Association between gait speed deterioration and EEG abnormalities.

Physical and cognitive decline at an older age is preceded by changes that accumulate over time until they become clinically evident difficulties. These changes, frequently overlooked by patients and health professionals, may respond better than fully established conditions to strategies designed to prevent disabilities and dependence in later life. The objective of this study was twofold; to provide further support for the need to screen for early functional changes in older adults and to look for an early association between decline in mobility and cognition. A cross-sectional cohort study was conducted on 95 active functionally independent community-dwelling older adults in Havana, Cuba. We measured their gait speed at the usual pace and the cognitive status using the MMSE. A value of 0.8 m/s was used as the cut-off point to decide whether they presented a decline in gait speed. A quantitative analysis of their EEG at rest was also performed to look for an associated subclinical decline in brain function. Results show that 70% of the sample had a gait speed deterioration (i.e., lower than 0.8 m/s), of which 80% also had an abnormal EEG frequency composition for their age. While there was no statistically significant difference in the MMSE score between participants with a gait speed above and below the selected cut-off, individuals with MMSE scores below 25 also had a gait speed<0.8 m/s and an abnormal EEG frequency composition. Our results provide further evidence of early decline in older adults-even if still independent and active-and point to the need for clinical pathways that incorporate screening and early intervention targeted at early deterioration to prolong the years of functional life in older age.

Type I interferon regulation by USP18 is a key vulnerability in cancer.

Precise regulation of Type I interferon signaling is crucial for combating infection and cancer while avoiding autoimmunity. Type I interferon signaling is negatively regulated by USP18. USP18 cleaves ISG15, an interferon-induced ubiquitin-like modification, via its canonical catalytic function, and inhibits Type I interferon receptor activity through its scaffold role. USP18 loss-of-function dramatically impacts immune regulation, pathogen susceptibility, and tumor growth. However, prior studies have reached conflicting conclusions regarding the relative importance of catalytic versus scaffold function. Here, we develop biochemical and cellular methods to systematically define the physiological role of USP18. By comparing a patient-derived mutation impairing scaffold function (I60N) to a mutation disrupting catalytic activity (C64S), we demonstrate that scaffold function is critical for cancer cell vulnerability to Type I interferon. Surprisingly, we discovered that human USP18 exhibits minimal catalytic activity, in stark contrast to mouse USP18. These findings resolve human USP18's mechanism-of-action and enable USP18-targeted therapeutics.

Prognostic Utility of Society for Cardiovascular Angiography and Interventions Shock Stage Approach for Classifying Cardiogenic Shock Severity in Takotsubo Syndrome.

BACKGROUND: Cardiogenic shock (CS) is a significant complication of Takotsubo syndrome (TTS), contributing to heightened mortality and morbidity. Despite this, the Society for Cardiovascular Angiography and Interventions (SCAI) staging system for CS severity lacks validation in patients with TTS and CS. This study aimed to characterize a patient cohort with TTS using the SCAI staging system and assess its utility in cases of TTS complicated by CS. METHODS AND RESULTS: From a TTS national registry, 1591 consecutive patients were initially enrolled and stratified into 5 SCAI stages (A through E). Primary outcome was all-cause in-hospital mortality; secondary end points were TTS-related in-hospital complications and 1-year all-cause mortality. After exclusions, the final cohort comprised 1163 patients, mean age 71.0±11.8 years, and 87% were female. Patients were categorized across SCAI shock stages as follows: A 72.1%, B 12.2%, C 11.2%, D 2.7%, and E 1.8%. Significant variations in baseline demographics, comorbidities, clinical presentations, and in-hospital courses were observed across SCAI shock stages. After multivariable adjustment, each higher SCAI shock stage showed a significant association with increased in-hospital mortality (adjusted odds ratio: 1.77-29.31) compared with SCAI shock stage A. Higher SCAI shock stages were also associated with increased 1-year mortality. CONCLUSIONS: In a large multicenter patient cohort with TTS, the functional SCAI shock stage classification effectively stratified mortality risk, revealing a continuum of escalating shock severity with higher stages correlating with increased in-hospital mortality. This study highlights the applicability and prognostic value of the SCAI staging system in TTS-related CS.

Renal impairment and outcome in Takotsubo syndrome: Insights from a national multicentric cohort.

INTRODUCTION: Data on the association between kidney function and Takotsubo syndrome (TTS) outcomes are scarce and conflictive. OBJECTIVE: To assess the impact of chronic kidney disease (CKD) and acute renal failure (ARF) in patients with TTS. MATERIAL AND METHODS: Patients from the prospective nation-wide (RETAKO) registry were included and divided into quartiles of maximum creatinine (Cr) level during hospitalization. RESULTS: The prevalence of CKD and ARF in the whole RETAKO cohort was 5.4% and 11.7%, respectively. Compared to Q1 (Cr <0.71), patients within Q4 (Cr > 1.1) had lower left ventricular ejection fraction on admission (38.5 ± 12 vs 43.3 ± 11.3, p = 0.002) and higher bleeding rates during hospitalization (6.7% vs 2%, p = 0.005). In addition, compared to Q1, Q4 patients have a greater incidence of cardiogenic shock (17.3% vs 5.6%, p < 0.001), and a higher rate of 5-year all-cause death and major adverse cardiovascular events (31.5% vs 15.8%, p < 0.001 and 22.5% vs 9.3%, p < 0.001, respectively). CONCLUSIONS: TTS patients with CKD have a higher incidence of ARF and exhibit greater Cr on admission, which were linked with higher rates of cardiogenic shock, bleeding during hospitalization as well as major adverse cardiovascular events and all-cause death during a 5-year follow-up.

Chemical tools for the Gid4 subunit of the human E3 ligase C-terminal to LisH (CTLH) degradation complex.

We have developed a novel chemical handle (PFI-E3H1) and a chemical probe (PFI-7) as ligands for the Gid4 subunit of the human E3 ligase CTLH degradation complex. Through an efficient initial hit-ID campaign, structure-based drug design (SBDD) and leveraging the sizeable Pfizer compound library, we identified a 500 nM ligand for this E3 ligase through file screening alone. Further exploration identified a vector that is tolerant to addition of a linker for future chimeric molecule design. The chemotype was subsequently optimized to sub-100 nM Gid4 binding affinity for a chemical probe. These novel tools, alongside the suitable negative control also identified, should enable the interrogation of this complex human E3 ligase macromolecular assembly.

Peripartum Takotsubo Cardiomyopathy: A Review and Insights from a National Registry.

Takotsubo syndrome (TTS) during the peripartum period is a relevant cause of morbidity in this population; its clinical course and prognosis, compared to the general TTS population, is yet to be elucidated. Our aim was to analyze the clinical features and prognosis of peripartum TTS in a nationwide prospective specifically oriented registry database and consider the published literature. Peripartum TTS patients from the prospective nationwide RETAKO registry-as well as peripartum TTS patients from the published literature-were included, and multiple comparisons between groups were performed in order to assess for statistically and clinically relevant prognostic differences between the groups. Patients with peripartum TTS exhibit a higher prevalence of secondary forms, dyspnea, atypical symptoms, and echocardiographic patterns, as well as less ST-segment elevation than the general TTS population. In the literature, patients with peripartum TTS had a higher Killip status on admission. TTS during the peripartum period has a higher prevalence of angina and dyspnea, as well as physical triggers, neither of which are related to a worse prognosis. Killip status on admission was higher in the literature for patients with TTS but with excellent mid- and long-term prognoses after the acute phase, despite mostly being secondary forms.

A protein kinase C α and ß inhibitor blunts hyperphagia to halt renal function decline and reduces adiposity in a rat model of obesity-driven type 2 diabetes.

Type 2 diabetes (T2D) and its complications can have debilitating, sometimes fatal consequences for afflicted individuals. The disease can be difficult to control, and therapeutic strategies to prevent T2D-induced tissue and organ damage are needed. Here we describe the results of administering a potent and selective inhibitor of Protein Kinase C (PKC) family members PKCα and PKCß, Cmpd 1, in the ZSF1 obese rat model of hyperphagia-induced, obesity-driven T2D. Although our initial intent was to evaluate the effect of PKCα/ß inhibition on renal damage in this model setting, Cmpd 1 unexpectedly caused a marked reduction in the hyperphagic response of ZSF1 obese animals. This halted renal function decline but did so indirectly and indistinguishably from a pair feeding comparator group. However, above and beyond this food intake effect, Cmpd 1 lowered overall animal body weights, reduced liver vacuolation, and reduced inguinal adipose tissue (iWAT) mass, inflammation, and adipocyte size. Taken together, Cmpd 1 had strong effects on multiple disease parameters in this obesity-driven rodent model of T2D. Further evaluation for potential translation of PKCα/ß inhibition to T2D and obesity in humans is warranted.

Trastornos del ritmo cardiaco en pacientes con síndrome de Tako-tsubo / Heart rate disorders in patients with Tako-tsubo syndrome

Objetivos El presente estudio pretende evaluar la incidencia, el pronóstico y el tratamiento de los trastornos del ritmo (TdR) en el síndrome de Tako-tsubo (STT). Antecedentes El STT se asocia frecuentemente a TdR. El valor pronóstico de estos TdR aún no está bien caracterizado en el STT. Material y métodos Se analizaron los TdR de los pacientes incluidos en el REgistro nacional multicéntrico sobre síndrome de Tako-tsubo, ingresados entre 2002 y 2018, aportados por 38 hospitales de todo el país. Analizamos en los pacientes TdR previos, en el ingreso y en el seguimiento a largo plazo. Resultados Se describió cualquier tipo de TdR en 259 (23,5%) casos, de una cohorte de 1.097 pacientes consecutivos con STT. Los TdR se presentan más en pacientes con diabetes mellitus, tabaquismo, hiperuricemia, apnea del sueño y anemia, además de con una fracción de eyección del ventrículo izquierdo (FEVI) menor al ingreso. El TdR más frecuente fue el inicio de fibrilación auricular. Durante el ingreso hospitalario, los pacientes con TdR mostraron más complicaciones, como shock al ingreso, hemorragia mayor, insuficiencia renal aguda y el combinado de infecciones. En el seguimiento, presentaron mayor mortalidad y numéricamente más episodios adversos combinados. Conclusiones Los TdR no son infrecuentes en fase aguda del STT. El STT asociado a TdR se presenta con más complicaciones y peor pronóstico tanto hospitalario como a largo plazo (AU)

Objectives This study sought to evaluate the incidence, prognosis and treatment of heart rhythm disorders (HRD) in Tako-tsubo syndrome (TTS). Background TTS is associated with HRD. The HRD prognostic value is not well characterized in TTS yet. Methods The HRD of patients included in the National Registry of Tako-tsubo syndrome, admitted between 2002 and 2018 and coming from 38 hospitals throughout the country, was analyzed. We analyzed any heart rhythm disorder in patients presented before admission, at admission and in long-term follow-up. Results All types of HRD were described in 259 (23.5%) cases, from a cohort of 1,097 consecutive patients with TTS. HRD was more associated with diabetes mellitus, smoking, hyperuricemia, sleep apnea, anemia with a worse LVEF on admission. The most frequent HRD was a new onset of atrial fibrillation. During hospitalization, patients with HRD showed more complications such as shock on admission, major bleeding, acute renal failure, and combined infections. At follow-up, they presented higher mortality and more major adverse cardiac events, but with a non-significant correlation. Conclusions The incidence of HRD in patients with TTS is not infrequent. TTS, when associated with HRD, presents more complications and a worse prognosis both in hospital and in the long term (AU)

Predictors of the response to phosphodiesterase-5 inhibitors in pulmonary arterial hypertension: an analysis of the Spanish registry.

BACKGROUND: Achieving and maintaining a low-risk profile is associated with favorable outcome in pulmonary arterial hypertension (PAH). The effects of treatment on risk profile are variable among patients. OBJECTIVE: To Identify variables that might predict the response to treatment with phosphodiesterase-5 inhibitors (PDE-5i) in PAH. METHODS: We carried out a cohort analysis of the Spanish PAH registry in 830 patients diagnosed with PAH that started PDE5i treatment and had > 1 year follow-up. 644 patients started PDE-5i either in mono- or add-on therapy and 186 started combined treatment with PDE-5i and endothelin receptor antagonist (ERA). Responders were considered when at 1 year they: (1) were alive; (2) did not present clinical worsening; and (3) improved European Society of Cardiology/European Respiratory Society (ESC/ERS) risk score or remained in low-risk. Univariate and multivariate logistic regression models were used to analyze variables associated with a favorable response. RESULTS: Two hundred and ten patients (33%) starting PDE-5i alone were classified as responders, irrespective of whether it was mono- or add-on therapy. In addition to known predictors of PAH outcome (low-risk at baseline, younger age), male sex and diagnosis of portopulmonary hypertension (PoPH) or HIV-PAH were independent predictors of favorable response to PDE-5i. Diffusing capacity for carbon monoxide (DLco) ≤ 40% of predicted was associated with an unfavorable response. When PDE-5i were used in upfront combination, 58% of patients were responders. In this group, diagnosis of idiopathic PAH (IPAH) was an independent predictor of favorable response, whereas connective tissue disease-PAH was associated with an unfavorable response. CONCLUSION: Male sex and diagnosis of PoPH or HIV-PAH are predictors of favorable effect of PDE-5i on risk profile when used as mono- or add-on therapy. Patients with IPAH respond more favorably to PDE-5i when used in upfront combination. These results identify patient profiles that may respond favorably to PDE-5i in monotherapy and those who might benefit from alternative treatment strategies.

Relationship between gait parameters and cognitive indexes in adult aging.

PURPOSE: This study aimed to identify the most effective summary cognitive index predicted from spatio-temporal gait features (STGF) extracted from gait patterns. METHODS: The study involved 125 participants, including 40 young (mean age: 27.65 years, 50% women), and 85 older adults (mean age: 73.25 years, 62.35% women). The group of older adults included both healthy adults and those with Mild Cognitive Impairment (MCI). Participant´s performance in various cognitive domains was evaluated using 12 cognitive measures from five neuropsychological tests. Four summary cognitive indexes were calculated for each case: 1) the z-score of Mini-Mental State Examination (MMSE) from a population norm (MMSE z-score); 2) the sum of the absolute z-scores of the patients' neuropsychological measures from a population norm (ZSum); 3) the first principal component scores obtained from the individual cognitive variables z-scores (PCCog); and 4) the Mahalanobis distance between the vector that represents the subject's cognitive state (defined by the 12 cognitive variables) and the vector corresponding to a population norm (MDCog). The gait patterns were recorded using a body-fixed Inertial Measurement Unit while participants executed four walking tasks (normal, fast, easy- and hard-dual tasks). Sixteen STGF for each walking task, and the dual-task costs for the dual tasks (when a subject performs an attention-demanding task and walks at the same time) were computed. After applied Principal Component Analysis to gait measures (96 features), a robust regression was used to predict each cognitive index and individual cognitive variable. The adjusted proportion of variance (adjusted-R2) coefficients were reported, and confidence intervals were estimated using the bootstrap procedure. RESULTS: The mean values of adjusted-R2 for the summary cognitive indexes were as follows: 0.0248 for MMSE z-score, 0.0080 for ZSum, 0.0033 for PCCog, and 0.4445 for MDCog. The mean adjusted-R2 values for the z-scores of individual cognitive variables ranged between 0.0009 and 0.0693. Multiple linear regression was only statistically significant for MDCog, with the highest estimated adjusted-R2 value. CONCLUSIONS: The association between individual cognitive variables and most of the summary cognitive indexes with gait parameters was weak. However, the MDCog index showed a stronger and significant association with the STGF, exhibiting the highest value of the proportion of the variance that can be explained by the predictor variables. These findings suggest that the MDCog index may be a useful tool in studying the relationship between gait patterns and cognition.

[Highlights 56th SEPAR Congress]. / Highlights del 56° Congreso SEPAR.

The Spanish Society of Pneumology and Thoracic Surgery (SEPAR) has held its 56th congress in Granada from 8 to 10 June 2023. The SEPAR congress has established itself as the leading scientific meeting for specialists in medicine and respiratory care, reaching a record of participation this year with 2600 attendees. Our society thus demonstrates its leadership in the management of respiratory diseases, as well as its growth and progress in order to achieve excellence. In this review, we offer a summary of some notable issues addressed in six selected areas of interest: chronic obstructive pulmonary disease (COPD), asthma, interstitial lung diseases (ILDs), tuberculosis and respiratory infections, pulmonary circulation, and respiratory nursing.

Awake Prone Decubitus Positioning in COVID-19 Patients: A Systematic Review and MetaAnalysis.

To date, recommendations for the implementation of awake prone positioning in patients with hypoxia secondary to SARSCoV2 infection have been extrapolated from prior studies on respiratory distress. Thus, we carried out a systematic review and metaanalysis to evaluate the benefits of pronation on the oxygenation, need for endotracheal intubation (ETI), and mortality of this group of patients. We carried out a systematic search in the PubMed and Embase databases between June 2020 and November 2021. A randomeffects metaanalysis was performed to evaluate the impact of pronation on the ETI and mortality rates. A total of 213 articles were identified, 15 of which were finally included in this review. A significant decrease in the mortality rate was observed in the group of pronated patients (relative risk [RR] = 0.69; 95% confidence interval [CI]: 0.480.99; p = 0.044), but no significant effect was observed on the need for ETI (RR = 0.79; 95% CI: 0.631.00; p = 0.051). However, a subgroup analysis of randomized clinical trials (RCTs) did reveal a significant decrease in the need for this intervention (RR = 0.83; 95% CI: 0.710.97). Prone positioning was found to significantly reduce mortality, also diminishing the need for ETI, although this effect was statistically significant only in the subgroup analysis of RCTs. Patients' response to awake prone positioning could be greater when this procedure is implemented early and in combination with noninvasive mechanical ventilation (NIMV) or highflow nasal cannula (HFNC) therapy.

Takotsubo Syndrome, Stressful Triggers, and Risk of Recurrence.

The risk of recurrence in takotsubo syndrome (TTS) appears to be low, although previous studies have shown conflicting results and factors associated with recurrences are unclear. The aim of this study is to evaluate the incidence and predictors of TTS recurrences. Adult patients included in the Spanish Multicenter REgistry of TAKOtsubo syndrome (RETAKO) between January 2003 and September 2019 were identified. Patients were categorized based on recurrences during follow-up and a multivariate logistic regression model was used to identify factors associated with recurrences. A total of 1097 patients (mean age 71.0±11.9 years, 87% females) were included, repeated TTS events were documented in 44 patients (4.0%), including 13 patients with prior TTS and 31 patients with recurrent TTS during a median follow-up of 279 days. Two patients (0.02%) had two episodes of recurrence. Compared to patients who had no recurrence of TTS, those with recurrent TTS more frequently had no identifiable stressful trigger in the index admission (20 [64.5%] vs 352 [33.0%], p <0.001). Primary TTS, defined as TTS without physical trigger, was also more common in the recurrence group (93.5% vs 68.3%, p <0.001). The only factor independently associated with recurrences was the absence of an identifiable trigger (odds ratio 3.7 [95% confidence interval 1.8-7.8], p=0.001). In conclusion, our data indicate that for patients presenting with TTS, the rate of early recurrent TTS is approximately 4% per year. Among TTS patients, those who have no identifiable trigger events appear to have a higher rate of recurrence.

Fisioterapia respiratoria en sujetos adultos cursando internación por neumonía adquirida en la comunidad. Revisión bibliográfica / Respiratory physiotherapy in adult subjects hospitalized for community-acquired pneumonia. Literature review

Introducción: La neumonía adquirida en la comunidad (NAC) es una infección respiratoria en la cual es frecuente observar la indicación de fisioterapia respiratoria (FR). Sin embargo, en la actualidad las recomendaciones respecto a su uso en NAC son controvertidas, no existiendo evidencia que respalde su uso y permita conocer su real alcance. Objetivos: Revisar la evidencia respecto al impacto de la FR en pacientes adultos que cursan internación por NAC. Resultados: 5 estudios cumplieron los criterios de inclusión de esta revisión. Las maniobras de FR incluyeron ejercicios respiratorios, drenaje postural, percusión, vibración, espirometría incentivada, resistencia espiratoria, asistencia torácica durante movimientos respiratorios, tos dirigida y presión positiva intermitente. En los estudios incluidos la FR no disminuyó la mortalidad ni mejoró los valores espirométricos en los pacientes con NAC, así como tampoco los días hasta la curación ni la estadía hospitalaria. Respecto a los costos, el uso de FR en pacientes con NAC presentó un incremento significativo de los mismos. Conclusión: No hay evidencia que respalde el uso de manera rutinaria de FR en los pacientes adultos con NAC. Consideramos que se requieren de futuras investigaciones que permitan conocer el impacto de la FR en pacientes adultos con NAC, así como establecer consensos respecto a su indicación, selección de maniobras, estandarización de técnicas, tiempos y dosificación.

Introduction: Community-acquired pneumonia (CAP) is a respiratory infection in which the indication for respiratory physiotherapy (RF) is frequently observed. However, currently the recommendations regarding its use in CAP are controversial, and there is no evidence to support its use and allow us to know its real scope. Objectives: To review the evidence regarding the impact of RF in adult patients who are hospitalized for CAP. Results: 5 studies met the inclusion criteria of this review. RF maneuvers included breathing exercises, postural drainage, percussion, vibration, incentive spirometry, expiratory resistance, chest support during respiratory movements, directed cough, and intermittent positive pressure. In the included studies, RF did not reduce mortality or improve spirometric values in patients with CAP, nor did it improve days to cure or hospital stay. Regarding costs, the use of RF in patients with CAP presented a significant increase in costs. Conclusion: There is no evidence to support the routine use of RF in adult patients with CAP. We believe that future research is required to determine the impact of RF in adult patients with CAP, as well as to establish consensus regarding its indication, selection of maneuvers, standardization of techniques, times, and dosage.

Fisioterapia respiratoria en sujetos adultos cursando internación por neumonía adquirida en la comunidad. Revisión bibliográfica

Introducción: La neumonía adquirida en la comunidad (NAC) es una infección respiratoria en la cual es frecuente observar la indicación de fisioterapia respiratoria (FR). Sin embargo, en la actualidad las recomendaciones respecto a su uso en NAC son controvertidas, no existiendo evidencia que respalde su uso y permita conocer su real alcance. Objetivos: Revisar la evidencia respecto al impacto de la FR en pacientes adultos que cursan internación por NAC. Resultados: 5 estudios cumplieron los criterios de inclusión de esta revisión. Las maniobras de FR incluyeron ejercicios respiratorios, drenaje postural, percusión, vibración, espirometría incentivada, resistencia espiratoria, asistencia torácica durante movimientos respiratorios, tos dirigida y presión positiva intermitente. En los estudios incluidos la FR no disminuyó la mortalidad ni mejoró los valores espirométricos en los pacientes con NAC, así como tampoco los días hasta la curación ni la estadía hospitalaria. Respecto a los costos, el uso de FR en pacientes con NAC presentó un incremento significativo de los mismos. Conclusión: No hay evidencia que respalde el uso de manera rutinaria de FR en los pacientes adultos con NAC. Consideramos que se requieren de futuras investigaciones que permitan conocer el impacto de la FR en pacientes adultos con NAC, así como establecer consensos respecto a su indicación, selección de maniobras, estandarización de técnicas, tiempos y dosificación.

Introduction: Community-acquired pneumonia (CAP) is a respiratory infection in which the indication for respiratory physiotherapy (RF) is frequently observed. However, currently the recommendations regarding its use in CAP are controversial, and there is no evidence to support its use and allow us to know its real scope. Objectives: To review the evidence regarding the impact of RF in adult patients who are hospitalized for CAP. Results: 5 studies met the inclusion criteria of this review. RF maneuvers included breathing exercises, postural drainage, percussion, vibration, incentive spirometry, expiratory resistance, chest support during respiratory movements, directed cough, and intermittent positive pressure. In the included studies, RF did not reduce mortality or improve spirometric values in patients with CAP, nor did it improve days to cure or hospital stay. Regarding costs, the use of RF in patients with CAP presented a significant increase in costs. Conclusion: There is no evidence to support the routine use of RF in adult patients with CAP. We believe that future research is required to determine the impact of RF in adult patients with CAP, as well as to establish consensus regarding its indication, selection of maneuvers, standardization of techniques, times, and dosage.

Management of Pulmonary Hypertension Associated with Chronic Lung Disease.

Pulmonary hypertension (PH) is a common complication of chronic lung diseases, particularly in chronic obstructive pulmonary disease (COPD) and interstitial lung diseases (ILD) and especially in advanced disease. It is associated with greater mortality and worse clinical course. Given the high prevalence of some respiratory disorders and because lung parenchymal abnormalities might be present in other PH groups, the appropriate diagnosis of PH associated with respiratory disease represents a clinical challenge. Patients with chronic lung disease presenting symptoms that exceed those expected by the pulmonary disease should be further evaluated by echocardiography. Confirmatory right heart catheterization is indicated in candidates to surgical treatments, suspected severe PH potentially amenable with targeted therapy, and, in general, in those conditions where the result of the hemodynamic assessment will determine treatment options. The treatment of choice for these patients who are hypoxemic is long-term oxygen therapy and pulmonary rehabilitation to improve symptoms. Lung transplant is the only curative therapy and can be considered in appropriate cases. Conventional vasodilators or drugs approved for pulmonary arterial hypertension (PAH) are not recommended in patients with mild-to-moderate PH because they may impair gas exchange and their lack of efficacy shown in randomized controlled trials. Patients with severe PH (as defined by pulmonary vascular resistance >5 Wood units) should be referred to a center with expertise in PH and lung diseases and ideally included in randomized controlled trials. Targeted PAH therapy might be considered in this subset of patients, with careful monitoring of gas exchange. In patients with ILD, inhaled treprostinil has been shown to improve functional ability and to delay clinical worsening.

Effects of Exercise Training on Circulating Biomarkers of Endothelial Function in Pulmonary Arterial Hypertension.

INTRODUCTION: In stable patients with pulmonary arterial hypertension (PAH), pulmonary rehabilitation (PR) is an effective, safe and cost-effective non-pharmacological treatment. However, the effects of PR on vascular function have been poorly explored. This study aimed to compare the amounts of circulating progenitor cells (PCs) and endothelial microvesicles (EMVs) in patients with PAH before and after 8 weeks of endurance exercise training as markers of vascular competence. METHODS: A prospective study of 10 consecutive patients with PAH that successfully finished a PR program (8 weeks) was carried out before and after this intervention. Levels of circulating PCs defined as CD34+CD45low progenitor cells and levels of EMVs (CD31+ CD42b-) were measured by flow cytometry. The ratio of PCs to EMVs was taken as a measure of the balance between endothelial damage and repair capacity. RESULTS: All patients showed training-induced increases in endurance time (mean change 287 s). After PR, the number of PCs (CD34+CD45low/total lymphocytes) was increased (p < 0.05). In contrast, after training, the level of EMVs (CD31+ CD42b-/total EMVs) was reduced. The ratio of PCs to EMVs was significantly higher after training (p < 0.05). CONCLUSION: Our study shows, for the first time, that endurance exercise training in patients with stable PAH has a positive effect, promoting potential mechanisms of damage/repair in favor of repair. This effect could contribute to a positive hemodynamic and clinical response.

[Heart rate disorders in patients with Tako-tsubo syndrome]. / Trastornos del ritmo cardiaco en pacientes con síndrome de Tako-tsubo.

OBJECTIVES: This study sought to evaluate the incidence, prognosis and treatment of heart rhythm disorders (HRD) in Tako-tsubo syndrome (TTS). BACKGROUND: TTS is associated with HRD. The HRD prognostic value is not well characterized in TTS yet. METHODS: The HRD of patients included in the National Registry of Tako-tsubo syndrome, admitted between 2002 and 2018 and coming from 38 hospitals throughout the country, was analyzed. We analyzed any heart rhythm disorder in patients presented before admission, at admission and in long-term follow-up. RESULTS: All types of HRD were described in 259 (23.5%) cases, from a cohort of 1,097 consecutive patients with TTS. HRD was more associated with diabetes mellitus, smoking, hyperuricemia, sleep apnea, anemia with a worse LVEF on admission. The most frequent HRD was a new onset of atrial fibrillation. During hospitalization, patients with HRD showed more complications such as shock on admission, major bleeding, acute renal failure, and combined infections. At follow-up, they presented higher mortality and more major adverse cardiac events, but with a non-significant correlation. CONCLUSIONS: The incidence of HRD in patients with TTS is not infrequent. TTS, when associated with HRD, presents more complications and a worse prognosis both in hospital and in the long term.

Comparación de la mortalidad en pacientes en quimioterapia o inmunoterapia durante y antes de la pandemia de COVID-19. Estudio multicéntrico de cohortes emparejadas en Argentina / Comparison of mortality in patients on chemotherapy or immunotherapy during and before COVID-19 pandemic. Multicenter matched cohort study in Argentina

RESUMEN Objetivos. Comparar la mortalidad por todas las causas de pacientes oncológicos no vacunados que recibieron quimioterapia o inmunoterapia durante la pandemia, con aquellos tratados antes de la pandemia. Materiales y métodos. Realizamos un estudio de cohortes en cuatro hospitales terciarios en Argentina. Pacientes ambulatorios con una neoplasia sólida de cualquier estadio en tratamiento citotóxico o inmune intravenoso fueron elegibles. La cohorte pandémica se enroló durante la fase inicial del brote y se comparó con una cohorte de un período anterior a la pandemia utilizando emparejamiento por puntuación de propensión (PSM, por sus siglas en inglés). Los sujetos se emparejaron por edad, sexo, seguro de salud, factores de riesgo para complicaciones graves por COVID-19, estado funcional, tipo de cáncer y tratamiento, línea de tratamiento e índice de masa corporal. La mortalidad por todas las causas se estimó en ambas cohortes después de seis meses de seguimiento. Resultados. 169 pacientes fueron reclutados entre abril y agosto de 2020 para la cohorte pandémica y 377 para la cohorte prepandémica en el mismo período de 2019, 168 pacientes fueron emparejados. Luego de la PSM, la mortalidad por todas las causas fue del 17,9% en la cohorte pandémica y del 18,5% en la cohorte prepandémica, Riesgo Relativo: 0,97 (intervalo de confianza al 95 %: 0,61-1,52; p=0,888). En la cohorte pandémica, 30/168 pacientes fallecieron, ninguno por infección por COVID-19. Conclusiones. No hemos observado un aumento de mortalidad en pacientes ambulatorios no vacunados en tratamiento oncológico endovenoso activo durante la pandemia por COVID-19.

ABSTRACT Objectives. To compare all-cause mortality of unvaccinated oncology patients who received chemotherapy or immunotherapy during the pandemic with those treated before the pandemic. Materials and methods. We conducted a cohort study in four tertiary hospitals in Argentina. Outpatients with a solid neoplasm of any stage under-going cytotoxic or intravenous immunotherapy were eligible. The pandemic cohort was enrolled during the initial phase of the outbreak and compared with a pre-pandemic cohort using propensity score matching (PSM). Subjects were matched for age, sex, health insurance, risk factors for severe COVID-19 complications, performance status, cancer type and treatment, line of treatment, and body mass index. All-cause mortality was estimated for both cohorts after 6 months of follow-up. Results. A total of 169 patients were recruited between April and August 2020 for the pandemic cohort and 377 for the pre-pandemic cohort in the same months of 2019; 168 patients were matched. After PSM, all-cause mortality was 17.9% in the pandemic cohort and 18.5% in the pre-pandemic cohort; the Relative Risk was 0.97 (95 % confidence interval: 0.61-1.52; p=0.888). In the pandemic cohort, 30/168 patients died, but none from COVID-19. Conclusions. Our findings show that the mortality rate of unvaccinated ambulatory patients on active intravenous oncology treatment during the COVID-19 pandemic did not increase.

Two staged phase II clinical trial of Eribulin monotherapy in advanced or recurrent cervical cancer.

BACKGROUND: Eribulin a microtubule targeting agent and analog of Halichondrin B, a natural product isolated from marine sponge H. okadai, has proven clinical efficacy in metastatic pretreated breast cancer and liposarcoma. We conducted a 2-stage Phase II study of eribulin in patients with advanced/recurrent cervical cancer to examine its clinical activity and evaluate biomarkers for predictors of response. METHODS: Women with advanced/recurrent cervical cancer after ≤1 prior chemotherapy regimen, measurable disease and ECOG performance status ≤2 were treated with eribulin (1.4 mg/m2 IV day 1 and 8, every 21 days) with tumor assessments every 2 cycles. Primary endpoint was 6-month progression-free survival (PFS6); secondary were best overall response (RECISTv1.1), toxicity (CTCAEv4.03) and overall survival (OS). Exploratory endpoints were associations of biomarkers with clinical activity. Immunohistochemistry was performed on archival tumor samples. Overexpression was defined when both intensity and distribution scores were ≥ 2. RESULTS: 32 patients enrolled from 11/2012-5/2017. 29/32 patients had prior chemotherapy with cisplatin/paclitaxel/bevacizumab (n = 12) or cisplatin/gemcitabine (n = 12) as the most common regimens. 14 patients received prior paclitaxel. 1 (3%) had a complete response, 5 (16%) had a partial response and 13 (41%) had stable disease for ORR of 19% (95% CI 8, 37). Those who are paclitaxel naïve experienced the greatest benefit with a 29% ORR (95% CI 12, 54). Patients who received prior paclitaxel responded less favorably than those who did not (p = .002) and had a shorter PFS and OS. Grade 3/4 adverse events occurring in >10% of patients were anemia (n = 12, 38%), neutropenia (n = 7, 22%) and leukopenia (n = 6, 19%). Analysis of correlative predictors of response revealed that patients who did not overexpress ßII and BAX were significantly more likely to respond to e`ribulin. PFS was significantly shorter in patients with ßII and BAX overexpression, OS was significantly shorter in those with ßIII and BAX overexpression. These associations remained after multivariate analysis. CONCLUSIONS: Eribulin shows modest activity in patients with recurrent/advanced cervical cancer with a favorable toxicity profile. Prior paclitaxel exposure is associated with decreased eribulin response. ßII, ßIII tubulin subtypes and BAX are predictors of response and survival. Eribulin may be an option for women with paclitaxel-naïve recurrent/advanced cervical cancer.