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Background: Chinese American adults experience health disparities at the end of life. Culturally tailored advance care planning (ACP) may promote goal-concordant care across the continuum of serious illness. However, seriously ill Chinese Americans' preferences for ACP remain unknown. Objective: To explore barriers and facilitators to ACP among Chinese patients with advanced cancer and their caregivers. Design: Informed by socioecological theory, we conducted an exploratory qualitative study using semistructured interviews that were thematically analyzed. Setting/Participants: We recruited participants at one U.S. comprehensive cancer center. Of 27 eligible patients approached, we recruited 20 patients (74.1%) and 8 accompanying caregivers. Overall, participants were middle aged (55.6 ± 13.5 years), 60.7% female, 85.7% partnered/married, 89.3% college educated, and had low acculturation (mean Suinn-Lew Asian Self-Identify Acculturation = 2.0 ± 1.6/5.0). More patients were privately insured (35%) than self-pay (30%), Medicare (25%), and Medicaid (10%). Caregivers were split between "spouse" and "child." Results: Findings highlight participants' trust in their clinicians and the study institution as primary supports for clinicians to lead ACP. However, participants' preconceptions of clinicians' professional responsibilities and participants' belief in an uncertain future may hinder an open discussion of goals and values for future medical care. A key moderating factor in how participants view ACP may be their level of acculturation to local care, behavioral, and communication norms. Conclusions: Chinese patients may prefer a routinized clinician-led ACP approach that supports their actionable priorities in the present by leveraging patient-clinician trust, gauging acculturation level, and using indirect communication strategies. Future studies should investigate preferred communication strategies to support in-the-moment care planning.

BACKGROUND: Improved understanding of the pathways associated with airway pathophysiologic features in COPD will identify new predictive biomarkers and novel therapeutic targets. RESEARCH QUESTION: Which physiologic pathways are altered in the airways of patients with COPD and will predict exacerbations? STUDY DESIGN AND METHODS: We applied a mass spectrometric panel of metabolomic biomarkers related to mucus hydration and inflammation to sputa from the multicenter Subpopulations and Intermediate Outcome Measures in COPD Study. Biomarkers elevated in sputa from patients with COPD were evaluated for relationships to measures of COPD disease severity and their ability to predict future exacerbations. RESULTS: Sputum supernatants from 980 patients were analyzed: 77 healthy nonsmokers, 341 smokers with preserved spirometry, and 562 patients with COPD (178 with Global Initiative on Chronic Obstructive Lung Disease [GOLD] stage 1 disease, 303 with GOLD stage 2 disease, and 81 with GOLD stage 3 disease) were analyzed. Biomarkers from multiple pathways were elevated in COPD and correlated with sputum neutrophil counts. Among the most significant analytes (false discovery rate, 0.1) were sialic acid, hypoxanthine, xanthine, methylthioadenosine, adenine, and glutathione. Sialic acid and hypoxanthine were associated strongly with measures of disease severity, and elevation of these biomarkers was associated with shorter time to exacerbation and improved prediction models of future exacerbations. INTERPRETATION: Biomarker evaluation implicated pathways involved in mucus hydration, adenosine metabolism, methionine salvage, and oxidative stress in COPD airway pathophysiologic characteristics. Therapies that target these pathways may be of benefit in COPD, and a simple model adding sputum-soluble phase biomarkers improves prediction of pulmonary exacerbations. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01969344; URL: www.clinicaltrials.gov

We hypothesized that combining adoptively transferred autologous T cells with a cancer vaccine strategy would enhance therapeutic efficacy by adding antimyeloma idiotype (Id)–keyhole limpet hemocyanin (KLH) vaccine to vaccine-specific costimulated T cells. In this randomized phase 2 trial, patients received either control (KLH only) or Id-KLH vaccine, autologous transplantation, vaccine-specific costimulated T cells expanded ex vivo, and 2 booster doses of assigned vaccine. In 36 patients (KLH, n = 20; Id-KLH, n = 16), no dose-limiting toxicity was seen. At last evaluation, 6 (30%) and 8 patients (50%) had achieved complete remission in KLH-only and Id-KLH arms, respectively (P = .22), and no difference in 3-year progression-free survival was observed (59% and 56%, respectively; P = .32). In a 594 Nanostring nCounter gene panel analyzed for immune reconstitution (IR), compared with patients receiving KLH only, there was a greater change in IR genes in T cells in those receiving Id-KLH relative to baseline. Specifically, upregulation of genes associated with activation, effector function induction, and memory CD8+ T-cell generation after Id-KLH but not after KLH control vaccination was observed. Similarly, in responding patients across both arms, upregulation of genes associated with T-cell activation was seen. At baseline, all patients had greater expression of CD8+ T-cell exhaustion markers. These changes were associated with functional Id-specific immune responses in a subset of patients receiving Id-KLH. In conclusion, in this combination immunotherapy approach, we observed significantly more robust IR in CD4+ and CD8+ T cells in the Id-KLH arm, supporting further investigation of vaccine and adoptive immunotherapy strategies. This trial was registered at www.clinicaltrials.gov as #NCT01426828.

Healthcare institutions with mandatory influenza vaccination policies have over 90% vaccination rates among healthcare workers (HCWs) resulting in a population that has received the influenza vaccine in many, consecutive years. This study explored the impact of sex and other host factors in pre- and post-vaccination neutralizing antibody (nAb) titers and seroconversion against the H1N1 and H3N2 influenza A viruses (IAVs) among HCWs enrolled into a cross-sectional serosurvey during the annual Johns Hopkins Hospital employee vaccination campaign in the 2017–18 and 2018–19 seasons. The study enrolled 111 participants (male = 38, female = 73) in 2017–18 and 163 (male = 44, female = 119) in 2018–19. Serum samples were collected immediately prior to vaccination and approximately 28 days later and nAb titers to vaccine strains determined. An intersectional approach was used to disaggregate the combined effects of sex with age and body mass index (BMI) in the nAb response. Differences between the pre- or post-vaccination geometric mean nAb titers between male and female HCWs were not observed. Male HCWs were 2.86 times more likely to seroconvert compared to female HCWs in 2017–2018, but the same trend was not observed in the following year. When data were disaggregated by age and sex, older female HCWs had higher H1N1 pre- and post-vaccination nAb titers compared to male HCWs in the same age group for both vaccination campaign seasons. In both years, the decline in H3N2 pre-vaccination titers with increasing BMI was greater in female than male HCW. The sex-specific effects of age and BMI on nAb responses to seasonal influenza vaccines require greater consideration.

The Centers for AIDS Research (CFAR) program was established by the National Institutes of Health in 1988 to catalyze and support high-impact HIV research and to develop the next generation of HIV investigators at academic institutions throughout the United States. In 2014, the Penn CFAR, the Johns Hopkins University CFAR and the District of Columbia CFAR developed a partnership—the Mid-Atlantic CFAR Consortium (MACC)—to promote cross-CFAR scientific collaboration, mentoring, and communication and to address the regional HIV epidemic. Over the past 6 years, the creation of the MACC has resulted in a rich web of interconnectivity, which has fostered scientific collaboration through working groups on the black men who have sex with men (MSM) and Latinx regional HIV epidemics, joint peer-reviewed publications, and successful collaborative grant applications on topics ranging from HIV prevention in young MSM, transgender women, implementation science, and clinical epidemiology; supported developmental activities through the MACC Scholars program, cross-CFAR mentoring, joint symposia, cross-CFAR seminar participation, and keynote speakers; and promoted strategic communication through advisory committees, best practices consultations, and the social and behavioral science research network. The MACC has been highly impactful by promoting HIV science through regional collaboration, supporting a diverse network of scholars across three cities and focusing on the epidemic in underrepresented and marginalized communities. Lessons learned from this consortium may have implications for scientific research centers beyond the field of HIV.

PURPOSE The optimum number of treatment courses for younger patients with acute myeloid leukemia (AML) is uncertain. The United Kingdom National Cancer Research Institute AML17 trial randomly assigned patients who were not high risk to a total of three versus four courses. PATIENTS AND METHODS Patients received two induction courses based on daunorubicin and cytarabine (Ara-C), usually with gemtuzumab ozogamicin. Following remission, 1,017 patients were randomly assigned to a third course, MACE (amsacrine, Ara-C, and etoposide), plus a fourth course of MidAc (mitoxantrone and Ara-C) and following an amendment to one or two courses of high-dose Ara-C. Primary end points were cumulative incidence of relapse (CIR), relapse-free survival (RFS), and overall survival (OS). Outcomes were correlated with patient characteristics, mutations, cytogenetics, induction treatments, and measurable residual disease (MRD) postinduction. RESULTS In logrank analyses, CIR and RFS at 5 years were improved in recipients of four courses (50% v 58%: hazard ratio [HR] 0.81 [0.69-0.97], P = .02 and 43% v 36%: HR 0.83 [0.71-0.98], P = .03, respectively). While OS was not significantly better (63% v 57%: HR 0.84 [0.69-1.03], P = .09), the noninferiority of three courses to four courses was not established. The impact on relapse was only significant when the fourth course was Ara-C. In exploratory analyses, although MRD impacted survival, a fourth course had no effect in either MRD-positive or MRD-negative patients. A fourth course was beneficial in patients who lacked a mutation of FLT3 or NPM1, had < 3 mutations in other genes, or had a presenting WBC of < 10 × 109 L−1. CONCLUSION Although a fourth course of high-dose Ara-C reduced CIR and improved RFS, it did not result in a significant OS benefit. Subsets including those with favorable cytogenetics, those lacking a mutation of FLT3 or NPM1, or those with < 3 other mutations may derive survival benefit.

Background: Both sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists reduce cardiovascular events among patients with type 2 diabetes. However, no cardiovascular outcome trial has evaluated the long-term effects of their combined use. The AMPLITUDE-O trial (Effect of Efpeglenatide on Cardiovascular Outcomes) reported that once-weekly injections of the glucagon-like peptide-1 receptor agonists efpeglenatide (versus placebo) reduced major adverse cardiovascular events (MACEs); MACEs, coronary revascularization, or unstable angina hospitalization (expanded MACEs); a renal composite outcome; and MACEs or death in people with type 2 diabetes and cardiovascular or renal disease. The trial uniquely stratified randomization by baseline or anticipated use of SGLT2 inhibitors and included the highest prevalence at baseline (N=618, 15.2%) of SGLT2 inhibitor use among glucagon-like peptide-1 receptor agonist cardiovascular outcome trials to date. Its results were analyzed to estimate the combined effect of SGLT2 inhibitors and efpeglenatide on clinical outcomes. Methods: Cardiovascular and renal outcomes were analyzed with Cox proportional hazards models adjusted for region, SGLT2 inhibitor randomization strata, and the SGLT2 inhibitor–by–treatment interaction. Continuous variables were analyzed with a mixed-effects models for repeated measures that also included an interaction term. Results: The effect (hazard ratio [95% CI]) of efpeglenatide versus placebo in the absence and presence of baseline SGLT2 inhibitors on MACEs (0.74 [0.58–0.94] and 0.70 [0.37–1.30], respectively), expanded MACEs (0.77 [0.62–0.96] and 0.87 [0.51–1.48]), renal composite (0.70 [0.59–0.83] and 0.52 [0.33–0.83]), and MACEs or death (0.74 [0.59–0.93] and 0.65 [0.36–1.19]) did not differ by baseline SGLT2 inhibitor use ( P for all interactions >0.2). The reduction of blood pressure, body weight, low-density lipoprotein cholesterol, and urinary albumin-to-creatinine ratio by efpeglenatide also appeared to be independent of concurrent SGLT2 inhibitor use (all interaction P ≥0.08). Last, adverse events did not differ by baseline SGLT2 inhibitor use. Conclusions: The efficacy and safety of efpeglenatide appear to be independent of concurrent SGLT2 inhibitor use. These data support combined SGLT2 inhibitor and glucagon-like peptide-1 receptor agonist therapy in type 2 diabetes. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT03496298.

Epstein-Barr virus–positive (EBV-positive) B-cell lymphomas are common in immunocompromised patients and remain an unmet medical need. Here we report that MDM2 inhibitors (MDM2is) navtemadlin and idasanutlin have potent in vivo activity in EBV-positive B-cell lymphoma established in immunocompromised mice. Tumor regression was observed in all 5 EBV-positive xenograft–associated B-cell lymphomas treated with navtemadlin or idasanutlin. Molecular characterization showed that treatment with MDM2is resulted in activation of p53 pathways and downregulation of cell cycle effectors in human lymphoma cell lines that were either EBV-positive or had undetectable expression of BCL6, a transcriptional inhibitor of the TP53 gene. Moreover, treatment with navtemadlin resulted in tumor regression and prevented systemic dissemination of EBV-positive lymphoma derived from 2 juvenile patients with posttransplant lymphoproliferative diseases, including 1 whose tumor was resistant to virus-specific T-cell therapy. These results provide proof-of-concept for targeted therapy of EBV-positive lymphoma with MDM2is and the feasibility of using EBV infection or loss of BCL6 expression to identify responders to MDM2is.

Rationale: Individuals with Chronic Obstructive Pulmonary Disease (COPD) have a high prevalence of depression, which is associated with increased COPD hospitalizations and readmissions. Objectives:...

Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by insulin deficiency and resultant hyperglycemia. Complex interactions of genetic and environmental factors trigger the onset of autoimmune mechanisms responsible for development of autoimmunity to β cell antigens and subsequent development of T1D. A potential role of virus infections has long been hypothesized, and growing evidence continues to implicate enteroviruses as the most probable triggering viruses. Recent studies have strengthened the association between enteroviruses and development of autoimmunity in T1D patients, potentially through persistent infections. Enterovirus infections may contribute to different stages of disease development. We review data from both human cohort studies and experimental research exploring the potential roles and molecular mechanisms by which enterovirus infections can impact disease outcome. Expected final online publication date for the Annual Review of Medicine, Volume 73 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

A new model is presented for multisite statistical downscaling of temperature and precipitation using convolutional conditional neural processes (convCNPs). ConvCNPs are a recently developed class of models that allow deep learning techniques to be applied to off-the-grid spatio-temporal data. This model has a substantial advantage over existing downscaling methods in that the trained model can be used to generate multisite predictions at an arbitrary set of locations, regardless of the availability of training data. The convCNP model is shown to outperform an ensemble of existing downscaling techniques over Europe for both temperature and precipitation taken from the VALUE intercomparison project. The model also outperforms an approach that uses Gaussian processes to interpolate single-site downscaling models at unseen locations. Importantly, substantial improvement is seen in the representation of extreme precipitation events. These results indicate that the convCNP is a robust downscaling model suitable for generating localised projections for use in climate impact studies, and motivates further research into applications of deep learning techniques in statistical downscaling., 26 pages, 12 figures

Key Points The incidence of acute cardiac toxicity remains low and manageable after matched allo-HCT in the era of PTCy prophylaxis.Older age, hypertension, arrhythmia, diabetes, and cardiac comorbidities increase this risk of cardiac toxicity but PTCy did not., Visual Abstract, Graft-versus-host disease (GVHD) is one of the leading causes of nonrelapse mortality (NRM) after allogeneic hematopoietic cell transplantation (allo-HCT). Posttransplant cyclophosphamide (PTCy) has shown promise in managing GVHD. However, cyclophosphamide has known cardiac toxicity, and few studies have evaluated the cardiac toxicities that arise after PTCy. We completed a retrospective analysis of patients who underwent matched-donor allo-HCT at our institution and who received PTCy- or non-PTCy–based GVHD prophylaxis, with the goal of determining the incidence of cardiac toxicities up to 100 days after allo-HCT. We included 585 patients in our analysis and found that 38 (6.5%) experienced cardiac toxicity after allo-HCT. The toxicities included arrhythmias (n = 21), heart failure (n = 14), pericardial effusion (n = 10), and myocardial infarction or ischemia (n = 7). Patients who received PTCy had a 7.4% incidence of cardiac toxicity, whereas non-PTCy recipients had an incidence of 5.8% (P = .4). We found that age >55 years (P = .02) and a history of hypertension (P = .01), arrhythmia (P = .003), diabetes (P = .04), and cardiac comorbidities (P < .001) were significant predictors of cardiac toxicity, whereas none of the preparative and GVHD prophylaxis regimens were predictive. From these findings, we proposed the use of a Cardiac Risk Stratification Score to quantify the risk of cardiac toxicity after allo-HCT. We found that a higher score correlated with an incidence of cardiac toxicity. Furthermore, the development of cardiac toxicity was associated with worse 1-year overall survival (OS) and NRM. The use of PTCy was associated with improvements in 1-year OS and NRM rates.

OBJECTIVE To estimate the actual excess costs of care for delivery admissions complicated by severe maternal morbidity (SMM) compared with uncomplicated deliveries. STUDY DESIGN This is a retrospective cohort study of all deliveries between October 2015 and September 2018 at a single tertiary academic center. Pregnant individuals ≥ 20 weeks' gestation who delivered during a hospital admission (i.e., a "delivery admission") were included. The primary exposure was SMM, as defined by Centers for Disease Control and Prevention (CDC) criteria, CDC criteria excluding blood transfusion, or by validated hospital-defined criteria (intensive care unit admission or ≥ 4 units of blood products). Potential SMM events identified via administrative and blood bank data were reviewed to confirm SMM events had occurred. Primary outcome was total actual costs of delivery admission derived from time-based accounting and acquisition costs in the institutional Value Driven Outcomes database. Cost of delivery admissions with SMM events was compared with the cost of uncomplicated delivery using adjusted generalized linear models, with separate models for each of the SMM definitions. Relative cost differences are reported due to data restrictions. RESULTS Of 12,367 eligible individuals, 12,361 had complete cost data. Two hundred and eighty individuals (2.3%) had confirmed SMM events meeting CDC criteria. CDC criteria excluding transfusion alone occurred in 1.0% (n = 121) and hospital-defined SMM in 0.6% (n = 76). In adjusted models, SMM events by CDC criteria were associated with a relative cost increase of 2.45 times (95% confidence interval [CI]: 2.29-2.61) the cost of an uncomplicated delivery. SMM by CDC criteria excluding transfusion alone was associated with a relative increase of 3.26 (95% CI: 2.95-3.60) and hospital-defined SMM with a 4.19-fold (95% CI: 3.64-4.83) increase. Each additional CDC subcategory of SMM diagnoses conferred a relative cost increase of 1.60 (95% CI: 1.43-1.79). CONCLUSION SMM is associated with between 2.5- and 4-fold higher cost than uncomplicated deliveries. KEY POINTS · Severe maternal morbidity as defined by CDC criteria confers a 2.5-fold increase in delivery hospitalization costs.. · Intensive care unit admission or ≥ 4 units of blood products confer a fourfold increase in cost.. · Costs of maternal morbidity may motivate SMM review..

The literature on deindustrialisation often neglects the role of finance in the decline in manufacturing, despite the increasing shift towards financial speculation relative to real investments. This paper tries to bridge this gap in the literature by examining the role of finance in Nigeria's premature deindustrialisation, particularly banks’ drive for short-term profits and their choice to lend to the oil and gas sector over manufacturing. We show that deindustrialisation in Nigeria can be traced back to the effect of the neoliberal policies of the 1980s and the take-off of financial liberalisation, corresponding to the decline in manufacturing value added. In the same period, employment share in manufacturing declined, however, at a distinctly lower rate than manufacturing value added. Therefore, higher productivity of labour is considered a less prominent factor for premature deindustrialisation in Nigeria, not least due to the low level of technological upgrading. We argue that the disproportionate flow of bank credit to the oil and gas and services sectors relative to manufacturing is further incentivised by the government's failed subsidy to the oil industry, which guarantees rent extraction for private interests. Using the Autoregressive Distributed lag (ARDL) estimation for the period 1981-2018, we find evidence that suggests a significant negative impact of domestic credit by banks on manufacturing value added in Nigeria. The disproportionate flow of domestic bank credit to the oil and gas and services sectors in Nigeria also indicates a significant negative impact on the country's manufacturing. On the other hand, net domestic credit by financial institutions, which includes financial flows by domestic development banks, has a significant positive impact on manufacturing.

Key Points First report of an FLT3-targeted therapy added to nonintensive chemotherapy that has improved survival in older FLT3-ITD patients with AML.Quizartinib is well tolerated, improves response and survival in older FLT3-ITD AML patients and merits consideration in future therapies. Now amended as text above., Visual Abstract, Survival for older patients with acute myeloid leukemia (AML) unsuitable for intensive chemotherapy is unsatisfactory. Standard nonintensive therapies have low response rates and only extend life by a few months. Quizartinib is an oral Fms-like tyrosine kinase 3 (FLT3) inhibitor with reported activity in wild-type patients. As part of the AML LI trial, we undertook a randomized evaluation of low-dose ara-C (LDAC) with or without quizartinib in patients not fit for intensive chemotherapy. Overall, survival was not improved (202 patients), but in the 27 FLT3-ITD patients, the addition of quizartinib to LDAC improved response (P = .05) with complete remission/complete remission with incomplete haematological recovery for quizartinib + LDAC in 5/13 (38%) vs 0/14 (0%) in patients receiving LDAC alone. Overall survival (OS) in these FLT3-ITD+ patients was also significantly improved at 2 years for quizartinib + LDAC (hazard ratio 0.36; 95% confidence intervals: 0.16, 0.85, P = .04). Median OS was 13.7 months compared with 4.2 months with LDAC alone. This is the first report of an FLT3-targeted therapy added to standard nonintensive chemotherapy that has improved survival in this population. Quizartinib merits consideration for future triplet-based treatment approaches. This trial was registered at www.clinicaltrials.gov as ISRCTN #ISRCTN40571019 and EUDRACT @2011-000749-19.

Objectives In Brazil, annual tuberculin skin tests (TST) are recommended for people living with HIV (PLWH) with CD4>350, with tuberculosis preventive therapy (TPT) provided upon test conversion. We aimed to determine the yield of repeat TST for PLWH. Design Secondary analysis of the stepped-wedge, cluster-randomized THRio trial for isoniazid preventive therapy (IPT) to prevent tuberculosis (TB). Methods We analyzed data from newly registered PLWH with negative baseline TST results. We calculated the number of TST conversions after 1 and/or 2 years among patients eligible for follow-up TSTs; the proportion of converters initiating IPT; and incidence of TB/death. Results Among 1,770 PLWH with a negative baseline TST, 679 (38%) were female and median age was 36 years (IQR 29-43). Eighty-six (5%) developed TB or died within 1 year. Among 1,684 eligible for a follow-up 1-year TST, 582 (35%) were tested and 53 (9%) were positive. Forty-nine (92%) converters started IPT. Of 529 patients with a negative 1-year TST, 7 (1%) developed TB or died over the following year. Of 522 patients eligible for a 2-year TST, 158 (30%) were tested and 13 (8%) were positive. Ten (77%) converters started IPT. Of 1,102 patients who did not receive a 1-year TST, 33 (3%) developed TB or died. Of the 1,069 patients eligible for a 2-year TST, 259 (24%) were tested and 34 (13%) were positive. Thirty (88%) converters started IPT. Conclusions In this cohort of PLWH in Brazil, TST conversion was high among those re-tested, but only 48% received a follow-up TST within 2 years.

Introduction While clonal hematopoiesis (CH) can precede the development of AML, preleukemic CH can persist after attaining remission. In rare cases, non-leukemic CH can also emerge after remission. Long-term clonal dynamics of persistent CH or emerging CH (together, post-remission CH) in AML patients during consolidation therapies or maintenance therapies is not well understood. Furthermore, the clinical implications of post-remission CH have not been systematically studied. Since AML patients receive various types of post-remission consolidation therapies, including allogeneic stem cell transplant (allo-SCT), analysis of clonal dynamics of post-remission CH offers unique opportunity to study the response of CH to therapies. Such knowledge may be translated into the development of therapeutic strategy targeting CH. Here, we analyzed multiple longitudinal samples from AML patients after remission and analyzed clonal behavior of post-remission CH during consolidation and maintenance therapies. Methods We studied 164 AML patients who attained complete remission (CR) after induction therapies and analyzed baseline and CR marrow by targeted deep sequencing of 295 genes (median 403x depth). Among the patients who were identified to have post-remission CH, we analyzed multiple longitudinal marrows and tracked clonal dynacmis of post-remission CH. We defined “persistent CH” when patients had mutations that were originally detected in AML and persisted after CR with variant allele frequency (VAF) > 2.5%. On the other hand, we defined “ emerging CH” when the patients had new mutations arising after attaining CR. Results Among the 164 AML patients, 79 (48%) patients were found to have post-remission CH at first CR. Of those, we were able to analyze multiple post-remission marrows in 54 patients (median 6 samples/patient, IQR 4-7.75),of which 44 (66%) had persistent CH and 1 (1.9%) had emerging CH, and 9 (17%) had both. The median age of these 54 patients cohort was 59 (IQR: 51-68). 34 (63%) patients attained CR after intensive chemotherapies (IC, idarubicin with high-dose cytarabine based), whereas 20 (37%) patients received low-intensity chemotherapies as induction (hypomethylating agent [HMA]-based N=3, low dose cytarabine-based N=17). All 34 patients treated with IC induction subsequently received consolidation chemotherapies with high-dose cytarabine (HDAC) regimens for median 2 cycles (IQR 2-3.25). Among the 20 patients treated with low-intensity chemotherapies, all patients received consolidation therapies with HMA-based regimen. A subset of patients received maintenance therapies under clinical trials: lenalidomide (N = 1), venetoclax (N = 2), and nivolumab (N = 1). 29 patients underwent allo-SCT (23 with myeloablative conditioning [MAC], and 6 with reduced-intensity conditioning [RIC]). The most frequently mutated genes for persistent CH were DNMT3A (N = 23), followed by TET2 (N = 17), IDH2 (N = 10), and SRSF2 (N = 10). For emerging CH, we observed emergence of JAK2 (N = 2), RUNX1 (N = 2), TET2 (N = 2), BRAF (N = 1), BCOR (N = 1), TP53 (N = 1), KDM6A (N = 1), and NRAS (N = 1). Longitudinal clonal analysis revealed that post-remission CH persisted in 52 of 54 (96%) patients during consolidation and maintenance therapies. Neither cytarabine based chemotherapies, HMA, venetoclax, lenalidomide, and nivolumab, reduced the VAF of post-remission CH, except in 2 (4%) patients, in which post-remission CH (IDH2 and TET2 mutations) were cleared with high dose cytarabine regimen. Although consolidation or maintenance therapies did not reduce post-remission CH, 17 out of 19 (89.4%) patients who underwent for allo-SCT had clearance of post-remission CH with both MAC and RIC. Overall, post-remission CH did not impact the risk of relapse or overall survival. Furthermore, post-remission CH did not affect long-term blood counts (neutrophil counts, hemoglobin, and platelet counts). Conclusion Post-remission CH persisted long-term in AML patients during consolidation and maintenance therapies without having significant impact on blood counts, relapse, and survival. Therapies with cytarabine-based chemotherapies and HMA did not affect the clonal size of post-remission CH, suggesting that these therapies may not be useful to treat CH in pre-leukemic context either. The novel therapeutic approach is warranted to target CH. Disclosures DiNardo: celgene: Consultancy, Honoraria; abbvie: Consultancy, Honoraria; syros: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; daiichi sankyo: Honoraria; agios: Consultancy, Honoraria; medimmune: Honoraria; jazz: Honoraria. Kadia: Bioline RX: Research Funding; Celgene: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; AbbVie: Consultancy, Research Funding. Ravandi: Selvita: Research Funding; Macrogenix: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xencor: Consultancy, Research Funding; Menarini Ricerche: Research Funding; Cyclacel LTD: Research Funding. Konopleva: Astra Zeneca: Research Funding; Agios: Research Funding; Ablynx: Research Funding; Kisoji: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Genentech: Honoraria, Research Funding; Ascentage: Research Funding; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Cellectis: Research Funding; Amgen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Eli Lilly: Research Funding; Forty-Seven: Consultancy, Honoraria; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Calithera: Research Funding. Kantarjian: Takeda: Honoraria; AbbVie: Honoraria, Research Funding; BMS: Research Funding; Jazz Pharma: Research Funding; Pfizer: Honoraria, Research Funding; Ariad: Research Funding; Amgen: Honoraria, Research Funding; Cyclacel: Research Funding; Daiichi-Sankyo: Research Funding; Immunogen: Research Funding; Astex: Research Funding; Agios: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding. Champlin: Johnson and Johnson: Consultancy; Sanofi-Genzyme: Research Funding; Actinium: Consultancy. Garcia-Manero: Onconova: Research Funding; H3 Biomedicine: Research Funding; Astex: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Amphivena: Consultancy, Research Funding; Merck: Research Funding. Takahashi: Symbio Pharmaceuticals: Consultancy.

Rationale: Diagnosis of chronic obstructive pulmonary disease (COPD) relies on abnormal spirometry. However, spirometry may underestimate the effects of smoking, missing smokers with respiratory di...

Introduction ECMO is a support modality for refractory critical illness. This study reviews the incidence and utility of central venous line (CVL) placement at pediatric ECMO decannulation. Methods A single-institution retrospective study of patients undergoing open neck decannulation from 2015 to 2019. Patients were divided into two groups: ≤ 28-days and > 28-days. Results Of 65 patients, 31% had a CVL placed at decannulation. Sepsis and pneumonia were the most common indications for ECMO in the older-group compared to CDH in neonates. The most common indications for CVL were hemodialysis (45%), monitoring (25%), and access (25%). 89% of neonates had an access line placed, whereas 73% of the older group received hemodialysis catheters. Median CRRT requirement was 20 days. 85% of lines were functional at time of removal or death. None were removed for infection. 40% of the patients not receiving a CVL at decannulation required one within 30 days. Conclusion 69% of patients did not have a CVL placed at decannulation, however 40% required a CVL within 30 days. Most lines placed at decannulation remained functional and none were removed for infection. Decannulation removes the circuit as a route for vascular access, but it also presents an opportunity to safely place an essential CVL.

Background Not every lead contributes equally in the interpretation of an ECG. There are some abnormalities in which the lead importance is not clear either from cardiac electrophysiology or experience. Therefore, it is beneficial to develop an algorithm to quantify the lead importance in the reading of ECGs, namely to determine how much to weigh the evidence from each individual lead when interpreting ECG. Methods One representative beat per ECG lead was constructed for each ECG in a database. An algorithm was developed to find the top K (K = 1, 5, 10, 20, 50, 100) ECGs in the database that had the most similar morphology to the query ECG, independently for each lead. For each lead, the query ECG was interpreted based on the weighted average voting on the most similar ECGs by applying a variety of thresholds. For each category of abnormality, we found the threshold that maximized the median F1 score of sensitivity and positive predictive value among all ECG leads. Finally, the F1 score of each lead at this chosen threshold was defined as the importance value for that lead. Results Eighteen morphology-based categories of abnormality were investigated for two databases. For most, the lead importance confirmed what expert ECG readers already know. However, it also revealed new insights. For example, lead aVR appeared in the top 6 most important leads in 11 and 12 categories of abnormality in two databases respectively, and ranked first among 12 leads if summarizing all categories. Conclusions Lead importance information may be useful in selecting only the most important leads to screen for a specific abnormality, for example using wearable patches.

BACKGROUND: The 12-lead ECG plays an important role in triaging patients with symptomatic coronary artery disease, making automated ECG interpretation statements of “Acute MI” or “Acute Ischemia” crucial, especially during prehospital transport when access to physician interpretation of the ECG is limited. However, it remains unknown how automated interpretation statements correspond to adjudicated clinical outcomes during hospitalization. We sought to evaluate the diagnostic performance of prehospital automated interpretation statements to four well-defined clinical outcomes of interest: confirmed ST- segment elevation myocardial infarction (STEMI); presence of actionable coronary culprit lesions, myocardial necrosis, or any acute coronary syndrome (ACS). METHODS: An observational cohort study that enrolled consecutive patients with non-traumatic chest pain transported via ambulance. Prehospital ECGs were obtained with the Philips MRX monitor from the medical command center and re-processed using manufacturer-specific diagnostic algorithms to denote the likelihood of >>>Acute MI<<< or >>>Acute Ischemia<<

Summary Background We previously described the contributions of increased total airway mucin concentrations to the pathogenesis and diagnosis of the chronic bronchitic component of chronic obstructive pulmonary disease (COPD). Here, we investigated the relative contribution of each of the major airway gel-forming mucins, MUC5AC and MUC5B, to the initiation, progression, and early diagnosis of airways disease in COPD. Methods SPIROMICS was a multicentre, observational study in patients aged 40–80 years recruited from six clinical sites and additional subsites in the USA. In this analysis, MUC5AC and MUC5B were quantitated by stable isotope-labelled mass spectrometry in induced sputum samples from healthy never-smokers, ever-smokers at risk for COPD, and ever-smokers with COPD. Participants were extensively characterised using results from questionnaires, such as the COPD assessment test (CAT) and St George's Respiratory Questionnaire; quantitative CT, such as residual volume/total lung capacity ratio (RV/TLC) and parametric response mapping-functional small airway disease (PRM-fSAD); and pulmonary function tests, such as FEV1, forced vital capacity (FVC), and forced expiratory flow, midexpiratory phase (FEF25–75%). Absolute concentrations of both MUC5AC and MUC5B were related to cross-sectional (baseline, initial visit) and 3-year follow-up longitudinal data, including lung function, small airways obstruction, prospective acute exacerbations, and smoking status as primary outcomes. This study is registered with ClinicalTrials.gov (NCT01969344). Findings This analysis included 331 participants (mean age 63 years [SEM 9·40]), of whom 40 were healthy never-smokers, 90 were at-risk ever-smokers, and 201 were ever-smokers with COPD. Increased MUC5AC concentrations were more reliably associated with manifestations of COPD than were MUC5B concentrations, including decreased FEV1 and FEF25–75%, and increased prospective exacerbation frequency, RV/TLC, PRM-fSAD, and COPD assessment scores. MUC5AC concentrations were more reactive to cigarette smoke exposure than were MUC5B concentrations. Longitudinal data from 3-year follow-up visits generated a multivariate-adjusted odds ratio for two or more exacerbations of 1·24 (95% CI 1·04–1·47, p=0·015) for individuals with high baseline MUC5AC concentration. Increased MUC5AC, but not MUC5B, concentration at baseline was a significant predictor of FEV1, FEV1/FVC, FEF25–75%, and CAT score decline during the 3-year follow-up. Moreover, current smokers in the at-risk group showed raised MUC5AC concentrations at initial visits and decreased lung function over 3 years. By contrast, former smokers in the at-risk group showed normal MUC5AC concentrations at the initial visit and preserved lung function over 3 years. Interpretation These data indicate that increased MUC5AC concentration in the airways might contribute to COPD initiation, progression, exacerbation risk, and overall pathogenesis. Compared with MUC5B, greater relative changes in MUC5AC concentrations were observed as a function of COPD severity, and MUC5AC concentration seems to be an objective biomarker to detect disease in at-risk and pre-COPD individuals. These data suggest that MUC5AC-producing pathways could be potential targets for future therapeutic strategies. Thus, MUC5AC could be a novel biomarker for COPD prognosis and for testing the efficacy of therapeutic agents. Funding National Institutes of Health; National Heart, Lung, and Blood Institute.

Background Based on interim analyses and modeling data, lower doses of bamlanivimab and etesevimab together (700/1400 mg) were investigated to determine optimal dose and expand availability of treatment. Methods This Phase 3 portion of the BLAZE-1 trial characterized the effect of bamlanivimab with etesevimab on overall patient clinical status and virologic outcomes in ambulatory patients ≥12 years old, with mild-to-moderate coronavirus disease 2019 (COVID-19), and ≥1 risk factor for progressing to severe COVID-19 and/or hospitalization. Bamlanivimab and etesevimab together (700/1400 mg) or placebo were infused intravenously within 3 days of patients’ first positive COVID-19 test. Results In total, 769 patients were infused (median age [range]; 56.0 years [12, 93], 30.3% of patients ≥65 years of age and median duration of symptoms; 4 days). By day 29, 4/511 patients (0.8%) in the antibody treatment group had a COVID-19-related hospitalization or any-cause death, as compared with 15/258 patients (5.8%) in the placebo group (Δ[95% confidence interval {CI}] = −5.0 [−8.0, −2.1], P Conclusions These data support the use of bamlanivimab and etesevimab (700/1400 mg) for ambulatory patients at high risk for severe COVID-19. Evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants will require continued monitoring to determine the applicability of this treatment. Clinical Trials Registration NCT04427501.

The role that traditional and hybrid in-person schooling modes contribute to the community incidence of SARS-CoV-2 infections relative to fully remote schooling is unknown. We conducted an event study using a retrospective nationwide cohort evaluating the effect of school mode on SARS-CoV-2 cases during the 12 weeks after school opening (July-September 2020, before the Delta variant was predominant), stratified by US Census region. After controlling for case rate trends before school start, state-level mitigation measures and community activity level, SARS-CoV-2 incidence rates were not statistically different in counties with in-person learning versus remote school modes in most regions of the United States. In the South, there was a significant and sustained increase in cases per week among counties that opened in a hybrid or traditional mode versus remote, with weekly effects ranging from 9.8 (95% confidence interval (CI) = 2.7-16.1) to 21.3 (95% CI = 9.9-32.7) additional cases per 100,000 persons, driven by increasing cases among 0-9 year olds and adults. Schools can reopen for in-person learning without substantially increasing community case rates of SARS-CoV-2; however, the impacts are variable. Additional studies are needed to elucidate the underlying reasons for the observed regional differences more fully.

Donor-specific anti-HLA antibodies (DSAs) are a major cause of engraftment failure in patients receiving haploidentical stem cell transplantation (HaploSCT). Effective treatments are needed for these patients, who often have no other donor options and/or are in need to proceed urgently to transplantation. We studied a multimodality treatment with alternate-day plasma exchange (PE), rituximab, intravenous γ globulin (IVIg) and an irradiated donor buffy coat for patients with DSAs at 2 institutions. Thirty-seven patients with a median age of 51 years were treated with this desensitization protocol. Treatment outcomes were compared with a control group of HaploSCT patients without DSAs (n = 345). The majority of patients in the DSA group were female (83.8% vs 37.1% in controls, P < .001) and received stem cells from a child as the donor (67.6% vs 44.1%, P = .002). Mean DSA level before and after desensitization was 10 198 and 5937 mean fluorescence intensity (MFI), respectively, with mean differences of 4030 MFI. Fourteen of 30 tested patients (46.7%) had C1q positivity, while 8 of 29 tested patients (27.6%) remained positive after desensitization. In multivariable analysis, patients with initial DSA > 20 000 MFI and persistent positive C1q after desensitization had a significantly lower engraftment rate, which resulted in significantly higher non-relapse mortality and worse overall survival (OS) than controls, whereas graft outcome and survival of patients with initial DSA < 20 000 MFI and those with negative C1q after treatment were comparable with controls. In conclusion, treatment with PE, rituximab, IVIg, and donor buffy coat is effective in promoting engraftment in patients with DSAs ≤20 000 MFI.

Reduced intensity conditioning (RIC) transplantation is increasingly offered to older patients with acute myeloblastic leukemia. We have previously shown that a RIC allograft, particularly from a sibling donor, is beneficial in intermediate-risk patients aged 35-65 years. We here present analyses from the NCRI AML16 trial extending this experience to older patients aged 60-70 inclusive lacking favorable-risk cytogenetics. Nine hundred thirty-two patients were studied, with RIC transplant in first remission given to 144 (sibling n=52, matched unrelated donor n=92) with a median follow-up for survival from complete remission of 60 months. Comparisons of outcomes of patients transplanted versus those not were carried out using Mantel-Byar analysis. Among the 144 allografted patients, 93 had intermediate-risk cytogenetics, 18 had adverse risk and cytogenetic risk group was unknown for 33. In transplanted patients survival was 37% at 5 years, and while the survival for recipients of grafts from siblings (44%) was better than that for recipients of grafts from matched unrelated donors (34%), this difference was not statistically significant (P=0.2). When comparing RIC versus chemotherapy, survival of patients treated with the former was significantly improved (37% versus 20%, hazard ratio = 0.67 [0.53-0.84]; P

Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) is an aggressive hematological malignancy; however, some patients achieve durable remission with allogeneic hematopoietic cell transplantation (allo-HCT). We report on all 17 patients with BPDCN who underwent allo-HCT at our center between 2000 and 2020. The median age was 39 (18-67) years. All (n = 16, 94%), except one patient, had systemic disease involving bone marrow and/or other organs. Ten patients (59%) were in first complete remission (CR1) at allo-HCT. The donor source was matched related or unrelated in ten (59%) and alternate donor in seven (41%) patients. Five (31%) patients developed acute graft-versus-host disease (GVHD), all grade I-II. The cumulative incidence (CI) of chronic GVHD at five-year was 34%. The CI of non-relapse mortality at one-year was 29%. Progression-free survival (PFS) rates at two-year and five-year were 49% (95% CI = 22-71%) and 39% (95% CI = 14-64%), respectively. The two-year and five-year overall survival (OS) rates were 65% (95% CI = 38-82%) and 40% (95% CI = 12-68%), respectively. The five-year rate for both PFS and OS was 80% in CR1 patients versus 0% in patients not in CR1. In conclusion, allo-HCT provides long-lasting remissions in BPDCN patients, particularly when performed in CR1.

Background Patients with underlying medical conditions are at increased risk for severe coronavirus disease 2019 (Covid-19). Whereas vaccine-derived immunity develops over time, neutralizing monoclonal-antibody treatment provides immediate, passive immunity and may limit disease progression and complications. Methods In this phase 3 trial, we randomly assigned, in a 1:1 ratio, a cohort of ambulatory patients with mild or moderate Covid-19 who were at high risk for progression to severe disease to receive a single intravenous infusion of either a neutralizing monoclonal-antibody combination agent (2800 mg of bamlanivimab and 2800 mg of etesevimab, administered together) or placebo within 3 days after a laboratory diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The primary outcome was the overall clinical status of the patients, defined as Covid-19–related hospitalization or death from any cause by day 29. Results A total of 1035 patients underwent randomization and received an infusion of bamlanivimab–etesevimab or placebo. The mean (±SD) age of the patients was 53.8±16.8 years, and 52.0% were adolescent girls or women. By day 29, a total of 11 of 518 patients (2.1%) in the bamlanivimab–etesevimab group had a Covid-19–related hospitalization or death from any cause, as compared with 36 of 517 patients (7.0%) in the placebo group (absolute risk difference, −4.8 percentage points; 95% confidence interval [CI], −7.4 to −2.3; relative risk difference, 70%; P

Objective To evaluate patient safety, resource utilization, and transfusion-related cost after a policy change from universal type and screen to selective type and screen on admission to labor and delivery. Methods Between October 2017 and September 2019, we performed a single-center implementation study focusing on risk-based type and screen instead of universal type and screen. Implementation of our policy was October 2018 and compared 1 year preimplementation with 1 year postimplementation. Patients were risk-stratified in alignment with California Maternal Quality Care Collaborative recommendations. Under the new policy, the blood bank holds a blood sample for processing (hold clot) on patients at low- and medium-risk of hemorrhage. Type and screen and crossmatch are obtained on high-risk patients or with a prior positive antibody screen. We collected patient outcomes, safety and cost data, and compliance and resource utilization metrics. Cost included direct costs of transfusion-related testing in the labor and delivery unit during the study period, from a health system perspective. Results In 1 year postimplementation, there were no differences in emergency-release transfusion events (4 vs 3, P>.99). There were fewer emergency-release red blood cell (RBC) units transfused (9 vs 24, P=.002) and O-negative RBC units transfused (8 vs 18, P=.016) postimplementation compared with preimplementation. Hysterectomies (0.05% vs 0.1%, P=.44) and intensive care unit admissions (0.45% vs 0.51%, P=.43) were not different postimplementation compared with preimplementation. Postimplementation, mean monthly type and screen-related costs (ABO typing, antibody screen, and antibody workup costs) were lower, $9,753 compared with $20,676 in the preimplementation year, P Conclusion Implementation of selective type and screen policy in the labor and delivery unit was associated with projected annual savings of $181,000 in an institution with 4,000 deliveries per year, without evidence of increased maternal morbidity.

Background The clinical diagnosis of multiple system atrophy (MSA) is challenged by overlapping features with Parkinson's disease (PD) and late-onset ataxias. Additional biomarkers are needed to confirm MSA and to advance the understanding of pathophysiology. Positron emission tomography (PET) imaging of the translocator protein (TSPO), expressed by glia cells, has shown elevations in MSA. Objective In this multicenter PET study, we assess the performance of TSPO imaging as a diagnostic marker for MSA. Methods We analyzed [11 C]PBR28 binding to TSPO using imaging data of 66 patients with MSA and 24 patients with PD. Group comparisons were based on regional analysis of parametric images. The diagnostic readout included visual reading of PET images against clinical diagnosis and machine learning analyses. Sensitivity, specificity, and receiver operating curves were used to discriminate MSA from PD and cerebellar from parkinsonian variant MSA. Results We observed a conspicuous pattern of elevated regional [11 C]PBR28 binding to TSPO in MSA as compared with PD, with "hotspots" in the lentiform nucleus and cerebellar white matter. Visual reading discriminated MSA from PD with 100% specificity and 83% sensitivity. The machine learning approach improved sensitivity to 96%. We identified MSA subtype-specific TSPO binding patterns. Conclusions We found a pattern of significantly increased regional glial TSPO binding in patients with MSA. Intriguingly, our data are in line with severe neuroinflammation in MSA. Glia imaging may have potential to support clinical MSA diagnosis and patient stratification in clinical trials on novel drug therapies for an α-synucleinopathy that remains strikingly incurable. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Background Emergency Departments (EDs) have served as critical surveillance sites for infectious diseases. We sought to determine the prevalence and temporal trends of acute (by PCR) and convalescent (by antibody [Ab]) SARS-CoV-2 infection during the earliest phase of the pandemic among patients in an urban ED in Baltimore City. Methods We tested remnant blood samples from 3255 unique ED patients, collected between March 16th and May 31st 2020 for SARS-CoV-2 Ab. PCR for acute SARS-CoV-2 infection from nasopharyngeal swabs was obtained on any patients based on clinical suspicion. Hospital records were abstracted and factors associated with SARS-CoV-2 infection were assessed. Results Of 3255 ED patients, 8.2% (95%CI: 7.3%, 9.2%) individuals had evidence of SARS-CoV-2 infection; 155 PCR+, 78 Ab+, and 35 who were both PCR+ and Ab+. Prevalence of disease increased throughout the study period, ranging from 3.2% (95%CI: 1.8%, 5.2%) PCR+ and 0.6% (95%CI: 0.1%, 1.8%) Ab+ in March, to 6.2% (95%CI: 5.1%, 7.4%) PCR+ and 4.2% (95%CI: 3.3%, 5.3%) Ab+ in May. The highest SARS-CoV-2 prevalence was found in Hispanic individuals who made up 8.4% (95%CI: 7.4%, 9.4%) of individuals screened, but 35% (95%CI: 29%, 41%) of infections (PCR and/or Ab+). Demographic and clinical factors independently associated with acute infection included Hispanic ethnicity, loss of smell or taste, subjective fever, cough, muscle ache and fever. Factors independently associated with convalescent infection were Hispanic ethnicity and low oxygen saturation. Conclusions The burden of COVID-19 in Baltimore City increased dramatically over the 11-week study period and was disproportionately higher among Hispanic individuals. ED-based surveillance methods are important for identifying both acute and convalescent SARS-CoV-2 infections and provides important information regarding demographic and clinical correlates of disease in the local community.

Approximately 60,000 cemented femoral stems are implanted in the UK each year with the majority being manufactured from stainless steel containing 10–15% nickel. Nickel hypersensitivity has been reported in up to 13% of the general population and there is a concern that nickel hypersensitivity might adversely affect the outcome of total hip replacement (THR). We reviewed the current literature on the potential link between nickel hypersensitivity and THR complications, and the usefulness of patch testing. We conducted a literature search in PubMed, MEDLINE and EMBASE databases. The level of evidence and the quality of the selected studies were assessed using the Oxford Centre for Evidence-Based Medicine Criteria and the Methodological Index for Non-Randomised Studies tool, respectively. Twenty-six studies met the inclusion criteria, reporting on 1852 patients who underwent primary or revision THR. All studies detailed skin patch testing and recorded prevalence of nickel hypersensitivity from 1.5% to 33.3%. Five studies reported a rise in Nickel hypersensitivity following THR, while four reported a decreased prevalence post-operatively. Eight studies concluded that metal hypersensitivity could have developed following THR, while seven studies did not support a link between metal hypersensitivity and THR complications. Four of the studies recommended routine patch testing pre-operatively, but three others concluded that routine patch testing was not indicated. We have not identified a link between nickel hypersensitivity and THR complications, and the role of patch testing remains unclear. Further large-scale studies would be required to investigate this relationship and to clarify the role of patch testing in facilitating implant selection.Cite this article: EFORT Open Rev 2021;6:825-838. DOI: 10.1302/2058-5241.6.210051

Objectives:The Core Elements of Outpatient Antibiotic Stewardship provides a framework to improve antibiotic use, but cost-effectiveness data on implementation of outpatient antibiotic stewardship interventions are limited. We evaluated the cost-effectiveness of Core Element implementation in the outpatient setting.Methods:An economic simulation model from the health-system perspective was developed for patients presenting to outpatient settings with uncomplicated acute respiratory tract infections (ARI). Effectiveness was measured as quality-adjusted life years (QALYs). Cost and utility parameters for antibiotic treatment, adverse drug events (ADEs), and healthcare utilization were obtained from the literature. Probabilities for antibiotic treatment and appropriateness, ADEs, hospitalization, and return ARI visits were estimated from 16,712 and 51,275 patient visits in intervention and control sites during the pre- and post-implementation periods, respectively. Data for materials and labor to perform the stewardship activities were used to estimate intervention cost. We performed a one-way and probabilistic sensitivity analysis (PSA) using 1,000,000 second-order Monte Carlo simulations on input parameters.Results:The proportion of ARI patient-visits with antibiotics prescribed in intervention sites was lower (62% vs 74%) and appropriate treatment higher (51% vs 41%) after implementation, compared to control sites. The estimated intervention cost over a 2-year period was $133,604 (2018 US dollars). The intervention had lower mean costs ($528 vs $565) and similar mean QALYs (0.869 vs 0.868) per patient compared to usual care. In the PSA, the intervention was dominant in 63% of iterations.Conclusions:Implementation of the CDC Core Elements in the outpatient setting was a cost-effective strategy.

Objective There is increasing demand for prediction of chronic pain treatment outcomes using machine‐learning models, in order to improve suboptimal pain management. In this exploratory study, we used baseline brain functional connectivity patterns from chronic pain patients with fibromyalgia (FM) to predict whether a patient would respond differentially to either milnacipran or pregabalin, 2 drugs approved by the US Food and Drug Administration for the treatment of FM. Methods FM patients participated in 2 separate double‐blind, placebo‐controlled crossover studies, one evaluating milnacipran (n = 15) and one evaluating pregabalin (n = 13). Functional magnetic resonance imaging during rest was performed before treatment to measure intrinsic functional brain connectivity in several brain regions involved in pain processing. A support vector machine algorithm was used to classify FM patients as responders, defined as those with a ≥20% improvement in clinical pain, to either milnacipran or pregabalin. Results Connectivity patterns involving the posterior cingulate cortex (PCC) and dorsolateral prefrontal cortex (DLPFC) individually classified pregabalin responders versus milnacipran responders with 77% accuracy. Performance of this classification improved when both PCC and DLPFC connectivity patterns were combined, resulting in a 92% classification accuracy. These results were not related to confounding factors, including head motion, scanner sequence, or hardware status. Connectivity patterns failed to differentiate drug nonresponders across the 2 studies. Conclusion Our findings indicate that brain functional connectivity patterns used in a machine‐learning framework differentially predict clinical response to pregabalin and milnacipran in patients with chronic pain. These findings highlight the promise of machine learning in pain prognosis and treatment prediction.