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Two mycobacteriophages were administered intravenously to a male with treatment-refractory Mycobacterium abscessus pulmonary infection and severe cystic fibrosis lung disease. The phages were engineered to enhance their capacity to lyse M. abscessus and were selected specifically as the most effective against the subject's bacterial isolate. In the setting of compassionate use, the evidence of phage-induced lysis was observed using molecular and metabolic assays combined with clinical assessments. M. abscessus isolates pre and post-phage treatment demonstrated genetic stability, with a general decline in diversity and no increased resistance to phage or antibiotics. The anti-phage neutralizing antibody titers to one phage increased with time but did not prevent clinical improvement throughout the course of treatment. The subject received lung transplantation on day 379, and systematic culturing of the explanted lung did not detect M. abscessus. This study describes the course and associated markers of a successful phage treatment of M. abscessus in advanced lung disease.
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Bacteriófagos , Fibrosis Quística , Infecciones por Mycobacterium no Tuberculosas , Mycobacterium abscessus , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Bacteriófagos/genética , Fibrosis Quística/tratamiento farmacológico , Humanos , Pulmón , Masculino , Infecciones por Mycobacterium no Tuberculosas/terapia , Mycobacterium abscessus/fisiologíaRESUMEN
BACKGROUND: In the BEST-CLI trial (Best Endovascular Versus Best Surgical Therapy for Patients With Chronic Limb-Threatening Ischemia), a prespecified secondary objective was to assess the effects of revascularization strategy on health-related quality of life (HRQoL). METHODS: Patients with chronic limb-threatening ischemia were randomized to surgical bypass (Bypass) or endovascular intervention (Endo) in 2 parallel trials. Cohort 1 included patients with single-segment great saphenous vein; cohort 2 included those lacking suitable single-segment great saphenous vein. HRQoL was assessed over the trial duration using Vascular Quality-of-Life (VascuQoL), European Quality-of-Life-5D (EQ-5D), the Short Form-12 (SF-12) Physical Component Summary (SF-12 PCS), SF-12 Mental Component Summary (SF-12 MCS), Utility Index Score (SF-6D R2), and numeric rating scales of pain. HRQoL was summarized by cohort and compared within and between groups using mixed-model linear regression. RESULTS: A total of 1193 and 335 patients in cohorts 1 and 2 with a mean follow-up of 2.9 and 2.0 years, respectively, were analyzed. In cohort 1, HRQoL significantly improved from baseline to follow-up for both groups across all measures. For example, mean (SD) VascuQoL scores were 3.0 (1.3) and 3.0 (1.2) for Bypass and Endo at baseline and 4.7 (1.4) and 4.8 (1.5) over follow-up. There were significant group differences favoring Endo when assessed with VascuQoL (difference, -0.14 [95% CI, -0.25 to -0.02]; P=0.02), SF-12 MCS (difference, -1.03 [95% CI, -1.89 to -0.18]; P=0.02), SF-6D R2 (difference, -0.01 [95% CI, -0.02 to -0.001]; P=0.03), numeric rating scale pain at present (difference, 0.26 [95% CI, 0.03 to 0.49]; P=0.03), usual level during previous week (difference, 0.26 [95% CI, 0.04 to 0.48]; P=0.02), and worst level during previous week (difference, 0.29 [95% CI, 0.02 to 0.56]; P=0.04). There was no difference between treatment arms on the basis of EQ-5D (difference, -0.01 [95% CI, -0.03 to 0.004]; P=0.12) or SF-12 PCS (difference, -0.41 [95% CI, -1.2 to 0.37]; P=0.31). In cohort 2, HRQoL also significantly improved from baseline to the end of follow-up for both groups based on all measures, but there were no differences between Bypass and Endo on any measure. CONCLUSIONS: Among patients with chronic limb-threatening ischemia deemed eligible for either Bypass or Endo, revascularization resulted in significant and clinically meaningful improvements in HRQoL. In patients with an available single-segment great saphenous vein for bypass, but not among those without one, Endo was statistically superior on some HRQoL measures; however, these differences were below the threshold of clinically meaningful difference.
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Isquemia Crónica que Amenaza las Extremidades , Calidad de Vida , Humanos , Procedimientos Quirúrgicos Vasculares , Dolor , Resultado del TratamientoRESUMEN
BACKGROUND: Patients with chronic limb-threatening ischemia (CLTI) require revascularization to improve limb perfusion and thereby limit the risk of amputation. It is uncertain whether an initial strategy of endovascular therapy or surgical revascularization for CLTI is superior for improving limb outcomes. METHODS: In this international, randomized trial, we enrolled 1830 patients with CLTI and infrainguinal peripheral artery disease in two parallel-cohort trials. Patients who had a single segment of great saphenous vein that could be used for surgery were assigned to cohort 1. Patients who needed an alternative bypass conduit were assigned to cohort 2. The primary outcome was a composite of a major adverse limb event - which was defined as amputation above the ankle or a major limb reintervention (a new bypass graft or graft revision, thrombectomy, or thrombolysis) - or death from any cause. RESULTS: In cohort 1, after a median follow-up of 2.7 years, a primary-outcome event occurred in 302 of 709 patients (42.6%) in the surgical group and in 408 of 711 patients (57.4%) in the endovascular group (hazard ratio, 0.68; 95% confidence interval [CI], 0.59 to 0.79; P<0.001). In cohort 2, a primary-outcome event occurred in 83 of 194 patients (42.8%) in the surgical group and in 95 of 199 patients (47.7%) in the endovascular group (hazard ratio, 0.79; 95% CI, 0.58 to 1.06; P = 0.12) after a median follow-up of 1.6 years. The incidence of adverse events was similar in the two groups in the two cohorts. CONCLUSIONS: Among patients with CLTI who had an adequate great saphenous vein for surgical revascularization (cohort 1), the incidence of a major adverse limb event or death was significantly lower in the surgical group than in the endovascular group. Among the patients who lacked an adequate saphenous vein conduit (cohort 2), the outcomes in the two groups were similar. (Funded by the National Heart, Lung, and Blood Institute; BEST-CLI ClinicalTrials.gov number, NCT02060630.).
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Isquemia Crónica que Amenaza las Extremidades , Recuperación del Miembro , Procedimientos Quirúrgicos Vasculares , Humanos , Isquemia Crónica que Amenaza las Extremidades/cirugía , Isquemia Crónica que Amenaza las Extremidades/terapia , Procedimientos Endovasculares/efectos adversos , Procedimientos Endovasculares/métodos , Recuperación del Miembro/efectos adversos , Recuperación del Miembro/métodos , Estudios Retrospectivos , Factores de Riesgo , Resultado del Tratamiento , Procedimientos Quirúrgicos Vasculares/efectos adversos , Procedimientos Quirúrgicos Vasculares/métodos , Vena Safena/trasplanteRESUMEN
Aggregation of the RNA-binding protein TAR DNA binding protein (TDP-43) is a hallmark of TDP-proteinopathies including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). As TDP-43 aggregation and dysregulation are causative of neuronal death, there is a special interest in targeting this protein as a therapeutic approach. Previously, we found that TDP-43 extensively co-aggregated with the dual function protein GEF (guanine exchange factor) and RNA-binding protein rho guanine nucleotide exchange factor (RGNEF) in ALS patients. Here, we show that an N-terminal fragment of RGNEF (NF242) interacts directly with the RNA recognition motifs of TDP-43 competing with RNA and that the IPT/TIG domain of NF242 is essential for this interaction. Genetic expression of NF242 in a fruit fly ALS model overexpressing TDP-43 suppressed the neuropathological phenotype increasing lifespan, abolishing motor defects and preventing neurodegeneration. Intracerebroventricular injections of AAV9/NF242 in a severe TDP-43 murine model (rNLS8) improved lifespan and motor phenotype, and decreased neuroinflammation markers. Our results demonstrate an innovative way to target TDP-43 proteinopathies using a protein fragment with a strong affinity for TDP-43 aggregates and a mechanism that includes competition with RNA sequestration, suggesting a promising therapeutic strategy for TDP-43 proteinopathies such as ALS and FTD.
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Esclerosis Amiotrófica Lateral , Proteínas de Unión al ADN , Modelos Animales de Enfermedad , Factores de Intercambio de Guanina Nucleótido , Fenotipo , Animales , Esclerosis Amiotrófica Lateral/metabolismo , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/patología , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Ratones , Humanos , Factores de Intercambio de Guanina Nucleótido/metabolismo , Factores de Intercambio de Guanina Nucleótido/genética , Drosophila , Ratones Transgénicos , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , MasculinoRESUMEN
OBJECTIVE: Cardiovascular complications after revascularization to treat chronic limb-threatening ischemia (CLTI) are a major concern that guides treatment. Our goal was to assess periprocedural cardiac and vascular serious adverse events (SAEs) in the Best Endovascular vs Best Surgical Therapy in Patients with CLTI (BEST-CLI) trial. METHODS: BEST-CLI was a prospective randomized trial comparing surgical (OPEN) and endovascular (ENDO) revascularization for patients with CLTI. Thirty-day SAEs, classified as cardiac or vascular, were analyzed. Adverse events are defined as serious when they affect safety in the trial, require prolonged hospitalization, result in significant disability or incapacitation, are life-threatening, or result in death. Interventions were analyzed in a per protocol fashion. RESULTS: In the BEST-CLI trial, 850 OPEN and 896 ENDO interventions were evaluated. Forty (4.7%) and 34 (3.8%) patients experienced at least one cardiac SAE after OPEN and ENDO intervention, respectively (P = .35). Overall, there were 53 cardiac SAEs (0.06 per patient) after OPEN and 40 (0.045 per patient) after ENDO interventions. Cardiac SAEs in the OPEN arm were classified as related to ischemia (50.9%), arrhythmias (17%), heart failure (15.1%), arrest (13.2%), and heart block (3.8%); in the ENDO arm, they were classified as ischemia (47.5%), heart failure (17.5%), arrhythmias (15%), arrest (15%), and heart block (5%). Approximately half of SAEs were classified as severe for both OPEN and ENDO. SAEs were definitely or probably related to the procedure in 30.2% and 25% in the OPEN and ENDO arms, respectively (P = .2). Vascular SAEs occurred in 58 (6.8%) and 86 (9.6%) of patients after OPEN and ENDO revascularization, respectively (P = .19). In total, there were 59 (0.07 per patient) and 87 (0.097 per patient) vascular SAEs after OPEN and ENDO procedures. Vascular SAEs in the OPEN arm were classified as distal ischemia/infection (44.1%), bleeding (16.9%), occlusive (15.3%), thromboembolic (15.3%), cerebrovascular (5.1%), and other (3.4%); in the ENDO arm, they were distal ischemia/infection (40.2%), occlusive (31%), bleeding (12.6%), thromboembolic (8%), cerebrovascular (1.1%), and other (4.6%). SAEs were classified as severe for OPEN in 45.8% and ENDO in 46%. SAEs were definitely or probably related to the procedure in 23.7% and 35.6% in the OPEN and ENDO arms (P = .35), respectively. CONCLUSIONS: Patients undergoing OPEN and ENDO revascularization experienced similar degrees of cardiac and vascular SAEs. The majority were not related to the index intervention, but approximately half were severe.
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Procedimientos Endovasculares , Humanos , Procedimientos Endovasculares/efectos adversos , Procedimientos Endovasculares/mortalidad , Estudios Prospectivos , Femenino , Masculino , Resultado del Tratamiento , Anciano , Factores de Tiempo , Factores de Riesgo , Enfermedad Arterial Periférica/cirugía , Enfermedad Arterial Periférica/diagnóstico por imagen , Persona de Mediana Edad , Isquemia/cirugía , Isquemia/etiología , Isquemia/diagnóstico , Isquemia Crónica que Amenaza las Extremidades/cirugía , Injerto Vascular/efectos adversos , Medición de RiesgoRESUMEN
OBJECTIVES: There has been significant variability in practice patterns and equipoise regarding treatment approach for chronic limb-threatening ischemia (CLTI). We aimed to assess treatment preferences of Best Endovascular vs Best Surgical Therapy in Patients with CLTI (BEST-CLI) investigators prior to and following the trial. METHODS: An electronic 60-question survey was sent to 1180 BEST-CLI investigators in 2022, after trial conclusion and before announcement of results. Investigators' preferences were assessed across clinical scenarios for both open (OPEN) and endovascular (ENDO) revascularization strategies. Vascular surgeon (VS) surgical and ENDO preferences were compared with a 2010 survey administered to prospective investigators before trial funding. RESULTS: For the 2022 survey, the response rate was 20.2% and was comprised of VSs (76.3%), interventional cardiologists (11.4%) and interventional radiologists (11.6%). The majority (72.6%) were in academic practice and 39.1% were in practice for >20 years. During initial CLTI work-up, 65.8%, 42.6%, and 55.9% of respondents always or usually ordered an arterial duplex, computed tomography angiography, and vein mapping, respectively. The most common practice distribution between ENDO and OPEN procedures was 70/30. Postoperatively, a majority reported performing routine duplex surveillance of vein bypass (99%), prosthetic bypass (81.9%), and ENDO interventions (86%). A minority reported always or usually using the wound, ischemia, and foot infection (WIfI) criteria (25.8%), GLASS (8.3%), and a risk calculator (14.8%). More than one-half (52.9%) agreed that the statement "no bridges are burned with an ENDO-first approach" was false. Intervention choice was influenced by availability of the operating room or ENDO suite, personal schedule, and personal skill set in 30.1%, 18.0%, and 45.9% of respondents, respectively. Most respondents reported routinely using paclitaxel-coated balloons (88.1%) and stents (67.5%); however, 73.3% altered practice when safety concerns were raised. Among surgeons, 17.8%, 2.9%, and 10.3% reported performing >10 annual alternative autogenous vein bypasses, composite vein composite vein bypasses, and bypasses to pedal targets, respectively. Among all interventionalists, 8%, 24%, and 8% reported performing >10 annual radial access procedures, pedal or tibial access procedures, and pedal loop revascularizations. The majority (89.1%) of respondents felt that CLTI teams improved care; however, only 23.2% had a defined team. The effectiveness of the teamwork at institutions was characterized as highly effective in 42.5%. When comparing responses by VSs to the 2010 survey, there were no changes in preferred treatment based on Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC) II classification or conduit preference. In 2022, OPEN surgery was preferred more for a popliteal occlusion. For clinical scenarios, there were no differences except a decreased proportion of respondents who felt there was equipoise for major tissue loss for major tissue loss (43.8% vs 31.2%) and increased ENDO choice for minor tissue loss (17.6% vs 30.8%) (P < .05). CONCLUSIONS: There is a wide range of practice patterns among vascular specialists treating CLTI. The majority of investigators in BEST-CLI had experience in both advanced OPEN and ENDO techniques and represent a real-world sample of technical expertise. Over the course of the decade of the BEST-CLI trial, there was overall similar equipoise among VSs.
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Procedimientos Endovasculares , Enfermedad Arterial Periférica , Humanos , Estudios Prospectivos , Resultado del Tratamiento , Procedimientos Endovasculares/métodos , Enfermedad Arterial Periférica/diagnóstico por imagen , Enfermedad Arterial Periférica/cirugía , Venas/cirugía , Isquemia , Isquemia Crónica que Amenaza las Extremidades , Recuperación del Miembro/métodos , Factores de Riesgo , Estudios RetrospectivosRESUMEN
OBJECTIVES: Patients undergoing revascularization for chronic limb-threatening ischemia experience a high burden of target limb reinterventions. We analyzed data from the Best Endovascular versus Best Surgical Therapy in Patients with Critical Limb Ischemia (BEST-CLI) randomized trial comparing initial open bypass (OPEN) and endovascular (ENDO) treatment strategies, with a focus on reintervention-related study endpoints. METHODS: In a planned secondary analysis, we examined the rates of major reintervention, any reintervention, and the composite of any reintervention, amputation, or death by intention-to-treat assignment in both trial cohorts (cohort 1 with suitable single-segment great saphenous vein [SSGSV], n = 1434; cohort 2 lacking suitable SSGSV, n = 396). We also compared the cumulative number of major and all index limb reinterventions over time. Comparisons between treatment arms within each cohort were made using univariable and multivariable Cox regression models. RESULTS: In cohort 1, assignment to OPEN was associated with a significantly reduced hazard of a major limb reintervention (hazard ratio [HR], 0.37; 95% confidence interval [CI], 0.28-0.49; P < .001), any reintervention (HR, 0.63; 95% CI, 0.53-0.75; P < .001), or any reintervention, amputation, or death (HR, 0.68; 95% CI, 0.60-0.78; P < .001). Findings were similar in cohort 2 for major reintervention (HR, 0.53; 95% CI, 0.33-0.84; P = .007) or any reintervention (HR, 0.71; 95% CI, 0.52-0.98; P = .04). In both cohorts, early (30-day) limb reinterventions were notably higher for patients assigned to ENDO as compared with OPEN (14.7% vs 4.5% of cohort 1 subjects; 16.6% vs 5.6% of cohort 2 subjects). The mean number of major (mean events per subject ratio [MR], 0.45; 95% CI, 0.34-0.58; P < .001) or any target limb reinterventions (MR, 0.67; 95% CI, 0.57-0.80; P < .001) per year was significantly less in the OPEN arm of cohort 1. The mean number of reinterventions per limb salvaged per year was lower in the OPEN arm of cohort 1 (MR, 0.45; 95% CI, 0.35-0.57; P < .001 and MR, 0.66; 95% CI, 0.55-0.79; P < .001 for major and all, respectively). The majority of index limb reinterventions occurred during the first year following randomization, but events continued to accumulate over the duration of follow-up in the trial. CONCLUSIONS: Reintervention is common following revascularization for chronic limb-threatening ischemia. Among patients deemed suitable for either approach, initial treatment with open bypass, particularly in patients with available SSGSV conduit, is associated with a significantly lower number of major and minor target limb reinterventions.
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Amputación Quirúrgica , Procedimientos Endovasculares , Isquemia , Recuperación del Miembro , Reoperación , Humanos , Procedimientos Endovasculares/efectos adversos , Procedimientos Endovasculares/mortalidad , Masculino , Femenino , Anciano , Isquemia/cirugía , Isquemia/mortalidad , Isquemia/fisiopatología , Isquemia/diagnóstico , Resultado del Tratamiento , Factores de Tiempo , Factores de Riesgo , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Enfermedad Arterial Periférica/cirugía , Enfermedad Arterial Periférica/mortalidad , Enfermedad Arterial Periférica/diagnóstico por imagen , Enfermedad Arterial Periférica/fisiopatología , Isquemia Crónica que Amenaza las Extremidades/cirugía , Enfermedad Crónica , Injerto Vascular/efectos adversos , Injerto Vascular/mortalidad , Análisis Multivariante , Enfermedad Crítica , Análisis de Intención de Tratar , Estimación de Kaplan-Meier , Vena Safena/trasplante , Vena Safena/cirugíaRESUMEN
OBJECTIVE: The recent publication of randomized trials comparing open bypass surgery to endovascular therapy in patients with chronic limb-threatening ischemia, namely, Best Endovascular vs Best Surgical Therapy in Patients with Critical Limb Ischemia (BEST-CLI) and Bypass versus Angioplasty in Severe Ischaemia of the Leg-2 (BASIL-2), has resulted in potentially contradictory findings. The trials differed significantly with respect to anatomical disease patterns and primary end points. We performed an analysis of patients in BEST-CLI with significant infrapopliteal disease undergoing open tibial bypass or endovascular tibial interventions to formulate a relevant comparator with the outcomes reported from BASIL-2. METHODS: The study population consisted of patients in BEST-CLI with adequate single segment saphenous vein conduit randomized to open bypass or endovascular intervention (cohort 1) who additionally had significant infrapopliteal disease and underwent tibial level intervention. The primary outcome was major adverse limb event (MALE) or all-cause death. MALE included any major limb amputation or major reintervention. Outcomes were evaluated using Cox proportional regression models. RESULTS: The analyzed subgroup included a total of 665 patients with 326 in the open tibial bypass group and 339 in the tibial endovascular intervention group. The primary outcome of MALE or all-cause death at 3 years was significantly lower in the surgical group at 48.5% compared with 56.7% in the endovascular group (P = .0018). Mortality was similar between groups (35.5% open vs 35.8% endovascular; P = .94), whereas MALE events were lower in the surgical group (23.3% vs 35.0%; P<.0001). This difference included a lower rate of major reinterventions in the surgical group (10.9%) compared with the endovascular group (20.2%; P = .0006). Freedom from above ankle amputation or all-cause death was similar between treatment arms at 43.6% in the surgical group compared with 45.3% the endovascular group (P = .30); however, there were fewer above ankle amputations in the surgical group (13.5%) compared with the endovascular group (19.3%; P = .0205). Perioperative (30-day) death rates were similar between treatment groups (2.5% open vs 2.4% endovascular; P = .93), as was 30-day major adverse cardiovascular events (5.3% open vs 2.7% endovascular; P = .12). CONCLUSIONS: Among patients with suitable single segment great saphenous vein who underwent infrapopliteal revascularization for chronic limb-threatening ischemia, open bypass surgery was associated with a lower incidence of MALE or death and fewer major amputation compared with endovascular intervention. Amputation-free survival was similar between the groups. Further investigations into differences in comorbidities, anatomical extent, and lesion complexity are needed to explain differences between the BEST-CLI and BASIL-2 reported outcomes.
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OBJECTIVE: Sustained clinical and hemodynamic benefit after revascularization for chronic limb-threatening ischemia (CLTI) is needed to resolve symptoms and prevent limb loss. We sought to compare rates of clinical and hemodynamic failure as well as resolution of initial and prevention of recurrent CLTI after endovascular (ENDO) vs bypass (OPEN) revascularization in the Best-Endovascular-versus-best-Surgical-Therapy-in-patients-with-CLTI (BEST-CLI) trial. METHODS: As planned secondary analyses of the BEST-CLI trial, we examined the rates of (1) clinical failure (a composite of all-cause death, above-ankle amputation, major reintervention, and degradation of WIfI stage); (2) hemodynamic failure (a composite of above-ankle amputation, major and minor reintervention to maintain index limb patency, failure to an initial increase or a subsequent decrease in ankle brachial index of 0.15 or toe brachial index of 0.10, and radiographic evidence of treatment stenosis or occlusion); (3) time to resolution of presenting CLTI symptoms; and (4) incidence of recurrent CLTI. Time-to-event analyses were performed by intention-to-treat assignment in both trial cohorts (cohort 1: suitable single segment great saphenous vein [SSGSV], N = 1434; cohort 2: lacking suitable SSGSV, N = 396), and multivariate stratified Cox regression models were created. RESULTS: In cohort 1, there was a significant difference in time to clinical failure (log-rank P < .001), hemodynamic failure (log-rank P < .001), and resolution of presenting symptoms (log-rank P = .009) in favor of OPEN. In cohort 2, there was a significantly lower rate of hemodynamic failure (log-rank P = .006) favoring OPEN, and no significant difference in time to clinical failure or resolution of presenting symptoms. Multivariate analysis revealed that assignment to OPEN was associated with a significantly lower risk of clinical and hemodynamic failure in both cohorts and a significantly higher likelihood of resolving initial and preventing recurrent CLTI symptoms in cohort 1, including after adjustment for key baseline patient covariates (end-stage renal disease [ESRD], prior revascularization, smoking, diabetes, age >80 years, WIfI stage, tissue loss, and infrapopliteal disease). Factors independently associated with clinical failure included age >80 years in cohort 1 and ESRD across both cohorts. ESRD was associated with hemodynamic failure in cohort 1. Factors associated with slower resolution of presenting symptoms included diabetes in cohort 1 and WIfI stage in cohort 2. CONCLUSIONS: Durable clinical and hemodynamic benefit after revascularization for CLTI is important to avoid persistent and recurrent CLTI, reinterventions, and limb loss. When compared with ENDO, initial treatment with OPEN surgical bypass, particularly with available saphenous vein, is associated with improved clinical and hemodynamic outcomes and enhanced resolution of CLTI symptoms.
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Mycobacterium abscessus is an intrinsically drug-resistant, rapidly growing, nontuberculous mycobacterium; extrapulmonary infections have been reported in association with medical tourism (1). During November-December 2022, two Colorado hospitals (hospitals A and B) treated patient A, a Colorado woman aged 30-39 years, for M. abscessus meningitis. In October 2022, she had received intrathecal donor embryonic stem cell injections in Baja California, Mexico to treat multiple sclerosis and subsequently experienced headaches and fevers, consistent with meningitis. Her cerebrospinal fluid revealed neutrophilic pleocytosis and grew M. abscessus in culture at hospital A. Hospital A's physicians consulted hospital B's infectious diseases (ID) physicians to co-manage this patient (2).
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Brotes de Enfermedades , Infecciones por Mycobacterium no Tuberculosas , Mycobacterium abscessus , Humanos , Colorado/epidemiología , Adulto , Femenino , México/epidemiología , Mycobacterium abscessus/aislamiento & purificación , Infecciones por Mycobacterium no Tuberculosas/epidemiología , Arizona/epidemiología , Trasplante de Células MadreRESUMEN
INTRODUCTION: We investigated whether novel plasma biomarkers are associated with cognition, cognitive decline, and functional independence in activities of daily living across and within neurodegenerative diseases. METHODS: Glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), phosphorylated tau (p-tau)181 and amyloid beta (Aß)42/40 were measured using ultra-sensitive Simoa immunoassays in 44 healthy controls and 480 participants diagnosed with Alzheimer's disease/mild cognitive impairment (AD/MCI), Parkinson's disease (PD), frontotemporal dementia (FTD) spectrum disorders, or cerebrovascular disease (CVD). RESULTS: GFAP, NfL, and/or p-tau181 were elevated among all diseases compared to controls, and were broadly associated with worse baseline cognitive performance, greater cognitive decline, and/or lower functional independence. While GFAP, NfL, and p-tau181 were highly predictive across diseases, p-tau181 was more specific to the AD/MCI cohort. Sparse associations were found in the FTD and CVD cohorts and for Aß42/40 . DISCUSSION: GFAP, NfL, and p-tau181 are valuable predictors of cognition and function across common neurodegenerative diseases, and may be useful in specialized clinics and clinical trials.
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Enfermedad de Alzheimer , Enfermedades Cardiovasculares , Disfunción Cognitiva , Demencia Frontotemporal , Enfermedades Neurodegenerativas , Humanos , Actividades Cotidianas , Péptidos beta-Amiloides , Ontario , Cognición , Biomarcadores , Proteínas tauRESUMEN
As the world continues to experience the effects of SARS-CoV-2, there is evidence to suggest that the sequelae of viral infection (the post-COVID-19 condition; PCC) at both an individual and population level will be significant and long-lasting. The history of pandemics or epidemics in the last 100 years caused by members of the RNA virus family, of which coronaviruses are a member, provides ample evidence of the acute neurological effects. However, except for the H1N1 influenza pandemic of 1918/1919 (the Spanish flu) with its associated encephalitis lethargica, there is little information on long-term neurological sequelae. COVID-19 is the first pandemic that has occurred in a setting of an aging population, especially in several high-income countries. Its survivors are at the greatest risk for developing neurodegenerative conditions as they age, rendering the current pandemic a unique paradigm not previously witnessed. The SARS-CoV-2 virus, among the largest of the RNA viruses, is a single-stranded RNA that encodes for 29 proteins that include the spike protein that contains the key domains required for ACE2 binding, and a complex array of nonstructural proteins (NSPs) and accessory proteins that ensure the escape of the virus from the innate immune response, allowing for its efficient replication, translation, and exocytosis as a fully functional virion. Increasingly, these proteins are also recognized as potentially contributing to biochemical and molecular processes underlying neurodegeneration. In addition to directly being taken up by brain endothelium, the virus or key protein constituents can be transported to neurons, astrocytes, and microglia by extracellular vesicles and can accelerate pathological fibril formation. The SARS-CoV-2 nucleocapsid protein is intrinsically disordered and can participate in liquid condensate formation, including as pathological heteropolymers with neurodegenerative disease-associated RNA-binding proteins such as TDP-43, FUS, and hnRNP1A. As the SARS-CoV-2 virus continues to mutate under the immune pressure exerted by highly efficacious vaccines, it is evolving into a virus with greater transmissibility but less severity compared with the original strain. The potential of its lingering impact on the nervous system thus has the potential to represent an ongoing legacy of an even greater global health challenge than acute infection.
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COVID-19 , Subtipo H1N1 del Virus de la Influenza A , Influenza Pandémica, 1918-1919 , Enfermedades Neurodegenerativas , Historia del Siglo XX , Humanos , Anciano , SARS-CoV-2/genéticaRESUMEN
MOTIVATION: Short-read whole-genome sequencing (WGS) is a vital tool for clinical applications and basic research. Genetic divergence from the reference genome, repetitive sequences and sequencing bias reduces the performance of variant calling using short-read alignment, but the loss in recall and specificity has not been adequately characterized. To benchmark short-read variant calling, we used 36 diverse clinical Mycobacterium tuberculosis (Mtb) isolates dually sequenced with Illumina short-reads and PacBio long-reads. We systematically studied the short-read variant calling accuracy and the influence of sequence uniqueness, reference bias and GC content. RESULTS: Reference-based Illumina variant calling demonstrated a maximum recall of 89.0% and minimum precision of 98.5% across parameters evaluated. The approach that maximized variant recall while still maintaining high precision (<99%) was tuning the mapping quality filtering threshold, i.e. confidence of the read mapping (recall = 85.8%, precision = 99.1%, MQ ≥ 40). Additional masking of repetitive sequence content is an alternative conservative approach to variant calling that increases precision at cost to recall (recall = 70.2%, precision = 99.6%, MQ ≥ 40). Of the genomic positions typically excluded for Mtb, 68% are accurately called using Illumina WGS including 52/168 PE/PPE genes (34.5%). From these results, we present a refined list of low confidence regions across the Mtb genome, which we found to frequently overlap with regions with structural variation, low sequence uniqueness and low sequencing coverage. Our benchmarking results have broad implications for the use of WGS in the study of Mtb biology, inference of transmission in public health surveillance systems and more generally for WGS applications in other organisms. AVAILABILITY AND IMPLEMENTATION: All relevant code is available at https://github.com/farhat-lab/mtb-illumina-wgs-evaluation. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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Mycobacterium tuberculosis , Tuberculosis , Humanos , Benchmarking , Mycobacterium tuberculosis/genética , Programas Informáticos , Análisis de Secuencia de ADN/métodos , Secuenciación de Nucleótidos de Alto Rendimiento/métodosRESUMEN
OBJECTIVE: The WIfI (Wound, Ischemia, foot Infection) stage measures the extent of wounds, ischemia, and foot infection in patients with chronic limb threatening ischemia (CLTI) and has been associated with the risk of major amputation. Patients with CLTI have impaired health-related quality of life (HRQoL), which can be multifactorial. We hypothesized that the severity of the limb threat (WIfI stage) would be associated with poor HRQoL among patients with CLTI presenting for revascularization. METHODS: The dataset of the BEST-CLI (best endovascular versus best surgical therapy in patients with CLTI) trial, a prospective, randomized trial comparing open and endovascular revascularization strategies, was queried for HRQoL assessments at patient enrollment. The HRQoL assessments included (1) Vascular Quality of Life; (2) 12-item short form survey (SF-12), containing the utility index score (short-form six-dimension R2 utility index, incorporating physical, emotional, and mental well-being) and mental and physical components; and (3) the EQ-5D. Multivariable regression analysis was used to identify the independent associations with the baseline HRQoL assessments. RESULTS: A total of 1568 patients with complete WIfI data were analyzed, of whom 71.5% were men. The WIfI distribution was 35.5% with stage 4, 29.6% with stage 3, 28.6% with stage 2, and 6.3% with stage 1. Patients presenting with WIfI stage 4, compared with stage 1 to 3, were more often men (74.9% vs 69.6%) and current smokers (25.4% vs. 17.6%), had had end-stage renal disease (13.3% vs 8.5%) and diabetes (83.6% vs 60.2%), were not independently ambulatory (56.8% vs 38.5%), and had had higher median morbidity scores (4 vs 3; P < .05 for all). On multivariable analysis, WIfI stage 4, compared with stage 1 to 3, was associated with lower SF-12 mental component scale scores (estimate, -2.43; 95% confidence interval, -3.73 to -1.13; P < .001) and short-form six-dimension R2 utility index scores (estimate, -0.02; 95% confidence interval, -0.03 to 0.001; P = .04). The WIfI stage was not independently associated with the baseline Vascular Quality of Life, SF-12 physical component scale, or EQ-5D assessments. CONCLUSIONS: WIfI stage was independently associated with poorer quality of life because of mental, rather than physical, health for patients with CLTI. Clinicians should be aware of the burden of mental stress borne by those with the greatest limb impairment.
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Procedimientos Endovasculares , Enfermedad Arterial Periférica , Masculino , Humanos , Femenino , Recuperación del Miembro/métodos , Calidad de Vida , Factores de Riesgo , Estudios Prospectivos , Resultado del Tratamiento , Enfermedad Arterial Periférica/diagnóstico , Enfermedad Arterial Periférica/cirugía , Isquemia/diagnóstico , Isquemia/cirugía , Isquemia Crónica que Amenaza las Extremidades , Estudios Retrospectivos , Procedimientos Endovasculares/efectos adversosRESUMEN
OBJECTIVES: The use of optimal medical therapy (OMT) in patients with chronic limb-threatening ischemia (CLTI) has not been well-studied. The Best Endovascular vs Best Surgical Therapy in Patients with CLTI study (BEST-CLI) is a multicenter, randomized, controlled trial sponsored by the National Institutes of Health comparing revascularization strategies in patients with CLTI. We evaluated the use of guideline-based OMT among patients with CLTI at the time of their enrollment into the trial. METHODS: A multidisciplinary committee defined OMT criteria related to blood pressure and diabetic management, lipid-lowering and antiplatelet medication use, and smoking status for patients enrolled in BEST-CLI. Status reports indicating adherence to OMT were provided to participating sites at regular intervals. Baseline demographic characteristics, comorbid medical conditions, and use of OMT at trial entry were evaluated for all randomized patients. A linear regression model was used to identify the relationship of predictors to the use of OMT. RESULTS: At the time of randomization (n = 1830 total enrolled), 87% of patients in BEST-CLI had hypertension, 69% had diabetes, 73% had hyperlipidemia, and 35% were currently smoking. Adherence to four OMT components (controlled blood pressure, not currently smoking, use of one lipid-lowering medication, and use of an antiplatelet agent) was modest. Only 25% of patients met all four OMT criteria; 38% met three, 24% met two, 11% met only one, and 2% met none. Age ≥80 years, coronary artery disease, diabetes, and Hispanic ethnicity were positively associated, whereas Black race was negatively associated, with the use of OMT. CONCLUSIONS: A significant proportion of patients in BEST-CLI did not meet OMT guideline-based recommendations at time of entry. These data suggest a persistent major gap in the medical management of patients with advanced peripheral atherosclerosis and CLTI. Changes in OMT adherence over the course of the trial and their impact on clinical outcomes and quality of life will be assessed in future analyses.
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Procedimientos Endovasculares , Enfermedad Arterial Periférica , Humanos , Anciano de 80 o más Años , Enfermedad Arterial Periférica/diagnóstico , Enfermedad Arterial Periférica/terapia , Calidad de Vida , Resultado del Tratamiento , Isquemia , Lípidos , Factores de Riesgo , Recuperación del Miembro , Procedimientos Endovasculares/efectos adversosRESUMEN
OBJECTIVE: Anticipated perioperative morbidity is an important factor for choosing a revascularization method for chronic limb-threatening ischemia (CLTI). Our goal was to assess systemic perioperative complications of patients treated with surgical and endovascular revascularization in the Best Endovascular vs Best Surgical Therapy in Patients with CLTI (BEST-CLI) trial. METHODS: BEST-CLI was a prospective randomized trial comparing open (OPEN) and endovascular (ENDO) revascularization strategies for patients with CLTI. Two parallel cohorts were studied: Cohort 1 included patients with adequate single-segment great saphenous vein (SSGSV), whereas Cohort 2 included those without SSGSV. Data were queried for major adverse cardiovascular events (MACE-composite myocardial infarction, stroke, death), non-serious (non-SAEs) and serious adverse events (SAEs) (criteria-death/life-threatening/requiring hospitalization or prolongation of hospitalization/significant disability/incapacitation/affecting subject safety in trial) 30 days after the procedure. Per protocol analysis was used (intervention received without crossover), and risk-adjusted analysis was performed. RESULTS: There were 1367 patients (662 OPEN, 705 ENDO) in Cohort 1 and 379 patients (188 OPEN, 191 ENDO) in Cohort 2. Thirty-day mortality in Cohort 1 was 1.5% (OPEN 1.8%; ENDO 1.3%) and in Cohort 2 was 1.3% (2.7% OPEN; 0% ENDO). MACE in Cohort 1 was 4.7% for OPEN vs 3.13% for ENDO (P = .14), and in Cohort 2, was 4.28% for OPEN and 1.05% for ENDO (P = .15). On risk-adjusted analysis, there was no difference in 30-day MACE for OPEN vs ENDO for Cohort 1 (hazard ratio [HR] 1.5; 95% confidence interval [CI], 0.85-2.64; P = .16) or Cohort 2 (HR, 2.17; 95% CI, 0.48-9.88; P = .31). The incidence of acute renal failure was similar across interventions; in Cohort 1 it was 3.6% for OPEN vs 2.1% for ENDO (HR, 1.6; 95% CI, 0.85-3.12; P = .14), and in Cohort 2, it was 4.2% OPEN vs 1.6% ENDO (HR, 2.86; 95% CI, 0.75-10.8; P = .12). The occurrence of venous thromboembolism was low overall and was similar between groups in Cohort 1 (OPEN 0.9%; ENDO 0.4%) and Cohort 2 (OPEN 0.5%; ENDO 0%). Rates of any non-SAEs in Cohort 1 were 23.4% in OPEN and 17.9% in ENDO (P = .013); in Cohort 2, they were 21.8% for OPEN and 19.9% for ENDO (P = .7). Rates for any SAEs in Cohort 1 were 35.3% for OPEN and 31.6% for ENDO (P = .15); in Cohort 2, they were 25.5% for OPEN and 23.6% for ENDO (P = .72). The most common types of non-SAEs and SAEs were infection, procedural complications, and cardiovascular events. CONCLUSIONS: In BEST-CLI, patients with CLTI who were deemed suitable candidates for open lower extremity bypass surgery had similar peri-procedural complications following either OPEN or ENDO revascularization: In such patients, concern about risk of peri-procedure complications should not be a deterrent in deciding revascularization strategy. Rather, other factors, including effectiveness in restoring perfusion and patient preference, are more relevant.
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Procedimientos Endovasculares , Enfermedad Arterial Periférica , Humanos , Isquemia Crónica que Amenaza las Extremidades , Estudios Prospectivos , Factores de Riesgo , Enfermedad Arterial Periférica/diagnóstico por imagen , Enfermedad Arterial Periférica/cirugía , Recuperación del Miembro , Isquemia/diagnóstico por imagen , Isquemia/etiología , Isquemia/cirugía , Extremidad Inferior/irrigación sanguínea , Resultado del Tratamiento , Estudios RetrospectivosRESUMEN
Rationale: Healthcare-associated transmission of nontuberculous mycobacteria (NTM) among people with cystic fibrosis (pwCF) has been investigated at CF centers worldwide, with conflicting conclusions. We investigated transmission at the Colorado Adult CF Program. Objectives: To systematically investigate healthcare-associated transmission and/or acquisition of NTM to determine similarity among respiratory and environmental isolates, and to compare home residence watershed mapping among pwCF having genetically similar NTM isolates. Methods: Whole-genome sequencing of NTM isolates from 80 pwCF was conducted to identify genetically similar isolate clusters (⩽30 SNP differences). Epidemiology, comparison of respiratory and environmental isolates, and home residence watershed mapping were analyzed. Measurements and Main Results: Whole-genome sequencing analysis revealed 11 clusters of NTM [6 Mycobacterium abscessus subspecies (ssp.) abscessus, 1 M. abscessus ssp. massiliense, 2 Mycobacterium avium, and 2 Mycobacterium intracellulare] among pwCF. Epidemiologic investigation demonstrated opportunities for healthcare-associated transmission in two M. abscessus and two M. avium clusters. Respiratory and healthcare environmental isolate comparisons revealed no genetic similarity. Individuals comprising one M. abscessus cluster, with no plausible healthcare-associated transmission, resided in the same watershed. Conclusions: This study suggests healthcare-associated transmission of M. abscessus is rare and includes a report of potential healthcare-associated transmission of M. avium among pwCF. One M. abscessus cluster possibly had common acquisition arising from residing in the same watershed. The presence of genetically similar isolates is insufficient to demonstrate healthcare-associated NTM transmission. Standardizing epidemiologic investigation, combined with environmental sampling and watershed analysis, will improve understanding of the frequency and nature of healthcare-associated NTM transmission among pwCF.
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Fibrosis Quística , Infecciones por Mycobacterium no Tuberculosas , Mycobacterium abscessus , Adulto , Colorado/epidemiología , Fibrosis Quística/complicaciones , Humanos , Infecciones por Mycobacterium no Tuberculosas/epidemiología , Infecciones por Mycobacterium no Tuberculosas/microbiología , Micobacterias no Tuberculosas/genéticaRESUMEN
Whole-genome sequencing (WGS) has recently been used to investigate acquisition of Mycobacterium abscessus. Investigators have reached conflicting conclusions about the meaning of genetic distances for interpretation of person-to-person transmission. Existing genomic studies were limited by a lack of WGS from environmental M. abscessus isolates. In this study, we retrospectively analyzed the core and accessory genomes of 26 M. abscessus subsp. abscessus isolates collected over 7 years. Clinical isolates (n = 22) were obtained from a large hospital-associated outbreak of M. abscessus subsp. abscessus, the outbreak hospital before or after the outbreak, a neighboring hospital, and two outside laboratories. Environmental M. abscessus subsp. abscessus isolates (n = 4) were obtained from outbreak hospital water outlets. Phylogenomic analysis of study isolates revealed three clades with pairwise genetic distances ranging from 0 to 135 single-nucleotide polymorphisms (SNPs). Compared to a reference environmental outbreak isolate, all seven clinical outbreak isolates and the remaining three environmental isolates had highly similar core and accessory genomes, differing by up to 7 SNPs and a median of 1.6% accessory genes, respectively. Although genomic comparisons of 15 nonoutbreak clinical isolates revealed greater heterogeneity, five (33%) isolates had fewer than 20 SNPs compared to the reference environmental isolate, including two unrelated outside laboratory isolates with less than 4% accessory genome variation. Detailed genomic comparisons confirmed environmental acquisition of outbreak isolates of M. abscessus subsp. abscessus. SNP distances alone, however, did not clearly differentiate the mechanism of acquisition of outbreak versus nonoutbreak isolates. We conclude that successful investigation of M. abscessus subsp. abscessus clusters requires molecular and epidemiologic components, ideally complemented by environmental sampling.
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Infección Hospitalaria , Brotes de Enfermedades , Infecciones por Mycobacterium no Tuberculosas , Mycobacterium abscessus , Infección Hospitalaria/epidemiología , Infección Hospitalaria/microbiología , Infección Hospitalaria/transmisión , Genómica , Hospitales , Humanos , Infecciones por Mycobacterium no Tuberculosas/epidemiología , Infecciones por Mycobacterium no Tuberculosas/microbiología , Infecciones por Mycobacterium no Tuberculosas/transmisión , Mycobacterium abscessus/genética , Estudios RetrospectivosRESUMEN
Nontuberculous mycobacteria (NTM) are opportunistic pathogens that cause chronic pulmonary disease (PD). NTM infections are thought to be acquired from the environment; however, the basal environmental factors that drive and sustain NTM prevalence are not well understood. The highest prevalence of NTM PD cases in the United States is reported from Hawai'i, which is unique in its climate and soil composition, providing an opportunity to investigate the environmental drivers of NTM prevalence. We used microbiological sampling and spatial logistic regression complemented with fine-scale soil mineralogy to model the probability of NTM presence across the natural landscape of Hawai'i. Over 7 years, we collected and microbiologically cultured 771 samples from 422 geographic sites in natural areas across the Hawaiian Islands for the presence of NTM. NTM were detected in 210 of these samples (27%), with Mycobacterium abscessus being the most frequently isolated species. The probability of NTM presence was highest in expansive soils (those that swell with water) with a high water balance (>1-m difference between rainfall and evapotranspiration) and rich in Fe-oxides/hydroxides. We observed a positive association between NTM presence and iron in wet soils, supporting past studies, but no such association in dry soils. High soil-water balance may facilitate underground movement of NTM into the aquifer system, potentially compounded by expansive capabilities allowing crack formation under drought conditions, representing further possible avenues for aquifer infiltration. These results suggest both precipitation and soil properties are mechanisms by which surface NTM may reach the human water supply. IMPORTANCE Nontuberculous mycobacteria (NTM) are ubiquitous in the environment, being found commonly in soils and natural bodies of freshwater. However, little is known about the environmental niches of NTM and how they relate to NTM prevalence in homes and other human-dominated areas. To characterize NTM environmental associations, we collected and cultured 771 samples from 422 geographic sites in natural areas across Hawai'i, the U.S. state with the highest prevalence of NTM pulmonary disease. We show that the environmental niches of NTM are most associated with highly expansive, moist soils containing high levels of iron oxides/hydroxides. Understanding the factors associated with NTM presence in the natural environment will be crucial for identifying potential mechanisms and risk factors associated with NTM infiltration into water supplies, which are ultimately piped into homes where most exposure risk is thought to occur.
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Enfermedades Pulmonares , Infecciones por Mycobacterium no Tuberculosas , Hawaii/epidemiología , Humanos , Hierro , Infecciones por Mycobacterium no Tuberculosas/epidemiología , Infecciones por Mycobacterium no Tuberculosas/microbiología , Micobacterias no Tuberculosas , Óxidos , Prevalencia , Suelo , Estados UnidosRESUMEN
OBJECTIVES: There are few contemporary data regarding health-related quality of life (HRQOL) measures in patients with chronic limb-threatening ischemia (CLI). METHODS: The Best Endovascular versus Best Surgical Therapy in Patients with CLI (BEST-CLI) trial is an ongoing, National Institutes of Health-sponsored, multicenter, randomized, controlled trial comparing revascularization strategies in patients with CLI. BEST-CLI baseline HRQOL measures were evaluated for patient-specific variables that were associated with poor HRQOL and then compared with published outcomes. The HRQOL measures Vascular Quality of Life Questionnaire (VascQOL), European Quality of Life 5D (EQ-5D), and the Short Form 12 (SF-12) Index score, physical component score (PCS) and mental component score (MCS) were aggregated from preoperative questionnaires completed by trial patients at baseline visits. Multivariable linear regression models were fit to determine which baseline characteristics were associated with poor HRQOL. RESULTS: We randomized 1830 patients into BEST-CLI. The majority (94.9%, 95.8%, and 95.8%) completed the VascQOL, EQ-5D, and SF-12 instruments at baseline, respectively. In the VascQOL, female sex, smoking history, opioid use, and nonindependent ambulation predicted lower HRQOL scores. Overall, VascuQOL scores were similar to those of participants in the Bypass versus Angioplasty in Severe Ischemia of the Leg (mean, 3.07 ± 1.2 vs mean, 2.9 ± 1.1; P = .07). In EQ-5D, nonindependent ambulation predicted lower HRQOL scores. In the SF-12, female sex, opioid use, nonindependent ambulation, and a history of smoking predicted lower HRQOL scores. The mean SF-12 PCS for all patients in the study was 33.0 ± 8.5 and for the MCS was 46.4 ± 12.0), significantly lower than the national SF-12 scores for US population ages more than 60 years, which is a PCS of 46.5 ± 11.4 and an MCS of 52.9 ± 8.7. CONCLUSIONS: Patients with CLI entering the BEST-CLI trial have very low HRQOL scores, comparable with patients suffering from other chronic conditions characterized by physical limitations and chronic pain. A history of smoking, impaired ambulation, opioid use, and female sex predicted lower HRQOL in patients with CLI, using multiple HRQOL measurement tools.