (Zoster Brief Pain Inventory pain score ≥3) and (ii) HZ-associated pain medication use and duration of use in participants with confirmed HZ ("breakthrough cases") from the 3 studies. Recombinant zoster vaccine effectively reduced the duration of clinically significant HZ-associated pain during HZ episodes by 38.5% ( P -value: 0.010) in the ZOE-HSCT study. Although a similar trend was observed in the ZOE-50 and ZOE-70 studies, the results were not statistically significant because of the high vaccine efficacy (VE) against HZ resulting in rare breakthrough cases. VE in reducing pain medication use (39.6%; P -value: 0.008) and duration of medication use (49.3%, P -value: 0.040) was reported in the ZOE-70 study; corresponding positive VE estimates were observed in the ZOE-50 and ZOE-HSCT studies but were not statistically significant. Data reported here demonstrate efficacy of RZV in reducing HZ-associated pain duration and pain medication use in breakthrough cases, thereby improving quality of life of those with HZ., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

We previously conducted a single-arm feasibility study (STRIDE1) of myeloablative bone marrow transplantation (BMT) in adolescents and young adults with sickle cell disease (SCD). The trial identified donors before entry, enrolled well, and found no unexpected regimen-related toxicity. Although many single-arm studies have been published, there are no controlled trials of either BMT or gene therapy in SCD. Therefore, we designed a comparative trial by biological assignment (available donor versus no donor). This multicenter National Institutes of Health-funded study (Blood and Marrow Transplant Clinical Trials Network 1503; STRIDE2) enrolled patients between 2016 and 2021 at 35 sites. Lagging recruitment led to study closure, and here we report the impediments to accrual. The BMT regimen and entry criteria were from STRIDE1, and 2-year survival was the primary endpoint. To minimize selection bias from prior HLA typing, STRIDE2 excluded individuals with previously identified donors. Accrual was stopped at 69% of target (138 enrolled; assigned 28 with donor, 96 with no donor). Barriers to enrollment included lower than expected frequency of HLA-matched related and unrelated donors; loss of enrollees owing to previously identified donors; conventional care arm dissuading some seeking BMT; challenging short-term endpoints in SCD, including incomplete documentation of sickle pain episodes; state Medicaid (primary insurers of SCD) denial of BMT coverage for adult SCD despite the study having secured Coverage with Evidence Development from the Center for Medicare & Medicaid Services; slowed accrual in 2019 to 2021 during the Coronavirus disease 2019 pandemic; and restriction of BMT resourcing for nonmalignant diseases by academic medical (cancer) centers. Social obstacles and access to BMT centers also limited entry, as did practitioner and participant concerns over suitability, cost, and toxicity. Planning for future controlled trials of curative therapy in SCD and other nonmalignant diseases likely will meet these enrollment challenges. Lessons from this trial may aid the development of future comparative studies., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Objectives: Myeloablative autologous haematopoietic stem cell transplant (HSCT) was recently demonstrated to provide significant benefit over cyclophosphamide (CYC) in the treatment of diffuse cutaneous systemic sclerosis (dcSSc) in the Scleroderma: Cyclophosphamide or Transplantation (SCOT) trial. As dysregulation of the B cell compartment has previously been described in dcSSc, we sought to gain insight into the effects of myeloablative autologous HSCT as compared with CYC., Methods: We sequenced the peripheral blood immunoglobulin heavy chain (IGH) repertoires in patients with dcSSc enrolled in the SCOT trial., Results: Myeloablative autologous HSCT was associated with a sustained increase in IgM isotype antibodies bearing a low mutation rate. Clonal expression was reduced in IGH repertoires following myeloablative autologous HSCT. Additionally, we identified a underusage of immunoglobulin heavy chain V gene 5-51 in patients with dcSSc, and usage normalised following myeloablative autologous HSCT but not CYC treatment., Conclusions: Together, these findings suggest that myeloablative autologous HSCT resets the IGH repertoire to a more naïve state characterised by IgM-expressing B cells, providing a possible mechanism for the elimination of pathogenic B cells that may contribute to the benefit of HSCT over CYC in the treatment of dcSSc., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Objective: Among individuals with systemic sclerosis (SSc) randomized to cyclophosphamide (CYC) (n = 34) or hematopoietic stem cell transplantation (HSCT) (n = 33), we examined longitudinal trends of clinical, pulmonary function, and quality of life measures while accounting for the influence of early failures on treatment comparisons., Methods: Assuming that data were missing at random, mixed-effects regression models were used to estimate longitudinal trends for clinical measures when comparing treatment groups. Results were compared to observed means and to longitudinal trends estimated from shared parameter models, assuming that data were missing not at random. Longitudinal trends for SSc intrinsic molecular subsets defined by baseline gene expression signatures (normal-like, inflammatory, and fibroproliferative signatures) were also studied., Results: Available observed means for pulmonary function tests appeared to improve over time in both arms. However, after accounting for participant loss, forced vital capacity in HSCT recipients increased by 0.77 percentage points/year but worsened by -3.70/year for CYC (P = 0.004). Similar results were found for diffusing capacity for carbon monoxide and quality of life indicators. Results for both analytic models were consistent. HSCT recipients in the inflammatory (n = 20) and fibroproliferative (n = 20) subsets had superior long-term trends compared to CYC for pulmonary and quality of life measures. HSCT was also superior for modified Rodnan skin thickness scores in the fibroproliferative subset. For the normal-like subset (n = 22), superiority of HSCT was less apparent., Conclusion: Longitudinal trends estimated from 2 statistical models affirm the efficacy of HSCT over CYC in severe SSc. Failure to account for early loss of participants may distort estimated clinical trends over the long term., (© 2021 American College of Rheumatology.)

Compared with the general population, older adults with immune senescence and individuals who are immunocompromised (IC) due to disease or immunosuppressive therapy are at increased risk for herpes zoster (HZ) and its associated complications, which can be debilitating and life-threatening. Vaccination can be an effective strategy against HZ and studies have shown that HZ vaccination in IC individuals can elicit immune responses and provide protection from infection. Recently, the first approvals have been granted in the United States and the European Union for the recombinant HZ vaccine (RZV) in adults ≥ 18 years of age at risk of HZ due to immunodeficiency or immunosuppression. Existing systematic reviews have highlighted the risks for HZ in limited immunocompromising conditions and have only examined clinical data for RZV. This review details the risks and burden of HZ in a broad range of clinically relevant IC populations and summarizes key efficacy and safety data for RZV and live HZ vaccine in these individuals. Research has shown IC individuals can benefit from HZ vaccination; however, these insights have yet to be fully incorporated into vaccination guidelines and clinical care. Clinicians should consider HZ vaccination in eligible at-risk populations to protect against HZ and its associated complications and thereby, reduce the burden that HZ poses on the healthcare system. Electronic health records and linked personal health records could be used to identify and contact patients eligible for HZ vaccination and provide clinical decision support-generated alerts for missing or delayed vaccinations. This review will help clinicians identify eligible IC individuals who may benefit from HZ vaccination. A video abstract linked to this article is available on Figshare https://doi.org/10.6084/m9.figshare.21517605., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: KMS has received consultancy fees from and been part of publication committees for GSK. FAF has received consultancy fees from Arena, BMS, Braintree Labs, GI reviewers, GSK, Iterative Scopes, Janssen, Pfizer and Sebela, is a stockholder in Innovation Pharmaceuticals and sits on the data safety monitoring board for Eli Lilly and Adiso Therapeutics. KLW has received consultancy fees from GSK, BMS, Pfizer, AbbVie, UCB, Eli Lilly, Galapagos, Roche, Gilead, Sanofi, Regeneron, AstraZeneca and Novartis, and research grants from BMS and Pfizer. DOW, PV and FTDS are employed by, and have restricted share stock ownership in, the GSK., (Copyright © 2022 GlaxoSmithKline Biologicals S.A. Published by Elsevier Ltd.. All rights reserved.)

Objectives: The Scleroderma: Cyclophosphamide or Transplantation (SCOT) trial compared hematopoietic stem cell transplant to CYC treatment in patients with early SSc with progressive skin and lung or kidney involvement. Here we describe lymphocyte phenotype abnormalities at study entry and the relation to prior DMARD therapy., Methods: Lymphocyte subsets (n = 26) measured by flow cytometry were compared in 123 heathy controls and 71 SCOT participants, including those given (n = 57) or not given (n = 14) DMARDs within 12 months of randomization., Results: Compared with healthy controls, individuals with SSc showed significant reductions in central memory CD8 T cells, activated total and CD4 T cells, γ/δ T cells, memory B cells, myeloid and plasmacytoid dendritic cells and FOXP3+CD25+ Treg cells and increases in naïve CD4 T cells, effector memory CD4 T cells and effector CD8 T cells. A greater bias towards a IL-4+ Th2/T cytotoxic 2 (Tc2) phenotype based on the Th2:Th1 CD4 ratio and Tc2:Tc1 CD8 T cells was also found. Notably, no difference in any lymphocyte subset was observed between those given or not given prior DMARDs., Conclusions: In patients with early, severe SSc, significant lymphocyte subset abnormalities were observed. Prior treatment with immunosuppressive therapy did not impact the immunophenotype, suggesting that lymphocyte disturbances in scleroderma appeared to be due to the disease itself., Trial Registration: ClinicalTrials.gov (https://clinicaltrials.gov), NCT00114530., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

To reduce the spread of the novel coronavirus disease 2019 (COVID-19), national governments implemented measures to limit contact between citizens. This study evaluated changes in physical activity and sitting in response to the first COVID-19 lockdown in England and factors associated with these changes. A cross-sectional online survey-based study collected data from 818 adults between 29 April and 13 May 2020. Participants self-reported demographic information, physical activity and sitting for a 'typical' week before and during lockdown. Participants were grouped into low, moderate and high physical activity, and low and high (≥8 hours/day) sitting. Paired samples t-tests compared physical activity (MET-min/week) before and during lockdown. Pearson's Chi-squared evaluated the proportion of participants in the physical activity and sitting categories. Logistic regression explored associations of demographic and behavioural factors with physical activity and sitting during lockdown. Walking and total physical activity significantly increased during lockdown by 241 (95% confidence interval [CI]: 176, 304) MET-min/week and 302 (CI: 155, 457) MET-min/week, respectively (P < 0.001). There was a 4% decrease in participants engaging in low physical activity and a 4% increase in those engaging in high physical activity from before to during lockdown (P < 0.001). The proportion engaging in high sitting increased from 29% to 41% during lockdown (P < 0.001). Lower education level (odds ratio [OR] = 1.65, P = 0.045) and higher BMI (OR = 1.05, P = 0.020) were associated with increased odds of low physical activity during lockdown, whereas non-White ethnicity (OR = 0.24, P = 0.001) was associated with reduced odds. Younger age was associated with increased odds of high sitting (OR = 2.28, P = 0.008). These findings suggest that physical activity and sitting both increased during lockdown. Demographic and behavioural factors associated with low physical activity and high sitting have been identified that could inform intervention strategies during situations of home confinement., Competing Interests: The authors have declared that no competing interests exist.

Hematopoietic cell transplant (HCT) is an increasingly common and curative treatment strategy to improve survival among individuals with malignant and nonmalignant diseases, with over one million HCTs having been performed worldwide. Neurocognitive dysfunction is a common and untoward consequence of HCT for many recipients, although few studies have examined the profile of neurocognitive impairments in HCT or their association with clinical features, such as frailty, or the incidence of pre-HCT neurocognitive impairments across all ages, which may influence post-HCT neurocognitive impairments. We examined the pattern and correlates of pre-transplant neurocognitive dysfunction in a prospective sample of adults undergoing HCT. Neurocognition was assessed using the Montreal Cognitive Assessment Battery. Frailty was assessed using the Short Physical Performance Battery. Linear regression analysis was used to examine the associations between neurocognitive performance and frailty. Neurocognitive screening profiles were also examined by partitioning MoCA into domain scores, including Executive Function and Memory. We also examined the associations between neurocognition, frailty, and clinical outcomes, including length of transplant hospitalization and survival. One hundred and ten adults were evaluated across a wide age range (range: 19-75; mean age = 54.7 [SD = 14.1]). Neurocognitive performance tended to fall below published normative levels (mean MoCA = 25.5 [SD = 4.1]), with 17% of participants demonstrating impaired performance compared with medical normative data (MoCA ≤ 22) and 34% exhibiting impaired performance relative to healthy samples (MoCA ≤ 25). Mild impairments (MoCA ≤ 25) were common across age ranges, including middle-aged patients (23% for age < 50; 35% for age 50-60, 41% for age ≥ 60), particularly for items assessing Executive Function. Greater levels of frailty associated with lower neurocognitive screening scores (r = -0.29, P < 0.01) and Executive Functioning (r = -0.24, P < 0.01), whereas greater age was associated with poorer Memory performance only (r = -0.33, P < 0.01). Greater levels of frailty prior to transplant associated with longer length of stay (β = 0.10, P = 0.046), but were not associated with survival. Neurocognitive impairments are common among adults undergoing HCT and the pattern of performance varies by age. Pre-transplant frailty is associated with neurocognitive functioning and may portend worse post-transplant early clinical outcomes., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Immunocompromised individuals, particularly autologous hematopoietic stem cell transplant (auHSCT) recipients, are at high risk for herpes zoster (HZ). We provide an in-depth description of humoral and cell-mediated immune (CMI) responses by age (protocol-defined) or underlying disease (post-hoc) as well as efficacy by underlying disease (post-hoc) of the adjuvanted recombinant zoster vaccine (RZV) in a randomized observer-blind phase III trial (ZOE-HSCT, NCT01610414). 1846 adult auHSCT recipients were randomized to receive a first dose of either RZV or placebo 50-70 days post-auHSCT, followed by the second dose at 1-2 months (M) later. In cohorts of 114-1721 participants, at 1 M post-second vaccine dose: Anti-gE antibody geometric mean concentrations (GMCs) and median gE-specific CD4[2+] T-cell frequencies (CD4 T cells expressing ≥2 of four assessed activation markers) were similar between 18-49 and ≥50-year-olds. Despite lower anti-gE antibody GMCs in non-Hodgkin B-cell lymphoma (NHBCL) patients, CD4[2+] T-cell frequencies were similar between NHBCL and other underlying diseases. The proportion of polyfunctional CD4 T cells increased over time, accounting for 79.6% of gE-specific CD4 T cells at 24 M post-dose two. Vaccine efficacy against HZ ranged between 42.5% and 82.5% across underlying diseases and was statistically significant in NHBCL and multiple myeloma patients. In conclusion, two RZV doses administered early post-auHSCT induced robust, persistent, and polyfunctional gE-specific immune responses. Efficacy against HZ was also high in NHBCL patients despite the lower humoral response.

This study aimed to determine the effect of the first English national COVID-19 lockdown on physical activity (PA), sitting time, eating behaviours and body mass in an adult cohort. This was further examined to determine whether conforming to recommended guidelines on PA and sedentary behaviour was improved. Based on an online survey ( n = 818) incorporating the International Physical Activity Questionnaire Short Form (IPAQ-SF), self-reported body mass change showed that in 32.2% of participants body mass increased, with 39.1% reporting an increase in food intake. Never exercising at the gym or undertaking an exercise class (online or live), increased by 50.8% during lockdown, with 53.5% changing from exercising frequently to never exercising, suggesting a lack of engagement with online and home workouts. However, outdoor running and cycling >2 times/week increased by 38% during lockdown. Walking at least 30 min continuously on >2 occasions/week increased by 70% during lockdown with minimum 10-min walks on 7 days per week increasing by 23%. The lockdown had a negative impact on sitting time (>8 h a day), which increased by 43.6% on weekdays and 121% at weekends. Furthermore, sitting <4 h/day decreased during lockdown (46.5% and 25.6% for weekdays and weekends, respectively). Those citing tiredness or lack of time as a barrier to exercise reduced by 16% and 60%, respectively, from pre-lockdown to during lockdown. More of the sedentary group met the Public Health England PA recommendations, however most participants still did not meet the UK Government guidelines for PA. Improvements in health per additional minutes of physical activity will be proportionately greater in those previously doing <30 min/week, the area where most improvements were found although, conversely sitting time was greatly increased. This study may assist in informing whether future lifestyle changes could improve the health of the population.

Objective: To provide a large-scale assessment of serum protein dysregulation in diffuse cutaneous systemic sclerosis (dcSSc) and to investigate serum protein correlates of SSc fibrotic features., Methods: We investigated serum protein profiles of 66 participants with dcSSc at baseline who were enrolled in the Scleroderma: Cyclophosphamide or Transplant Trial and 66 age- and sex-matched healthy control subjects. A panel of 230 proteins, including several cytokines and chemokines, was investigated. Whole blood gene expression profiling in concomitantly collected samples was performed., Results: Among the participants with dcSSc, the mean disease duration was 2.3 years. All had interstitial lung disease (ILD), and none were being treated with immunosuppressive agents at baseline. Ninety proteins were differentially expressed in participants with dcSSc compared to healthy control subjects. Similar to previous global skin transcript results, hepatic fibrosis, granulocyte and agranulocyte adhesion, and diapedesis were the top overrepresented pathways. Eighteen proteins correlated with the modified Rodnan skin thickness score (MRSS). Soluble epidermal growth factor receptor was significantly down-regulated in dcSSc and showed the strongest negative correlation with the MRSS, being predictive of the score's course over time, whereas α 1 -antichymotrypsin was significantly up-regulated in dcSSc and showed the strongest positive correlation with the MRSS. Furthermore, higher levels of cancer antigen 15-3 correlated with more severe ILD, based on findings of reduced forced vital capacity and higher scores of disease activity on high-resolution computed tomography. Only 14 genes showed significant differential expression in the same direction in serum protein and whole blood RNA gene expression analyses., Conclusion: Diffuse cutaneous SSc has a distinct serum protein profile with prominent dysregulation of proteins related to fibrosis and immune cell adhesion/diapedesis. The differential expression for most serum proteins in SSc is likely to originate outside the peripheral blood cells., (© 2021, American College of Rheumatology.)

The concept of prosthesis-patient mismatch (PPM) has gained much attention since first described 40 years ago. Previous studies have shown conflicting evidence regarding increased early and late morbidity and mortality with PPM after aortic valve replacement (AVR). The aim of this study was to evaluate the effects of PPM on short- and long-term mortality in low-risk patients after isolated AVR. A retrospective, single-center study involving 1707 consecutive patients ≤80 years of age with preserved left ventricular systolic function who underwent elective, primary isolated AVR operations from 2008 to 2018. Patients were stratified into 2 groups according to the presence of PPM (n = 96), defined as effective orifice area index <0.85 cm 2 /m 2 body surface area, and no-PPM (n = 1611). The effect of PPM on mortality was evaluated with univariate and multivariate analyses. 30-day mortality was 0.8% (4.2% in PPM group vs 0.6 in no-PPM group; P = 0.005). PPM occurred more in female gender, obese and older patients. PPM was highly associated with long-term all-cause mortality (median 4 years [Q1-Q3 2-7]; HR: 1.79, 95% CI: 1.27-2.55, P = 0.002), and remained strongly and independently associated after adjustment for other risk factors (HR: 1.60, 95% CI: 1.10-2.34, P = 0.014). In propensity score-matched analysis, the adjusted mortality risk was higher in PPM group (HR: 2.03, 95% CI: 1.22-3.39, P = 0.006) compared to no-PPM group. In a single-centre observational study, PPM increased early mortality and was independently associated with long-term all-cause mortality after low-risk, primary isolated AVR operations. Strategies to avoid PPM should be explored and implemented., (Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.)

Prophylactic donor lymphocyte infusions (DLI) are used to augment post-transplant immune recovery to reduce both infectious complications and disease recurrence. Preclinical studies implicate the naive T-cell subset as the primary driver of graft-versus-host disease (GvHD). In this phase I dose escalation study, we assessed the safety of a DLI that was depleted of CD45RA+ naive T cells. Sixteen adult patients received a prophylactic DLI at a median of 113 days (range 76-280 days) following an HLA-identical, non-myeloablative allogeneic hematopoietic stem cell transplantation. Three patients each received the naive T-cell depleted DLI with a CD3+ dose of 1 × 10 5 /kg, 1 × 10 6 /kg, and 5 × 10 6 /kg. The maximum dose of 1 × 10 7 /kg was expanded to 7 patients. No dose-limiting grade III/IV acute GvHD or adverse events attributable to the DLI were observed at any dose level. One patient developed grade 2 acute GvHD of skin and upper intestines, and another developed moderate chronic GvHD of the lungs following the DLI. With a median follow-up of 2.8 years, 2-year progression-free and overall survival is 50.0% and 68.8%, respectively. In conclusion, these data suggest that a DLI that has been depleted of CD45RA+ naive T cells is feasible and carries a low risk of acute or chronic GvHD.

Objective: The Scleroderma: Cyclophosphamide or Transplantation (SCOT) trial demonstrated clinical benefit of haematopoietic stem cell transplant (HSCT) compared with cyclophosphamide (CYC). We mapped PBC (peripheral blood cell) samples from the SCOT clinical trial to scleroderma intrinsic subsets and tested the hypothesis that they predict long-term response to HSCT., Methods: We analysed gene expression from PBCs of SCOT participants to identify differential treatment response. PBC gene expression data were generated from 63 SCOT participants at baseline and follow-up timepoints. Participants who completed treatment protocol were stratified by intrinsic gene expression subsets at baseline, evaluated for event-free survival (EFS) and analysed for differentially expressed genes (DEGs)., Results: Participants from the fibroproliferative subset on HSCT experienced significant improvement in EFS compared with fibroproliferative participants on CYC (p=0.0091). In contrast, EFS did not significantly differ between CYC and HSCT arms for the participants from the normal-like subset (p=0.77) or the inflammatory subset (p=0.1). At each timepoint, we observed considerably more DEGs in HSCT arm compared with CYC arm with HSCT arm showing significant changes in immune response pathways., Conclusions: Participants from the fibroproliferative subset showed the most significant long-term benefit from HSCT compared with CYC. This study suggests that intrinsic subset stratification of patients may be used to identify patients with SSc who receive significant benefit from HSCT., Competing Interests: Competing interests: MLW reports grants and personal fees from Celdara Medical, grants and personal fees from Bristol Myers Squib, personal fees from Acceleron, personal fees from Abbvie, grants and personal fees from Corbus, personal fees from Boehringer Ingelheim, outside the submitted work. MDM reports personal fees from Medtelligence, personal fees from Actelion Pharma, personal fees from Astellas, personal fees from Mitsubishi-Tanabe, grants from Bayer, grants from Reata, grants from Sanofi, grants from Corbus, grants and personal fees from Boehringer-Ingelheim, grants and personal fees from EICOS, grants and personal fees from Galapagos, grants from GSK, outside the submitted work. DEF reports grants from Actelion, grants and personal fees from Amgen, grants and personal fees from Bristol Myers Squibb, grants and personal fees from Galapagos, grants and personal fees from Novartis, grants and personal fees from Pfizer, grants from Sanofi, grants from Roche/Genentech, grants and personal fees from Corbus, grants from GSK, outside the submitted work. All other authors have nothing to disclose., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Delirium is common among adults undergoing hematopoietic stem cell transplantation (HCT), although the clinical and neuroimaging correlates of post-HCT delirium have not been adequately delineated. We therefore examined the frequency of delirium and neuroimaging correlates of post-transplant delirium in a retrospective cohort of 115 adults undergoing neuroimaging after allogeneic HCT. Delirium was established using previously validated methods for retrospective identification of chart-assessed postprocedural delirium. Chart reviews were independently conducted by a multidisciplinary team with expertise in HCT, psychiatry, and psychology on consecutive allogeneic HCT patients who underwent neuroimaging assessments and transplantation at a single center between January 2009 and December 2016. Neuroimaging markers of white matter damage and brain volume loss were also recorded. In total, 115 patients were included, ranging in age from 20 to 74 years (mean [SD] age, 49 [13]). Fifty-three patients (46%) developed post-HCT delirium. In an adjusted model, delirium incidence was associated with older age (odds ratio [OR], 1.92 [1.28, 2.87] per decade, P = .002), greater severity of white matter hyperintensities (OR, 1.95 [1.06, 3.57], P = .031), and conditioning intensity (OR, 6.37 [2.20, 18.45], P < .001) but was unrelated to cortical atrophy (P = .777). Delirium was associated with fewer hospital-free days (P = .023) but was not associated with overall survival (hazard ratio, 0.95 [0.56, 1.61], P = .844). Greater incidence of delirium following HCT was associated with greater age, microvascular burden, and conditioning intensity. Pre-HCT consideration of microvascular burden and other neuroimaging biomarkers of risk may be warranted., (Copyright © 2020. Published by Elsevier Inc.)

Allogeneic-HCT (allo-HCT), while potentially curative, can result in significant complications including graft versus host disease (GVHD). Prior studies suggest that metabolic syndrome may be one risk factor for GVHD. We hypothesized that hepatic steatosis on pre-HCT computed tomography (CT) scans may be a marker for development of GVHD and poor outcomes in allo-HCT. In this retrospective study, we reviewed the pre-HCT CT scans and transplant outcome data of patients who underwent allo-HCT at Duke University Medical Center from 2009 to 2017. The presence of steatosis was confirmed using CT attenuation measurements. We then assessed the association between pre-HCT hepatic steatosis and HCT-related outcomes including GVHD. 80 patients who had pre-HCT CT scans were included in the study. Pre-transplant hepatic steatosis was associated with the development of chronic GVHD (OR 4.2, p = 0.02), but was not associated with acute GVHD (OR 1.3, p = 0.7), non-relapse mortality (p = 0.81) or overall survival (p = 0.74). Based on this single center retrospective study, pre-transplant hepatic steatosis is associated with development of chronic GVHD. Further, prospective study with other imaging modalities including non-contrasted CT scans is needed to determine if this association is reproducible., Competing Interests: The authors have declared that no competing interests exist.

Objectives: The aim of this study was to characterize national variation in radionuclide calibrator activity response to a single National Institute of Standards and Technology (NIST) traceable reference Ge source used as a surrogate for F at clinical PET centres in England using National Physical Laboratory approved techniques., Methods: Readings from 20 instruments at 13 centres using local F and Ge factor settings were recorded with the source located in vial and syringe positions. Ten repeat measurements were conducted to investigate repeatability using % coefficient of variability (COV). Comparison ratios to investigate accuracy were made between calibrator responses and decay-corrected NISTref reference activity for syringe and vial position measurements., Results: The maximum %COV was 0.79%, while 90, 95 and 80% of calibrators conformed to 5% accuracy for F syringe, Ge syringe and Ge vial position readings, respectively. We revealed a trend towards reduced bias in measurements using Veenstra devices for F and using Capintec devices for Ge factor settings., Conclusions: This study demonstrated good repeatability in local device measurements. In total, 70% of English calibrators tested and 88% of all measurements performed achieved 5% accuracy. While statistically significant bias was exhibited between different vendor equipment dependent upon radioisotope selected, our study recommends regular traceability checks for optimum instrument performance conducted within National Metrology Institutes guidelines.

Objectives: Harmonisation is the process whereby standardised uptake values from different scanners can be made comparable. This PET/CT pilot study aimed to evaluate the effectiveness of harmonisation of a modern scanner with image reconstruction incorporating resolution recovery (RR) with another vendor older scanner operated in two-dimensional (2D) mode, and for both against a European standard (EARL). The vendor-proprietary software EQ•PET was used, which achieves harmonisation with a Gaussian smoothing. A substudy investigated effect of RR on harmonisation., Methods: Phantom studies on each scanner were performed to optimise the smoothing parameters required to achieve successful harmonisation. 80 patients were retrospectively selected; half were imaged on each scanner. As proof of principle, a cohort of 10 patients was selected from the modern scanner subjects to study the effects of RR on harmonisation., Results: Before harmonisation, the modern scanner without RR adhered to EARL specification. Using the phantom data, filters were derived for optimal harmonisation between scanners and with and without RR as applicable, to the EARL standard. The 80-patient cohort did not reveal any statistically significant differences. In the 10-patient cohort SUVmax for RR > no RR irrespective of harmonisation but differences lacked statistical significance (one-way ANOVA F(3.36) = 0.37, p = 0.78). Bland-Altman analysis showed that harmonisation reduced the SUVmax ratio between RR and no RR to 1.07 (95% CI 0.96-1.18) with no outliers., Conclusions: EQ•PET successfully enabled harmonisation between modern and older scanners and against the EARL standard. Harmonisation reduces SUVmax and dependence on the use of RR in the modern scanner., Advances in Knowledge: EQ•PET is feasible to harmonise different PET/CT scanners and reduces the effect of RR on SUVmax., (© 2020 The Authors. Published by the British Institute of Radiology.)

Diabetes and kidney disease commonly coexist and management is complex given frequent additional comorbidity. The East and North Herts Institute of Diabetes and Endocrinology (ENHIDE) renal diabetes telehealth project examined the feasibility of data extraction from primary care records for virtual consultant review as a prelude to a telehealth case-based discussion with primary care teams. Data extraction identified 2,356 cases from 16 general practices, of which 14 took part in a skype telehealth case-based discussion session. The service was well received by primary care as a workable means of delivering patient care. In addition, significant unmet clinical needs were identified with opportunities to empower patient self-management of acute metabolic and foot issues, and better coordination of care between specialist diabetes and renal teams. The increasing clinical burden in all care settings and the commitment in the NHS plan for wider use of digital healthcare and streamlining of outpatient care highlight the need for service reconfiguration., (© Royal College of Physicians 2020. All rights reserved.)

Herpes zoster (HZ) can have a substantial impact on quality of life (QoL). The vaccine efficacy (VE) of a recombinant zoster vaccine (RZV) was 68.2% (95% confidence interval [CI], 55.6% to 77.5%) in a phase 3 study in adult autologous hematopoietic stem cell transplant (HSCT) recipients (NCT01610414). Herein, we report the impact of RZV on patients' QoL. Autologous HSCT recipients were randomized 1:1 to receive 2 doses of RZV or placebo, given 1 to 2 months apart. QoL was measured by the Short Form Survey-36 and Euro-QoL-5 Dimension at baseline, 1 month, and 1 year postdose 2 and during suspected HZ episodes with the Zoster Brief Pain Inventory (ZBPI). The RZV impact on ZBPI burden of illness and burden of interference scores was estimated. The 2 scores were calculated from the area under the curve (days 0 to 182) of the ZBPI worst pain and ZBPI activities of daily living scores, respectively, assuming a score of 0 for patients not having a confirmed HZ episode. The ZBPI maximum worst pain score was significantly lower in the RZV than placebo group (mean: 5.8 versus 7.1, P = .011). Consequently, the VE estimates for HZ burden of illness (82.5%; 95% CI, 73.6 to 91.4) and burden of interference (82.8%; 95% CI, 73.3 to 92.3) were higher than the HZ VE estimate (ie, 68.2%). RZV showed significantly better QoL scores than placebo 1 week following rash onset among patients with confirmed HZ. In addition to reducing the risk of HZ and its complications, RZV significantly reduced the impact of HZ on patients' QoL in those who developed breakthrough disease., (Copyright © 2019 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: Autologous hematopoietic stem cell transplantation (HSCT) is a promising therapeutic modality for severe autoimmune diseases. In this review, we will outline the immunological mechanisms and the clinical evidence and experiences for therapeutic HSCT in autoimmune diseases, with particular focus on systemic sclerosis and multiple sclerosis., Recent Findings: Approximately 3000 patients with autoimmune diseases worldwide have been treated with HSCT. HSCT in systemic sclerosis has been shown in three randomized controlled trials to be associated with significant long-term event-free survival despite some transplant-related mortality in the first year. A recent controlled trial in multiple sclerosis has also show benefit with transplant., Summary: The aim of HSCT is to 'reset' one's immune system into a naïve and self-tolerant state through immune depletion and regulation. HSCT requires careful patient selection, close collaboration between physicians and expertise of transplant team to ensure optimal outcome.

Objective: In the randomised scleroderma: Cyclophosphamide Or Transplantation (SCOT trial) (NCT00114530), myeloablation, followed by haematopoietic stem cell transplantation (HSCT), led to improved clinical outcomes compared with monthly cyclophosphamide (CYC) treatment in systemic sclerosis (SSc). Herein, the study aimed to determine global molecular changes at the whole blood transcript and serum protein levels ensuing from HSCT in comparison to intravenous monthly CYC in 62 participants enrolled in the SCOT study., Methods: Global transcript studies were performed at pretreatment baseline, 8 months and 26 months postrandomisation using Illumina HT-12 arrays. Levels of 102 proteins were measured in the concomitantly collected serum samples., Results: At the baseline visit, interferon (IFN) and neutrophil transcript modules were upregulated and the cytotoxic/NK module was downregulated in SSc compared with unaffected controls. A paired comparison of the 26 months to the baseline samples revealed a significant decrease of the IFN and neutrophil modules and an increase in the cytotoxic/NK module in the HSCT arm while there was no significant change in the CYC control arm. Also, a composite score of correlating serum proteins with IFN and neutrophil transcript modules, as well as a multilevel analysis showed significant changes in SSc molecular signatures after HSCT while similar changes were not observed in the CYC arm. Lastly, a decline in the IFN and neutrophil modules was associated with an improvement in pulmonary forced vital capacity and an increase in the cytotoxic/NK module correlated with improvement in skin score., Conclusion: HSCT contrary to conventional treatment leads to a significant 'correction' in disease-related molecular signatures., Competing Interests: Competing interests: SA reports grants from National Institute of Health, grants from Karen Brown Scleroderma Foundation, grants from Department of Defense, during the conduct of the study; grants and personal fees from Boehringer Ingelheim, personal fees from Integrity Continuing Education, personal fees from Medscape, outside the submitted work. MDM reports personal fees from Boehringer Ingelheim, during the conduct of the study; personal fees from Galapagos NV (Pharma), personal fees from Medtelligence, personal fees from Actelion Pharma, personal fees from Astellas, personal fees from Mitsubishi-Tanabe, grants from Bayer, grants from Reata, grants from Sanofi, grants from Corbus, grants from Eicos/ Sciences, outside the submitted work. KMS reports grants from National Institutes of Health, NIAID, during the conduct of the study; personal fees from GlaxoSmith/Kline, grants from Astra Zeneca, grants from Takeda Millennium, personal fees from Magenta, personal fees from Aerotek, personal fees from Kiadis Pharma, from Genentech Roche, outside the submitted work., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Importance: Herpes zoster, a frequent complication following autologous hematopoietic stem cell transplantation (HSCT), is associated with significant morbidity. A nonlive adjuvanted recombinant zoster vaccine has been developed to prevent posttransplantation zoster., Objective: To assess the efficacy and adverse event profile of the recombinant zoster vaccine in immunocompromised autologous HSCT recipients., Design, Setting, and Participants: Phase 3, randomized, observer-blinded study conducted in 167 centers in 28 countries between July 13, 2012, and February 1, 2017, among 1846 patients aged 18 years or older who had undergone recent autologous HSCT., Interventions: Participants were randomized to receive 2 doses of either recombinant zoster vaccine (n = 922) or placebo (n = 924) administered into the deltoid muscle; the first dose was given 50 to 70 days after transplantation and the second dose 1 to 2 months thereafter., Main Outcomes and Measures: The primary end point was occurrence of confirmed herpes zoster cases., Results: Among 1846 autologous HSCT recipients (mean age, 55 years; 688 [37%] women) who received 1 vaccine or placebo dose, 1735 (94%) received a second dose and 1366 (74%) completed the study. During the 21-month median follow-up, at least 1 herpes zoster episode was confirmed in 49 vaccine and 135 placebo recipients (incidence, 30 and 94 per 1000 person-years, respectively), an incidence rate ratio (IRR) of 0.32 (95% CI, 0.22-0.44; P < .001), equivalent to 68.2% vaccine efficacy. Of 8 secondary end points, 3 showed significant reductions in incidence of postherpetic neuralgia (vaccine, n=1; placebo, n=9; IRR, 0.1; 95% CI, 0.00-0.78; P = .02) and of other prespecified herpes zoster-related complications (vaccine, n=3; placebo, n=13; IRR, 0.22; 95% CI, 0.04-0.81; P = .02) and in duration of severe worst herpes zoster-associated pain (vaccine, 892.0 days; placebo, 6275.0 days; hazard ratio, 0.62; 95% CI, 0.42-0.89; P = .01). Five secondary objectives were descriptive. Injection site reactions were recorded in 86% of vaccine and 10% of placebo recipients, of which pain was the most common, occurring in 84% of vaccine recipients (grade 3: 11%). Unsolicited and serious adverse events, potentially immune-mediated diseases, and underlying disease relapses were similar between groups at all time points., Conclusions and Relevance: Among adults who had undergone autologous HSCT, a 2-dose course of recombinant zoster vaccine compared with placebo significantly reduced the incidence of herpes zoster over a median follow-up of 21 months., Trial Registration: ClinicalTrials.gov Identifier: NCT01610414.

Importance: Cutaneous chronic graft-vs-host disease (cGVHD) is common after allogeneic hematopoietic stem cell transplant and is often associated with poor patient outcomes. A reliable and practical method for assessing disease severity and response to therapy among these patients is urgently needed., Objective: To evaluate the interrater agreement and reliability of skin-specific and range of motion (ROM) variables of the 2014 National Institutes of Health (NIH) response criteria for cGVHD and a skin sclerosis grading scale (SSG)., Design, Setting, and Participants: In this observational study performed at a single tertiary academic center, 6 academic blood and marrow transplant specialists and 4 medical dermatologists examined 8 patients with diagnosed cutaneous cGVHD on July 10, 2015. The patient cohort was enriched for patients with sclerotic features. Each patient was evaluated by using the skin-specific and ROM criteria of the 2014 NIH response criteria for cGVHD and an SSG ranging from 0 to 3. Each patient was also asked to complete quality-of-life scoring instruments. Interrater agreement and reliability were estimated by calculating the Krippendorff α and Cohen κ statistics. Data were analyzed from September 29, 2015, through November 22, 2018., Main Outcomes and Measures: Estimation of interrater agreement by interclass coefficient (Krippendorff α and Cohen κ statistics) for the skin-specific and ROM components of the 2014 NIH Response Criteria for Chronic GVHD and for the SSG., Results: The median age of the patients evaluated was 54 years (range, 46-58 years). Patients were predominantly male (6 [75%]). Six of the 8 patients had a predominantly sclerotic cutaneous phenotype. Interrater agreement among our experts was acceptable for NIH skin feature score (0.68; 95% CI, 0.30-0.86) and good for NIH ROM scoring (0.80; 95% CI, 0.68-0.86). Dermatologists had acceptable agreement for NIH skin GVHD score (0.69; 95% CI, 0.25-0.82) and skin feature score (0.78; 95% CI, 0.17-0.98), good agreement in ROM grading (0.85; 95% CI, 0.69-0.90), and near perfect agreement in identifying sclerosis (0.82; 95% CI, 0.27-0.97)., Conclusions and Relevance: Although dermatologists had acceptable agreement in NIH skin GVHD score and skin features score, near perfect agreement in identifying cutaneous sclerosis, better agreement in grading severity of cutaneous cGVHD, especially in the intermediate grades, appears to be needed.

Multiple sclerosis (MS) is a chronic, disabling, immune-mediated, demyelinating and degenerative disease of the central nervous system. Approved disease-modifying therapies may be incompletely effective in some patients with highly active relapsing disease and high risk of disability. The use of immunoablative or myeloablative therapy followed by autologous hematopoietic cell transplantation (AHCT) has been investigated in retrospective studies, clinical trials, and meta-analyses/systematic reviews as an approach to address this unmet clinical need. On behalf of the American Society for Blood and Bone Marrow Transplantation (ASBMT), a panel of experts in AHCT and MS convened to review available evidence and make recommendations on MS as an indication for AHCT. A review of recent literature identified 8 retrospective studies, 8 clinical trials, and 3 meta-analyses/systematic reviews. In aggregate, these studies indicate that AHCT is an efficacious and safe treatment for active relapsing forms of MS to prevent clinical relapse, magnetic resonance imaging-detectable lesion activity, and worsening disability and to reverse disability without unexpected adverse events. Based on the available evidence, the ASBMT recommends that treatment-refractory relapsing MS with high risk of future disability be considered a "standard of care, clinical evidence available" indication for AHCT. Collaboration of neurologists with expertise in treating MS and transplantation physicians with experience performing AHCT for autoimmune disease is crucial for ensuring appropriate patient selection and optimizing transplantation procedures to improve patient outcomes. Transplantation centers in the United States and Canada are strongly encouraged to report baseline and outcomes data on patients receiving AHCT for multiple sclerosis to the Center for International Blood and Marrow Transplant Research., (Copyright © 2019 American Society for Blood and Marrow Transplantation. All rights reserved.)

Introduction: In a society that perpetuates the strive for a perfect appearance, a fit body has become synonymous with success, but simultaneously hard to achieve. This represents a fertile ground for the development of Exercise Addiction (EA) alongside other disorders, such as Body Dysmorphic Disorder (BDD). This study aims to explore the diffusion of EA in fitness settings in the United Kingdom, Italy, Netherlands, Hungary and the previously unexplored association with appearance anxiety, BDD, self-esteem and the use of fitness supplements., Methods: A large cross-sectional sample (N = 1711) was surveyed in fitness settings using the Exercise Addiction Inventory (EAI), Appearance Anxiety Inventory (AAI) and Rosenberg's Self Esteem Scale (RSE) in addition to questions surrounding the use of fitness supplements., Results: Compulsive exercise, appearance anxiety and low self-esteem were present in this sample according to the psychometric measures used (EAI, AAI, RSE). 11.7% scored over the cut off for EA, with alarming peaks in the Netherlands (20.9%) and the United Kingdom (16.1%). 38.5% were found at risk of BDD, mainly female (47.2%). 39.8% used fitness enhancing supplements without medical consultation (95.5%). This cohort of supplement users scored higher in both EAI and AAI. The logistic regression model revealed a strong association between the consumption of sport products and the level of EA across the sample with an odds ratio (OR) of 3.03. Other co-variable factors among female were appearance anxiety (AAI; OR 1.59) and to a lesser extent self-esteem (RSE) (OR 1.08)., Conclusions: This study identified a high risk of EA, appearance anxiety and BDD amongst a cohort of gym users internationally. The previously-unexplored association between these disorders and the unsupervised use of a variety of fitness products, including illicit drugs, highlights the need for informed and integrated responses targeting such vulnerable individuals., Competing Interests: The authors have declared that no competing interests exist.

We conducted a multicenter pilot investigation of the safety and feasibility of bone marrow transplantation (BMT) in adults with severe sickle cell disease (SCD) (NCT 01565616) using a reduced toxicity preparative regimen of busulfan (13.2 mg/kg), fludarabine (175 mg/m 2 ) and thymoglobulin (6 mg/kg) and cyclosporine or tacrolimus and methotrexate for graft-vs-host disease (GVHD) prophylaxis. Twenty-two patients (median age 22 years; range 17-36) were enrolled at eight centers. Seventeen patients received marrow from an HLA-identical sibling donor and five patients received marrow from an 8/8 HLA-allele matched unrelated donor. Before BMT, patients had stroke, acute chest syndrome, recurrent pain events, were receiving regular red blood cell transfusions, or had an elevated tricuspid regurgitant jet (TRJ) velocity, which fulfilled eligibility criteria. Four patients developed grades II-III acute GVHD (18%) and six developed chronic GVHD (27%) that was moderate in two and severe in one patient. One patient died of intracranial hemorrhage and one of GVHD. Nineteen patients had stable donor chimerism, 1-year post-transplant. One patient who developed secondary graft failure survives disease-free after a second BMT. The one-year overall survival and event-free survival (EFS) are 91% (95% CI 68%-98%) and 86% (95% CI, 63%-95%), respectively, and 3-year EFS is 82%. Statistically significant improvements in the pain interference and physical function domains of health-related quality of life were observed. The study satisfied the primary endpoint of 1-year EFS ≥70%. This regimen is being studied in a prospective clinical trial comparing HLA-matched donor BMT with standard of care in adults with severe SCD (NCT02766465)., (© 2019 Wiley Periodicals, Inc.)

Objectives: To determine if unexpected aorta uptake seen in some patients is influenced by popular modern reconstruction algorithms using semi-quantitative and qualitative analysis., Methods: Twenty-five consecutive patients without suspected vascular disease were selected for 18 F-FDG positron emission tomography/ computed tomography (PET/CT) scanning and images of the aorta were created using iterative reconstruction (IT), IT + time of flight (TOF), IT + TOF + point spread function correction (referred collectively as UHD) with and without metal artefact reduction (MAR) algorithms. An experienced radiologist created aorta and blood pool (BP) regions of interests then copied these to all reconstructions for accurate positioning before recording target aorta standardized-uptake-values (SUV max ) and background BP SUV mean . Furthermore, target-to-background ratio (TBR max ) was defined by aorta SUV max -to-BP SUV mean ratio for more analysis., Results: For aorta SUV max with IT, IT + TOF, UHD, UHD + MAR reconstructions the mean ± standard deviation recorded were 2.15±0.43, 2.25±0.51, 2.25±0.45 and 2.09±0.4, respectively. Values for BP SUV mean were 1.61±0.31, 1.58±0.28, 1.58±0.28 and 1.47±0.25, respectively. Likewise, for TBR max these were 1.35±0.19, 1.43±0.21, 1.43±0.19, 1.43±0.18, respectively. ANOVA analysis revealed no significant differences for aorta SUV max (F(0.86) p=0.46), BP SUV mean (F(1.22) p=0.31) or TBR max (F(0.99) p=0.4). However, the qualitative visual analysis revealed significant differences between IT + TOF with UHD (p=0.02) or UHD + MAR (p=0.02)., Conclusion: Reconstruction algorithm effect on aorta SUV max or BP SUV mean or TBR max was not statistically significant. However, qualitative visual analysis showed significant differences between IT + TOF as compared with UHD or UHD + MAR reconstructions. Harmonization of techniques with a larger patient cohort is recommended in future clinical trials.

Approximately 35% to 50% of patients otherwise cured of hematologic malignancies after allogeneic hematopoietic stem cell transplantation will develop the pleomorphic autoimmune-like syndrome known as chronic graft-versus-host disease (cGVHD). Since in 2005, National Institutes of Health (NIH) consensus panels have proposed definitions and classifications of disease to standardize treatment trials. Recently, the first agent was approved by the US Food and Drug Administration for steroid-refractory cGVHD. Despite these advances, most individuals do not achieve durable resolution of disease activity with initial treatment. Moreover, standardized recommendations on how to best implement existing and novel immunomodulatory agents and taper salvage agents are often lacking. Given the potential life-threatening nature of cGVHD, we employ in our practice patient assessment templates at each clinic visit to elucidate known prognostic indicators and red flags. We find NIH scoring templates practical for ongoing assessments of these complex patient cases and determination of when changes in immunosuppressive therapy are warranted. Patients not eligible or suitable for clinical trials have systemic and organ-directed adjunctive treatments crafted in a multidisciplinary clinic. Herein, we review these treatment options and offer a management and monitoring scaffold for representative patients with cGVHD not responding to initial therapy., (© 2019 by The American Society of Hematology.)

Aims: The endogenous fibrinolytic system serves to prevent lasting thrombotic occlusion and infarction following initiation of coronary thrombosis. We aimed to determine whether impaired endogenous fibrinolysis can identify patients with ST-segment elevation myocardial infarction (STEMI) who remain at high cardiovascular risk despite dual antiplatelet therapy (DAPT)., Methods and Results: A prospective, observational study was conducted in 496 patients presenting with STEMI for primary percutaneous coronary intervention (PPCI). Blood was tested on arrival pre-PPCI, at discharge and at 30 days to assess thrombotic status using the automated point-of-care global thrombosis test and patients followed for 1 year for major adverse cardiovascular events (MACEs). Endogenous fibrinolysis was significantly impaired [baseline lysis time (LT) ≥2500 s] in 14% of patients and was highly predictive of recurrent MACE [hazard ratio (HR) 9.1, 95% confidence interval (CI) 5.29-15.75; P < 0.001], driven by cardiovascular death (HR 18.5, 95% CI 7.69-44.31; P < 0.001) and myocardial infarction (HR 6.2, 95% CI 2.64-14.73; P < 0.001), particularly within 30 days. Fibrinolysis remained strongly predictive of MACE after adjustment for conventional risk factors (HR 8.03, 95% CI 4.28-15.03; P < 0.001). Net reclassification showed that adding impaired fibrinolysis improved the prediction of recurrent MACE by >50% (P < 0.001). Patients with spontaneous ST-segment resolution pre-PPCI had more rapid, effective fibrinolysis [LT 1050 (1004-1125) s vs. 1501 (1239-1997) s, P < 0.001] than those without. Lysis time was not altered by standard of care STEMI treatment including DAPT and was unchanged at 30 days., Conclusion: Endogenous fibrinolysis assessment can identify patients with STEMI who remain at very high cardiovascular risk despite PPCI and DAPT. Further studies are needed to assess whether these patients may benefit from additional, personalized antithrombotic/anticoagulant medication to reduce future cardiovascular risk., Clinical Trial Registration: http://www.clinicaltrials.gov. Unique identifier: NCT02562690.

Objective: To assess survival and identify predictors of survival in patients with systemic sclerosis-interstitial lung disease (SSc-ILD) who participated in the Scleroderma Lung Studies (SLS) I and II., Methods: SLS I randomised 158 patients with SSc-ILD to 1  year of oral cyclophosphamide (CYC) vs placebo. SLS II randomised 142 patients to 1 year of oral CYC followed by 1 year of placebo vs 2 years of mycophenolate mofetil. Counting process Cox proportional hazard modelling identified variables associated with long-term mortality in SLS I and II. Internal validation was performed using joint modelling., Results: After a median follow-up of 8 years, 42% of SLS I patients died, and when known the cause of death was most often attributable to SSc. There was no significant difference in the time to death between treatment arms in SLS I or II. Higher baseline skin score, older age, and a decline in the forced vital capacity (FVC) and the diffusing capacity for carbon monoxide (DLCO) over 2 years were independently associated with an increased risk of mortality in SLS I. The Cox model identified the same mortality predictor variables using the SLS II data., Conclusion: In addition to identifying traditional mortality risk factors in SSc (skin score, age), this study demonstrated that a decline in FVC and DLCO over 2 years was a better predictor of mortality than baseline FVC and DLCO. These findings suggest that short-term changes in surrogate measures of SSc-ILD progression may have important effects on long-term outcomes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Systemic sclerosis is a progressive inflammatory disease that is frequently fatal and has limited treatment options. High-dose chemotherapy with autologous hematopoietic cell transplantation (AHCT) has been evaluated as treatment for this disease in observational studies, multicenter randomized controlled clinical trials, and meta-analyses. On behalf of the American Society for Blood and Marrow Transplantation (ASBMT), a panel of experts in transplantation and rheumatology was convened to review available evidence and make a recommendation on AHCT as an indication for systemic sclerosis. Three randomized trials have compared the efficacy of AHCT with cyclophosphamide only, and all demonstrated benefit for the AHCT arm for their primary endpoint (improvement in the American Scleroderma Stem Cell versus Immune Suppression Trial, event-free survival in Autologous Stem Cell Transplantation International Scleroderma trial, and change in global rank composite score in Scleroderma: Cyclophosphamide or Transplantation trial). AHCT recipients also had better overall survival and a lower rate of disease progression. These findings have been confirmed in subsequent meta-analyses. Based on this high-quality evidence, the ASBMT recommends systemic sclerosis should be considered as a "standard of care" indication for AHCT. Close collaboration between rheumatologists and transplant clinicians is critical for optimizing patient selection and patient outcomes. Transplant centers in the United States are strongly encouraged to report patient and outcomes data to the Center for International Blood and Marrow Transplant Research on their patients receiving AHCT for this indication., (Copyright © 2018 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

For patients with acute lymphoblastic leukemia (ALL), allogeneic hematopoietic cell transplantation (alloHCT) offers a potential cure. Life-threatening complications can arise from alloHCT that require the application of sophisticated health care delivery. The impact of country-level economic conditions on post-transplantation outcomes is not known. Our objective was to assess whether these variables were associated with outcomes for patients transplanted for ALL. Using data from the Center for Blood and Marrow Transplant Research, we included 11,261 patients who received a first alloHCT for ALL from 303 centers across 38 countries between the years of 2005 and 2013. Cox regression models were constructed using the following macroeconomic indicators as main effects: Gross national income per capita, health expenditure per capita, and Human Development Index (HDI). The outcome was overall survival at 100 days following transplantation. In each model, transplants performed within lower resourced environments were associated with inferior overall survival. In the model with the HDI as the main effect, transplants performed in the lowest HDI quartile (n = 697) were associated with increased hazard for mortality (hazard ratio, 2.42; 95% confidence interval, 1.64 to 3.57; P < .001) in comparison with transplants performed in the countries with the highest HDI quartile. This translated into an 11% survival difference at 100 days (77% for lowest HDI quartile versus 88% for all other quartiles). Country-level macroeconomic indices were associated with lower survival at 100 days after alloHCT for ALL. The reasons for this disparity require further investigation., (Copyright © 2018 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Context: - Graft-versus-host disease of the gastrointestinal tract is a common complication of hematopoietic stem cell transplant associated with significant morbidity and mortality. Accurate diagnosis can be difficult and is a truly clinicopathologic endeavor., Objectives: - To assess the diagnostic sensitivity of gastrointestinal graft-versus-host disease using the 2015 National Institutes of Health (NIH) histology consensus guidelines and to analyze histologic findings that support the guidelines., Design: - Patients with allogeneic hematopoietic stem cell transplants were identified via a retrospective search of our electronic medical records from January 1, 2005, to January 1, 2011. Endoscopies with available histology were reviewed by 2 pathologists using the 2015 NIH guidelines. The clinical diagnosis was used as the gold standard. A nontransplant set of endoscopic biopsies was used as a control., Results: - Of the 250 total endoscopies, 217 (87%) had a clinical diagnosis of gastrointestinal graft-versus-host disease. Use of the NIH consensus guidelines showed a sensitivity of 86% and a specificity of 65%. Thirty-seven of 58 (64%) cases with an initial false-negative histopathologic diagnosis were diagnosed as graft-versus-host disease on our review., Conclusions: - Use of the NIH histology consensus guidelines results in a high sensitivity and specificity, thereby decreasing false-negatives. Additionally, use of the NIH guidelines aids in creating uniformity and diagnostic clarity. Correlation with clinical and laboratory findings is critical in evaluating the differential diagnosis and to avoid false-positives. As expected, increased apoptosis with decreased inflammation was associated with a pathologic diagnosis of graft-versus-host disease and supports the NIH guidelines.