Lower Limit Of Normal Research Articles

Phase 2 Study of Tagraxofusp Therapy for BPDCN Patients Post-Autologous or Post-Allogeneic Hematopoietic Cell Transplantation

Background: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive hematologic malignancy with historical overall survival (OS) of 8-14 months from diagnosis. Tagraxofusp is a targeted therapy directed to CD123. The US FDA has approved tagraxofusp for the treatment of BPDCN in adult and pediatric patients 2 years and older. CD123 is ubiquitously expressed at high levels on plasmacytoid dendritic cells (pDCs), the cell of origin of BPDCN, and targeting of CD123 with tagraxofusp resulted in high response rates, durable remissions, and a significant proportion of patients bridged to hematopoietic cell transplant (HCT) in first remission (45%). While HCT has the potential to prolong remission of patients with hematologic cancers, relapses after transplantation still occur in patients with certain risk factors including minimal residual disease (MRD). This study is designed to assess the safety and efficacy of tagraxofusp monotherapy as a maintenance treatment in patients with BPDCN post-HCT. The study is open for enrollment and expected to recruit approximately 20 patients. NCT04317781 Rationale: Available data suggest long-term remission can be expected in approximately 50% of patients with BPDCN that undergo allo-HCT. Accordingly, strategies are needed to further reduce the risk of relapse post-HCT. Methods: The study is a Phase 2, single-center, open-label, single-arm clinical trial of tagraxofusp in patients with BPDCN that have undergone HCT. Planned enrollment is 20 patients. Treatment with tagraxofusp will be initiated between day 45 and 120 post-HCT, and dosed days 1-3 in cycles 1-4, and days 1-2 in cycles 5 and beyond. Each treatment cycle is 28 days. Duration of therapy for patients in complete response (CR) or clinical CR (CRc) post-transplant is 24 cycles, with patients who are MRD-positive or remain at high risk of relapse, eligible for continued treatment for as long as they derive benefit. In patients whose post-HCT disease status is either CR with incomplete blood count recovery (CRi) or partial response (PR), treatment will continue until disease progression or unacceptable toxicity. Major Inclusion/Exclusion Criteria : Age ≥18; >30 days post-transplant without active or chronic infections; Karnofsky PS ≥60%; Lansky ≥60; adequate organ function including LVEF ≥ lower limit of normal (LLN); creatinine ≤1.5 mg/dL; albumin ≥3.2 g/dL; bilirubin ≤1.5 upper limit of normal (ULN); AST/ALT ≤2.5 times ULN; and ANC ≥1000. For allo-HCT, no ≥ grade 2 visceral (gut or liver) acute graft versus host disease (GVHD) and no ≥ grade 3 or any other acute GVHD (chronic GVHD allowed at investigator discretion). Key exclusions: Persistent clinically significant non-hematologic toxicities ≥ grade 2; CNS involvement; receiving chemotherapy, radiotherapy, or other anti-cancer therapy within 14 days of first dose of study drug; uncontrolled infection; HIV/Hepatitis B and/or C; and clinically significant cardiopulmonary disease. Endpoints: Primary endpoints include safety and tolerability of tagraxofusp in patients with BPDCN post-HCT, with survival as secondary outcomes. Disclosures Bashir: Amgen: Other: Advisory Board; Purdue: Other: Advisory Board; Acrotech: Research Funding; StemLine: Research Funding; KITE: Other: Advisory Board; Takeda: Other: Advisory Board, Research Funding; Celgene: Research Funding. Shpall:Magenta: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Adaptimmune: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: Licensing Agreement; Zelluna: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Popat:Bayer: Research Funding; Novartis: Research Funding. Pemmaraju:Stemline Therapeutics: Honoraria, Research Funding; LFB Biotechnologies: Honoraria; Roche Diagnostics: Honoraria; Pacylex Pharmaceuticals: Consultancy; Blueprint Medicines: Honoraria; Samus Therapeutics: Research Funding; Novartis: Honoraria, Research Funding; Celgene: Honoraria; Plexxikon: Research Funding; Affymetrix: Other: Grant Support, Research Funding; AbbVie: Honoraria, Research Funding; Daiichi Sankyo: Research Funding; SagerStrong Foundation: Other: Grant Support; DAVA Oncology: Honoraria; MustangBio: Honoraria; Cellectis: Research Funding; Incyte Corporation: Honoraria. Champlin:Takeda: Patents & Royalties; Actinium: Consultancy; Omeros: Consultancy; Genzyme: Speakers Bureau; DKMS America: Membership on an entity's Board of Directors or advisory committees; Johnson and Johnson: Consultancy; Cytonus: Consultancy. Qazilbash:Bioline: Research Funding; Bioclinica: Consultancy; Amgen: Research Funding; Angiocrine: Research Funding; Janssen: Research Funding.

Fostamatinib for the Treatment of Warm Antibody Autoimmune Hemolytic Anemia (wAIHA): A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Global Study

Fostamatinib for the Treatment of Warm Antibody Autoimmune Hemolytic Anemia (wAIHA): A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Global Study

Priapism with Essential Thrombocythemia Review of Literature, Where We Stand and Where We Are Heading

Introduction Priapism is a persistent erection of the penis that is not associated with sexual stimulation or desire lasting more than 4 hours. Priapism can be classified as ischemic, non-ischemic, or stuttering. Stuttering priapism is defined as recurrent priapism lasting less than 4 hours. Commonly, no cause is identified, secondary causes include medications specially intracorporal injections or medical conditions such as hematological diseases particularly sickle cell disease, but it is uncommon to be seen with essential thrombocythemia (ET). It adversely affects the quality of life, sexual function, and physical wellness of the affected patients besides the risk of penile fibrosis and permanent erectile dysfunction. The underlying pathophysiology is not clearly understood but the mechanism involves disturbed nitrous oxide, phosphodiesterase enzyme activity, and disturbed auto-regulation of the penile circulation. Method Literature searched in google scholar, PubMed, and Scopus search engines with keywords priapism, essential thrombocythemia, essential thrombocytosis results found from 1960 to 2020. Results Using the keywords above we found 11 cases of ET devolved or presented with priapism. With the case in our center (not published) the total number of cases will be 12. The cases arranged by chronological order. Almost all age groups are involved from 7 years to 71 years. The table shows hematological parameters, type of mutation, and the management of priapism. Discussion In ET the mechanism of priapism is probably related to high platelet count and platelets sludging in the corpora cavernosa, similar to RBC sludging in sickle cell disease and WBC sludging in leukemia. Subsequent stasis and disturbed NO and cGMP signaling. This might be precipitated by increased viscosity or release of free hemoglobin secondary to hemolysis similar to sickle cell anemia as many patients had low hemoglobin levels (table-1). Looking at the table with the available data most hemoglobin levels are in the lower normal limits, but no patient had high hemoglobin levels, opposite to what can be expected that polycythemia might enhance the viscosity of the blood and enhance thrombosis. Observing other MPN who developed priapism, in one study 430 patients with CML 8 patients developed priapism at diagnosis, they had lower hemoglobin levels compared to CML patients who didn't develop priapism. The mean hemoglobin level in patients with priapism was 8.4 ± 2.3 g/dL, compared to 10.8 ± 2.5 g/dL in CML patients control who didn't develop priapism. To the best of our knowledge, there are no reports of cases of adults with polycythemia Vera who devolved priapism which might indicate that anemia has a synergistic effect with leukocytosis in the pathogenesis of priapism in CML patients. But, it is difficult to generalize this observation to ET. However, anemia can enhance thrombosis and the risk of thromboembolism by different mechanisms not related to reactive thrombocytosis. Some patients presented after years from the onset of priapism. This may indicate the complaint of priapism is underreported especially for patients with stuttering priapism who develop erection for a shorter duration of time and subsides spontaneously. While patients with ischemic priapism have prolonged, painful erection usually seeks medical attention from the first time. This can be the reason that CML reports of priapism are relatively more common 1.9 % compared to ET because CML type is predominantly ischemic. At the same time, ET can be ischemic or stuttering. Most of these cases are reported before 2008 WHO criteria for ET, which explains why no genetic studies done for the cases. This case is the first reported case of CLAR mutation associated with priapism. In the table 6/12 had splenomegaly or splenectomy a ratio close to general ET patients. Conclusion Priapism is a rare presentation and complication of ET. It can present as ischemic or stuttering types. ET with stuttering priapism might be underreported. The main risk factors aren't clear due to old and few reported cases. Splenomegaly, age, and type of mutation appear to have little impact. But the characteristic features are the high platelet count and lower hemoglobin level. Disclosures No relevant conflicts of interest to declare.

Lifelong exposure to air pollution and greenness in relation to asthma, rhinitis and lung function in adulthood

ObjectivesTo investigate if air pollution and greenness exposure from birth till adulthood affects adult asthma, rhinitis and lung function. Methods: We analysed data from 3428 participants (mean age 28) in the RHINESSA study in Norway and Sweden. Individual mean annual residential exposures to nitrogen dioxide (NO2), particulate matter (PM10 and PM2.5), black carbon (BC), ozone (O3) and greenness (normalized difference vegetation index (NDVI)) were averaged across susceptibility windows (0–10 years, 10–18 years, lifetime, adulthood (year before study participation)) and analysed in relation to physician diagnosed asthma (ever/allergic/non-allergic), asthma attack last 12 months, current rhinitis and low lung function (lower limit of normal (LLN), z-scores of forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and FEV1/FVC below 1.64). We performed logistic regression for asthma attack, rhinitis and LLN lung function (clustered with family and study centre), and conditional logistic regression with a matched case-control design for ever/allergic/non-allergic asthma. Multivariable models were adjusted for parental asthma and education. Results: Childhood, adolescence and adult exposure to NO2, PM10 and O3 were associated with an increased risk of asthma attacks (ORs between 1.29 and 2.25), but not with physician diagnosed asthma. For rhinitis, adulthood exposures seemed to be most important. Childhood and adolescence exposures to PM2.5 and O3 were associated with lower lung function, in particular FEV1 (range ORs 2.65 to 4.21). No associations between NDVI and asthma or rhinitis were revealed, but increased NDVI was associated with lower FEV1 and FVC in all susceptibility windows (range ORs 1.39 to 1.74). Conclusions: Air pollution exposures in childhood, adolescence and adulthood were associated with increased risk of asthma attacks, rhinitis and low lung function in adulthood. Greenness was not associated with asthma or rhinitis, but was a risk factor for low lung function.

Reference Range of Chest Expansion in Healthy Adult Living in al-Muthanna Governorate

Measurement of chest expansion is one of the important steps in clinical examination of respiratory systemand this can be done by chest palpation with hands or more accurately by using of tape measure. Assessmentof chest expansion can give an important idea about different disorders in the thoracic cage or in the lungitself by detection of any limitation of chest expansion. Also it used for evaluation of progression andtreatment response of many pulmonary, neurological and rheumatological diseases. In number of famousclinical text books the lower normal limit of chest expansion is 5 cm but we suggest that the reference rangeof chest expansion is varied in different races. In this study 130 healthy non smoker volunteers living inal-Muthanna governorate, 65 females(50%) and 65 males(50%), were involved by measuring of their chestexpansion with tape measure at level of the fourth intercostal space for two times and best reading was takenfor each participant. The body weight of the participants in this study range from 52 kg to 86 kg in femalesand from 50 kg to 90 kg in males. According to this study normal range of chest expansion was(2-5 cm)(mean=3.35cm,SD=0.685) for females and (2 - 5.5cm)(mean=3.38 cm, SD=0.734) for males where the bestresult was in athletics. There is age wise reduction of chest expansion for both male and female where themean chest expansion in 18-34 years age group is 3.74 cm for female and 3.72 for male, in 35-64 years agegroup is 3.57 cm for female and 3.66 cm for male and in those of 65 years and more is 2.63 cm for femaleand 2.66 for male. So the chest expansion lower normal limit of participants in this study (as sample of Iraqipeople) is vary from other reference ranges. This can be explained by the difference of life style and geneticfactors between societies and we should not depend on same reference range for chest expansion in deferentraces.

Comparison of five major airflow limitation criteria to identify high-risk individuals with COPD: a contemporary population-based cohort

BackgroundDifferent airflow limitation criteria are often used to diagnose COPD. We investigated head-to-head whether Global Initiative for Chronic Obstructive Lung Disease (GOLD) (FEV1/FVC <0.70) and four lower limit of normal...

Correlation study between blood cytokines and lymphocytes in early postoperative critical patients with compromised immune function.

Major surgery due to traumatic injury can activate early systemic postoperative pro-inflammatory responses and postoperative immunosuppression. However, the interaction between them is complex and not entirely clear. This study was performed in postoperative patients admitted to the intensive care unit (ICU) to elucidate the correlation between the systemic cellular immunity function and circulating cytokines levels in the early postoperative period.Twenty-four cases of postoperative patients admitted to the ICU were enrolled in this study. Twelve hours after admission, blood routine examination and measurement of circulating cytokines (interleukin-2 [IL-2], IL-4, IL-6, IL-10, IL-17A, interferon-γ, tumor necrosis factor-alpha [TNF-α], TNF-β, granulocyte-colony stimulating factor [G-CSF], and granulocyte-macrophage colony-stimulating factor [GM-CSF]) were performed. The correlation analysis between cytokines levels and absolute peripheral blood lymphocyte count or lymphocytes/neutrophils ratio was analyzed.The cytokines (IL-2, IL-4, IL-6, IL-10, IL-17A, TNF-α, G-CSF, and GM-CSF) levels were increased above the normal upper limit at 12 hours after surgery. The number of leukocytes and neutrophils were markedly increased. In contrast, the absolute count and relative ratio of lymphocytes decreased below the lower normal limit. Spearman correlation analysis showed a moderate negative correlation between absolute peripheral blood lymphocyte count and IL-2 or IL-4 level. A low-negative correlation between absolute peripheral blood lymphocyte count and GM-CSF levels was detected. We also found that lymphocytes/neutrophils ratio was also negatively correlated with plasma IL-2, IL-4, or GM-CSF level.In ICU patients with compromised immune function in the early postoperative period, the elevated levels of IL-2, IL-4, and GM-CSF may be the compensatory responses to systemic immunosuppression.

The impact of reduced duffusing capacity of the lung for carbon monoxide and fev1 on outcome after cardiac surgery

Introduction Impaired lung function is a well-known risk factor in cardiac surgery patients and reduced forced expiratory volume in one second (FEV1) is associated with increased mortality. However, there is limited knowledge regarding the influence of impaired diffusing capacity of the lungs for carbon monoxide (DLCO) in cardiac surgery patients. The aim of the study was to evaluate the impact of impaired DLCO and/or reduced FEV1 on postoperative mortality and morbidity in cardiac surgery patients. Methods In a prospective cohort study, 390 patients scheduled for elective cardiac surgery underwent a preoperative extended lung function test, including spirometry and DLCO measurements. We defined reduced FEV1 as FEV1 below lower limit of normal (LLN) and impaired DLCO as haemoglobin adjusted DLCO 72 hours) in intensive care unit (ICU) was used to evaluate impact also on morbidity. Results Mortality within one year (90-570 days) was significantly higher in patients with impaired DLCO (12% vs 3%, P=0.010) and with reduced FEV1 (9% vs 3%, P=0.028). Mortality was higher in patients with impaired DLCO, both in the presence and absence of FEV1 48 hours), postoperative tracheotomy, and postoperative pneumonia (Figure 1). Discussion In patients undergoing elective cardiac surgery, preoperative impaired FEV1 and DLCO were associated with increased mortality and morbidity. In multivariate analysis, only DLCO and age were independent predictors of a combined outcome with mortality and prolonged ICU stay.

Prediction of lung function and lung density of young adults who had bronchopulmonary dysplasia.

COPD risk is jointly determined by fetal lung development, lung growth rate and lung growth duration leading to the maximally attained level of lung function in early adulthood. Bronchopulmonary dysplasia (BPD) is considered a developmental arrest of alveolarisation. Long-term outcome studies of adult survivors born before the introduction of surfactant therapy (“old BPD”) showed impaired lung function. We aimed to predict adult lung function and lung density in a cohort of premature infants born in the surfactant era, representing “new BPD”.We studied a cohort of young adults born between 1987 and 1998, with (n=36) and without (n=28) BPD, treated in a single centre. Their perinatal characteristics and pulmonary function in infancy were studied by regression analysis for correlation with adult lung function and tissue lung density, all expressed by z-scores, at a mean age of 19.7±1.1 and 21±2.2 years, respectively.Although BPD adults had on average lower forced expiratory volume in 1 s (zFEV1)/forced vital capacity (FVC) and zFEV1 than those without, 55% of the BPD group had zFEV1/FVC values above the lower limit of normal (LLN). Moreover, above LLN values of diffusing capacity of the lung for carbon monoxide (zDLCO) was present in 89% of BPD adults and lung density in 71%. Only higher oxygen supply (FIO2) at 36 weeks post-conception of BPD subjects had a trend with lower zFEV1 (B=−6.4; p=0.053) and lower zDLCO (B=−4.1; p=0.023) at adulthood.No statistically significant predictors of new BPD were identified.

Plethysmographic data and profile of North-African patients with severe obstructive sleep apnea treated with continuous positive airway pressure

ABSTRACT Objectives In obstructive sleep apnea (OSA) patients, the frequencies of the different ventilatory defects are unknown and the studies examining their plethysmographic profiles and/or pulmonary function test data have contradictory results. The main aim of this prospective study was to establish the plethysmographic profile of severe OSA patients treated with continuous positive airway pressure (CPAP). Methods 100 (33 females) clinically consecutive stable patients with severe OSA treated with CPAP were included. Anthropometric, polysomnographic, and pulmonary function test data were collected. The following definitions were applied: large airways obstructive ventilatory defect (LAOVD): (FEV1/SVC or FEV1/FVC < lower limit of normal (LLN), small airways obstructive ventilatory defect (SAOVD): (FEV1/FVC and FVC) > LLN and maximal mid-expiratory flow (MMEF) < LLN, restrictive ventilatory defect (RVD): total lung capacity (TLC) < LLN, lung-hyperinflation: residual volume > upper limit of-normal, and nonspecific ventilatory defect (NSVD): (FVC and FEV1) < LLN and TLC > LLN and (FEV1/SVC or FEV1/FVC) > LLN. Results The plethysmographic profile of OSA patients included RVD (73%), SAOVD (50%), LAOVD (16%), mixed-VD (11%), lung-hyperinflation (11%), and NSVD (2%). Conclusion The plethysmographic profile of OSA patients was dominated by the presence of an RVD.

Prevalence and Determinants of COPD in Spain: EPISCAN II

BackgroundTwo previous national epidemiological studies, IBERPOC in 1997 and EPISCAN in 2007, determined the COPD burden in Spain. Changes in demographics and exposure to risk factors demand the periodic update of COPD prevalence and its determinants. MethodsEPISCAN II aimed to estimate the prevalence of COPD in the general population aged 40 years or older in all 17 regions of Spain. A random population screening sample, requiring 600 participants per region performed a questionnaire plus post-bronchodilator (post-BD) spirometry. ResultsA total of 12,825 subjects were initially contacted, and 9433 (73.6%) agreed to participate, of whom 9092 performed a valid spirometry. Baseline characteristics were: 52.6% women, mean±SD age 60±11 years, 19.8% current- and 34.2% former-smokers. The prevalence of COPD measured by post-BD fixed ratio FEV1/FVC<0.7 was 11.8% (95% C.I. 11.2–12.5) with a high variability by region (2.4-fold). Prevalence was 14.6% (95% C.I. 13.5–15.7) in males and 9.4% (95% C.I. 8.6–10.2) in females; according to the lower limit of normal (LLN) was 6.0% (95% C.I. 5.5–6.5) overall, by sex being 7.1% (95% C.I. 6.4–8.0) in males and 4.9% (95% C.I. 4.3–5.6) in females. Underdiagnosis of COPD was 74.7%. Cases with COPD were a mean of seven years older, more frequently male, of lower attained education, and with more smokers than the non-COPD population (p<0.001). However, the number of cigarettes and pack-years in non-COPD participants was substantial, as it was the reported use of e-cigarettes (7.0% vs. 5.5%) (p=0.045). There were also significant social and clinical differences including living alone, previous respiratory diagnoses, more comorbidities measured with the Charlson index, greater BODE and COTE scores, cognitive impairment, and depression (all p<0.001). ConclusionsCOPD remains prevalent in Spain and frequently underdiagnosed.

Prevalence and Characteristics of Undiagnosed COPD in Adults 40 Years and Older – Reports from the Tunisian Population-Based Burden of Obstructive Lung Disease Study

This study aimed to investigate the underdiagnosis of COPD and its determinants based on the Tunisian Burden of Obstructive Lung Disease study. We collected information on respiratory history symptoms and risk factors for COPD. Post-bronchodilator (Post-BD) FEV1/FVC < the lower limit of normal (LLN) was used to define COPD. Undiagnosed COPD was considered when participants had post-BD FEV1/FVC < LLN but were not given a diagnosis of emphysema, chronic bronchitis or COPD. 730 adults aged ⩾40 years selected from the general population were interviewed, 661 completed spirometry, 35 (5.3%) had COPD and 28 (80%) were undiagnosed with the highest prevalence in women (100%). When compared with patients with an established COPD diagnosis, undiagnosed subjects had a lower education level, milder airway obstruction (Post-BD FEV1 z-score −2.2 vs. −3.7, p < 0.001), fewer occurrence of wheezing (42.9% vs. 100%, p = 0.009), less previous lung function test (3.6% vs. 42.8%, p = 0.019) and less visits to the physician (32.1% vs. 85.7%, p = 0.020) in the past year. Multivaried analysis showed that the probability of COPD underdiagnosis was higher in subjects who had mild to moderate COPD and in those who did not visit a clinician and did not perform a spirometry in the last year. Collectively, our results highlight the need to improve the diagnosis of COPD in Tunisia. Wider use of spirometry should reduce the incidence of undiagnosed COPD. Spirometry should also predominately be performed not only in elderly male smokers but also in younger women in whom the prevalence of underdiagnosis is the highest.

Characterization and Association of Marker Chromosomes with Male Infertility

Background and objective A small supernumerary marker chromosome (sSMC) is a rare structurally abnormal chromosome in which no part can be identified by conventional cytogenetic banding technique. There is little known about the association of marker chromosomes with male infertility. We performed a molecular cyto-genetic characterization sSMCs and investigated their association with male infertility. Methods Among 4230 infertile male patients who underwent cytogenetic analyses from January 2008 to December 2018, the records of 15 patients who were diagnosed with sSMCs were reviewed. After ini-tial infertility evaluation, the patients received additional genetic tests including G-bands by trypsin using Giemsa (GTG-banding), Nucleolar organizer region (NOR) banding, Fluorescence in situ hybridization (FISH), and array comparative genomic hybridization (aCGH) analyses to further char-acterize and identify the origin of their marker chromosome. Testis biopsy was performed for the azoospermic patients to evaluate spermatogenic status. Results Among 15 infertile males with sSMCs, eight had nonobstructive azoospermia, five had severe oligozo-ospermia, and two had sperm concentrations above the lower normal limit. The marker chromosomes were identified as Y ring chromosomes (n&nbsp;=&nbsp;8), an isodicentric Y chromosome (n&nbsp;=&nbsp;1), a neocen-tromere Y chromosome (n = 1), a derivative chromosome 1 (n = 1), and an acrocentric short arms (n = 4).&nbsp; Conclusion Marker chromosomes appear to be a rare genetic cause of male infertility. Additional cytogenetic tests, including NOR banding, FISH, and aCGH, could help to characterize the origin of the marker chromosome. Appropriate genetic counseling for couples with infertility caused by a marker chromo-some should be recommended.&nbsp;

Higher neutrophil-to-lymphocyte ratio (NLR) increases the risk of suboptimal platelet inhibition and major cardiovascular ischemic events among ACS patients receiving dual antiplatelet therapy with ticagrelor

BackgroundNeutrophil to lymphocyte ratio (NLR) has emerged as a useful and easy-to-assess prognostic tool and biomarker of cardiovascular risk. However, few studies have evaluated its role on platelet inhibition among patients on dual antiplatelet therapy (DAPT), and especially in the settings of acute coronary syndromes (ACS). We aimed at assessing the impact of NLR on platelet reactivity and the risk of major ischemic events at long-term follow-up among ACS patients on DAPT with ticagrelor. MethodsPatients on dual antiplatelet therapy with ASA + ticagrelor (90 mg/twice a day) after percutaneous coronary revascularization for ACS were scheduled for platelet function assessment 30–90 days post-discharge. Aggregation tests were performed by Multiple Electrode Aggregometry (MEA). Suboptimal platelet inhibition (HRPR-high residual platelet reactivity was defined if above the lower limit of normality (417 AU*min). The primary study endpoint was defined as the occurrence of major cardiovascular events (a composite of cardiovascular death, recurrent acute coronary syndrome, target vessel revascularization) at longest available follow-up. ResultsWe included 397 patients, that were divided according to NLR tertiles. Patients with higher NLR were older (p < .001), less frequently smokers (p = .03), with higher rates of renal failure (p = .001), previous bypass surgery (p = .05) and use of statins (p = .03) and diuretics (p = .01). Higher white blood cells count and C-reactive protein (p < .001) and lower haemoglobin (p = .001) were associated with NLR. Mean platelet reactivity and the prevalence of high platelet reactivity (HRPR) on ticagrelor were significantly associated to higher NLR tertiles values (7% vs 12% vs 14.3%, p = .04), with a significant relationship between NLR and platelet reactivity being confirmed for all the different activating stimuli.At a mean follow-up of 939 ± 581.4 days, 21.2% of the patients experienced the primary composite endpoint, with a trend for a higher risk of events across NLR tertiles (15.4% vs 24.2% vs 24.4%, p = .09), that became statistically significant after correction for baseline confounders (adjusted HR[95%CI] = 1.13[1.008–1.26], p = .036). Moreover, NLR was significantly associated to overall mortality and recurrent ACS (adjusted p = .008, p = .06 and p = .02 respectively). ConclusionsIn the present study we found that among ACS patients treated with ASA and ticagrelor after PCI, suboptimal platelet inhibition despite DAPT was significantly increased for higher values of Neutrophil-to-Lymphocyte Ratio. Moreover, mortality and the risk of recurrent major ischemic events at long-term were associated to NLR.

Functional impact of sequelae in drug-susceptible and multidrug-resistant tuberculosis

BACKGROUND: Evidence on the impact of tuberculosis (TB) treatment on lung function is scarce. The aim of this study was to evaluate post-treatment sequelae in drug-susceptible and drug-resistant-TB (DR-TB) cases in Mexico and Italy.METHODS: At the end of TB treatment the patients underwent complete clinical assessment, functional evaluation of respiratory mechanics, gas exchange and a 6-minute walking test. Treatment regimens (and definitions) recommended by the World Health Organization were used throughout.RESULTS: Of 61 patients, 65.6% had functional impairment, with obstruction in 24/61 patients (39.4%), and 78% with no bronchodilator response. These effects were more prevalent among DR-TB cases (forced expiratory volume in 1 s/forced vital capacity [FEV1/FVC] < lower limit of normality, 14/24 vs. 10/34; P = 0.075). DR-TB patients showed moderately severe (FEV1 < 60%) and severe obstruction (FEV1 < 50%) (P = 0.008). Pre- and post-bronchodilator FEV1 and FEV1/FVC (% of predicted) were significantly lower among DR-TB cases. Plethysmography abnormalities (restriction, hyperinflation and/or air trapping) were more frequent among DR-TB cases (P = 0.001), along with abnormal carbon monoxide diffusing capacity (DLCO) (P = 0.003).CONCLUSION: The majority of TB patients suffer the consequences of post-treatment sequelae (of differing levels), which compromise quality of life, exercise tolerance and long-term prognosis. It is therefore important that lung function is comprehensively evaluated post-treatment to identify patient needs for future medication and pulmonary rehabilitation.

Fixed Ratio versus Lower Limit of Normality for Diagnosing COPD in Primary Care: Long-Term Follow-Up of EGARPOC Study.

PurposeThe best criterion for diagnosing airway obstruction in COPD, fixed ratio (FR: FEV1/FVC<0.7) or lower limit of normality (LLN), remains controversial. We compared the long-term evolution of COPD patients according to the initial obstruction criteria.Patients and MethodsBetween 2005 and 2008, we evaluated 1728 subjects over 45 years of age with smoking history, pertaining to a primary care center. A total of 424 patients were obstructive by FR, after a bronchodilator test. Of those, 289 patients met obstruction criteria for both FR and LLN and were considered concordant patients (FR+LLN+), while 135 patients were obstructive by FR but non-obstructive by LLN and were defined as discordant patients (FR+LLN-).ResultsForty-eight patients (11.3%) were lost in follow-up, and 158 died (37.3%). After a median time of 120.4 months (IQR 25–75%: 110.2–128.8), 215 patients were spirometrically reevaluated. The annualized loss of FEV1/FVC was greater in discordant (FR+LLN-) patients [0.54 (0.8) vs 0.82 (0.7); p = 0.008], while 81% became concordant (FR+LLN+) during the follow-up. Hospitalization for COPD exacerbations was more frequent in concordant (FR+LLN+) patients (1.57±3.51 vs 0.77±2.29; p = 0.002). Adjusting for age, concordant (FR+LLN+) patients had greater COPD mortality (HR: 2.97; CI 95%: 1.27–7.3; p = 0.02).ConclusionLLN seems to be less useful for COPD diagnosis in primary care. Discordant (FR+LLN-) patients lost more FEV1/FVC during their evolution and tended to become concordant. LLN predicted COPD hospitalizations and mortality more poorly.

Diffusing capacity in normal-for-age spirometry and spirometric impairments, using reference equations from the global lung function initiative.

Reference equations from the Global Lung Function Initiative (GLI) are now available for both spirometry and diffusion. However, respiratory phenotypes defined by GLI-based measures of diffusion have not yet been evaluated in GLI-based normal-for-age spirometry or spirometric impairments. We evaluated cross-sectional data from 2100 Caucasians, aged 40-85 years. GLI-based spirometric categories included normal-for-age and the impairments of restrictive-pattern and three-level severity of airflow-obstruction (mild, moderate, severe). GLI-based diffusion included diffusing capacity of the lung for carbon monoxide (DLCO) and measured components of alveolar volume (VA) and transfer coefficient (KCO): DLCO=[VA]x[KCO]. Using multivariable regression models, adjusted odds ratios (adjORs) for DLCO, VA, and KCO<lower limit of normal (LLN) were calculated for spirometric impairments, relative to normal-for-age spirometry. Relative to normal-for-age spirometry, the restrictive-pattern increased the adjORs (95% confidence intervals) for DLCO and VA<LLN-4.61 (3.62, 5.85) and 15.53 (11.8, 20.4), respectively, but not for KCO<LLN-1.02 (0.79, 1.33). Also relative to normal-for-age spirometry, airflow-obstruction from mild to severe increased the adjORs for DLCO<LLN-from 1.22 (0.80, 1.86) to 6.63 (4.91, 8.95), for VA<LLN-from 1.37 (0.85, 2.18) to 7.01 (5.20, 9.43), and for KCO<LLN-from 2.04 (1.33, 3.14) to 3.03 (2.29, 3.99). Notably, in normal-for-age spirometry, 34.5%, 19.7%, and 25.3% of participants had DLCO, VA, or KCO<LLN, respectively. Abnormal diffusion is most prevalent in spirometric impairments but also occurs in normal-for-age spirometry. These results further inform the respiratory phenotypes of GLI-based spirometric categories and, in turn, the spirometric evaluation of respiratory disease.

Obesity-hypoventilation Syndrome: Baseline Hemodynamic Status and Impact of Non-invasive Ventilation

IntroductionObesity-hypoventilation syndrome (OHS) is a risk factor for heart failure (HF). Some studies associate the use of non-invasive ventilation (NIV) with changes in hemodynamic parameters. Our objective was to describe the hemodynamic status of a group of patients with OHS and to study the effect of NIV. Patients and methodsPatients with stable OHS treated with NIV were included in this cross-sectional repeated measurements study. Hemodynamics were measured by bioimpedance: 30min at baseline and another 30min on NIV. Cardiac output (CO), cardiac index, and systolic volume were measured. The CO calculated for each patient expressed as a percentage of the lower limit of normal (LLN) was taken as reference, and 2 groups were formed: patients without HF and normal CO (≥100% of LLN) and patients with HF and low CO (<100% of LLN). The Mann–Whitney U test was used to compare independent variables and the Wilcoxon test was used for paired variables, with significance set at P<.05. ResultsThe final sample comprised 36 patients, aged 66 (±8) years, 19 (52%) men. In 17 (46%) patients, HF was detected with a CO of 3.7l/min (66%) compared to the group without HF, whose CO was 7l/min (107%). After NIV, patients with HF showed improvement in CO 4.5l/min (77%), P=.009, while the non-HF group remained unchanged, with CO 6.8l/min (104%), P=.2. ConclusionA total of 46% of patients with stable OHS present HF; NIV improves hemodynamics and does not affect patients with normal CO.

MON-361 Late Diagnosis in Adult Form of Hypophosphatasia

INTRODUCTION/BACKGROUND:Hypophosphatasia is a rare inborn error of metabolism that presents with important foot and thigh pain due to stress fractures. The diagnose of the adult form is routinely neglected, even though it presents symptomatic and with persistent low serum alkaline phosphatase (ALP).CLINICAL CASE (DIAGNOSTIC EVALUATION, TRATMANET AND FUP):A 43-year-old amateur athlete woman presented with pain in the right femur without any local trauma. Physical examination evidenced prolonged right tight pain and no other findings. Bone mineral density evaluated by dual-energy x-ray absorptiometry was unremarkable. Biochemical investigations showed normal inorganic phosphate, calcium, zinc, and magnesium, but low ALP. The patient had six previous ALP measurements and all of them were below the lower limit of normality (46 a 116 U/L). These measurements were done in regular ob-gyn checkups with no further investigation or follow-up. In light of the hypophosphatasemia and pathologic fracture, the serum pyridoxal 5’-phosphate concentration was measured and found to be elevated 35,8 mcg/L (normal 5,0 a 30,0 mcg/L).CLINICAL LESSONS/CONCLUSION:Hypophosphatasia occurs due to a deactivating mutation (or mutations) of the gene encoding Tissue-Nonspecific Alkaline Phosphatase (TNSALP), leading to a global deficiency of TNSALP activity and inadequate skeletal mineralization and fractures. The adult form presents during middle age with stress fractures. The first complaints maybe foot pain, which is due to stress fractures of the metatarsals, and thigh pain, due to pseudo fractures of the femur. Our patient illustrates the importance of low serum ALP activity in the assessment of these patients. The correct diagnosis should help to avoid the use of traditional therapies for osteoporosis or osteomalacia, which would be ineffective or potentially harmful.

Development of chronic lung impairment in Mozambican TB patients and associated risks

BackgroundPulmonary tuberculosis (PTB) is frequently associated with chronic respiratory impairment despite microbiological cure. There are only a few clinical research studies that describe the course, type and severity as well as associated risk factors for lung impairment (LI) in TB patients.MethodsA prospective cohort study was conducted at TB Research Clinic of Instituto Nacional de Saúde in Mavalane, Maputo, from June 2014 to June 2016. PTB patients were prospectively enrolled and followed for 52 weeks after TB diagnosis. Lung function was evaluated by spirometry at 8, 26 and 52 weeks after TB treatment initiation, and spirometric values of below the lower limit of normality were considered as LI. Descriptive statistical analysis was performed to summarize the proportion of patients with different lung outcomes at week 52, including type and severity of LI. Risk factors were analysed using multinomial regression analysis.ResultsA total of 69 PTB patients were enrolled, of which 62 had a valid spirometry result at week 52 after TB treatment start. At week 8, 26 and 52, the proportion of patients with LI was 78, 68.9 and 64.5%, respectively, and 35.5% had moderate or severe LI at week 52. The majority of patients with LI suffered from pulmonary restriction. Female sex, low haemoglobin and heavy smoking were significantly associated with LI.ConclusionModerate or severe LI can be observed in a third of cured TB patients. Further research is urgently needed to gain deeper insight into the characteristics of post TB LI, the causal pathways and potential treatment strategies.