Etapa subaguda de pos-COVID-19 grave o crítico. Rehabilitación musculoesquelética, respiratoria y uso de corticoides. Experiencia de la Unidad de Rehabilitación del Hospital del Banco de Seguros del Estado (URHBSE)

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Introduction: In patients with severe or critical COVID-19, the use of prednisone and musculoskeletal and respiratory rehabilitation has been described. The role of these interventions and the optimal time for their initiation are not clearly established. This study presents the results of the Rehabilitation Unit of the Banco de Seguro del Estado Hospital, which implemented a comprehensive rehabilitation program and the use of corticosteroids in the subacute stage of patients with severe or critical post-COVID-19, with a systematic approach, working interdisciplinary and centered on the person being treated. Findings at admission, oxygen requirement, Barthel scale, tomographic patterns, use of corticosteroids, their response, and complications are reported. The results of this approach on clinical, respiratory, and functional variables are described. Method: Descriptive, retrospective study of post-COVID-19 patients who completed rehabilitation at the Rehabilitation Unit of the Banco de Seguros del Estado Hospital (URHBSE) in the period April-August 2021. Data obtained from review of medical records, statistical analysis with PRISM (v8.2.1). Results: Eighty-four patients completed the rehabilitation program. Upon admission to the URHBSE, 55% had total or severe dependence on the Barthel scale. Forty-eight percent were unable to walk. Eighty-nine-point two percent required oxygen, with a mean saturation of 90.3 ± 4.8. Twenty-five percent of patients were admitted requiring a reservoir mask. All patients who entered the program were in the subacute phase of the disease (4 to 12 weeks) and received a comprehensive and individualized rehabilitation plan. The objective was to achieve a functional situation similar to what they had before COVID-19. The length of stay at the URHBSE was 23.5 ± 13.8 days. A total of 76 patients (90.5%) underwent high-resolution chest tomography (HRCT), which was pathological in 96.1% of cases. The predominant findings were ground-glass opacity in 49.3% of cases, consolidation in 8.23%, and a fibrosis-like pattern in 30.13%. "Non-typical" post-COVID damage tomographic alterations were detected (pleural effusion, cavitary nodules, apical cavities, etc.) in 11.8% of the tomographies. In 2 patients (2.6%), pulmonary aspergillosis was found, and in 6.6%, pulmonary thromboembolism. Forty-four patients (52.3%) received prednisone. In 63.4% of cases, oxygen supplementation was discontinued within the first 15 days from the start of prednisone. We found an association between the ground-glass opacity tomographic pattern and early discontinuation of oxygen supplementation from the start of prednisone (p = 0.047). Despite the high degree of colonization, we did not observe infections by colonizing microorganisms, even in those who used prednisone. Comparing admission and discharge, statistically significant differences were found in the following parameters: degree of dyspnea, oxygen requirement (only one patient was discharged with oxygen), saturation, degree of instrumentation (tracheostomy, nasogastric tube, etc.), and the Barthel dependency scale. Regarding respiratory variables, we only have data on the presence of dyspnea in the first 35 patients. Of these, 83% had dyspnea at admission, while only 17% had it at discharge (p < 0.0001). There were also significant differences in the oxygen requirement between admission and discharge (p < 0.0001) and in the degree of dependency measured on the Barthel scale. Fifty-five percent of patients had total or severe dependence at admission, compared to only 3.4% at discharge. Conclusions: The interventions carried out in the subacute stage of the disease were associated with significant improvements in clinical variables of interest. More studies are needed to define the role and the exact timing of the initiation of corticosteroids and rehabilitation in this group of patients.

Introdução: O uso de prednisona e reabilitação musculoesquelética e respiratória foi descrito no tratamento de pacientes com COVID-19 grave ou crítico. O papel destas intervenções e o momento ideal para o seu início não estão claramente estabelecidos. Este trabalho mostra os resultados da Unidade de Reabilitação Hospitalar do Banco de Seguro del Estado que implementou um programa abrangente de reabilitação e uso de corticosteroides na fase subaguda de pacientes graves ou críticos pós-COVID-19, com uma abordagem sistematizada, trabalhando de forma interdisciplinar e centrada no paciente. São relatados os achados na admissão, a necessidade de oxigênio, a escala de Barthel, os padrões tomográficos, o uso de corticosteroides, a resposta ao tratamento e as complicações. Os resultados desta abordagem sobre variáveis clínicas, respiratórias e funcionais são descritos. Material e métodos: Estudo descritivo e retrospectivo de pacientes pós-COVID-19 que completaram reabilitação na Unidade de Reabilitação do Hospital Banco de Seguros del Estado (URHBSE) no período de abril a agosto de 2021. Os dados foram obtidos dos prontuários de pacientes com posterior análise estatísticas usando PRISM (v8.2.1). Resultados: 84 pacientes completaram o programa de reabilitação. No momento da admissão na URHBSE, 55% apresentavam dependência total ou grave da escala de Barthel. 48% não conseguiam se mover. 89,2% necessitaram oxigênio com saturação média de 90,3 ± 4,8. 25% dos pacientes foram internados necessitando máscara com reservatório. Todos os pacientes que ingressaram no programa estavam na fase subaguda da doença (4 a 12 semanas) e receberam um plano de reabilitação abrangente e individualizado. O objetivo era alcançar uma situação funcional semelhante à que apresentavam antes da COVID-19. O tempo de permanência na URHBSE foi de 23,5±13,8 dias. A tomografia de tórax de alta resolução (TCAR) foi realizada em 76 pacientes (90,5%); os resultados foram patológicos em 96,1%. O vidro fosco predominou em 49,3% deles, a consolidação em 8,23% e o padrão fibroso em 30,13%. Alterações tomográficas "atípicas" de danos pós-COVID (derrame pleural, nódulos cavitados, cavidades apicais, etc.) foram detectadas em 11,8% dos exames tomográficos. Aspergilose pulmonar foi encontrada em 2,6% dos pacientes e tromboembolismo pulmonar em 6,6%. 44 pacientes (52,3%) receberam prednisona. Em 63,4% a oferta de oxigênio foi suspensa nos primeiros 15 dias após o início da mesma. Encontramos associação entre o padrão tomográfico em vidro fosco e a suspensão precoce da oferta de oxigênio desde o início da administração da prednisona (p = 0,047). Apesar do alto grau de colonização, mesmo naqueles que usaram prednisona, não observamos infecções. Em relação às variáveis respiratórias, só temos dados sobre a presença de dispneia nos primeiros 35 pacientes; destes, 83% apresentavam dispneia na admissão, enquanto apenas 17% a apresentavam na alta (p< 0,0001). Observou-se também diferenças significativas na necessidade de O2 entre a admissão e a alta (p< 0,0001) e no grau de dependência medido pela escala de Barthel, com 55% dos pacientes apresentando dependência total ou grave na admissão e apenas 3,4% na alta. Conclusões: As intervenções realizadas na fase subaguda da doença foram associadas a melhorias significativas nas variáveis de interesse clínico. São necessários mais estudos para definir o papel e o momento exato do início dos corticosteroides e da reabilitação neste grupo de pacientes.

A retrospective analysis of anticoagulant safety among heart transplant recipients undergoing endomyocardial biopsy.

BACKGROUND: Transvenous endomyocardial biopsy is an invasive procedure which is used to diagnose rejection following an orthotopic heart transplant. Endomyocardial biopsy is widely regarded as low risk with all-cause complication rates below 5% in most safety studies. Following transplant, some patients require therapeutic anticoagulation. It is unknown whether anticoagulation increases endomyocardial biopsy bleeding risk. METHODS: Records from 2061 endomyocardial biopsies performed for post-transplant rejection surveillance at our institution between November 2016 and August 2022 were reviewed. Bleeding complications were defined as vascular access-related hematoma or bleeding, procedure-related red blood cell transfusion, and new pericardial effusion. Relative risk and small sample-adjusted 95% confidence interval was calculated to investigate the association between bleeding complications and anticoagulation. RESULTS AND CONCLUSIONS: The overall risk of bleeding was 1.2% (25/2061 cases). There was a statistically significant increase in bleeding among patients on intravenous (RR 4.46, CI 1.09-18.32) but not oral anticoagulants (RR .62, CI .15-2.63) compared to patients without anticoagulant exposure. There was a trend toward increased bleeding among patients taking warfarin with INR ≥ 1.8 (RR 3.74, CI .90-15.43). Importantly, no bleeding events occurred in patients taking direct oral anticoagulants such as apixaban. Based on these results, intravenous rather than oral anticoagulation was associated with a significantly higher risk of bleeding complications following endomyocardial biopsy.

Parenteral treprostinil induction for rapid attainment of therapeutic doses of oral treprostinil.

RATIONALE: Oral treprostinil slows disease progression and improves exercise capacity in pulmonary arterial hypertension; however, titration can be prolonged. Published data suggests prostacyclin-naïve patients achieve total daily oral treprostinil doses of about 6 mg by Week 16, while those on prior parenteral treprostinil reach higher doses at the same timepoint. OBJECTIVES: EXPEDITE (NCT03497689), a single-arm, multicenter study, assessed the efficacy of rapid parenteral treprostinil induction to quickly reach higher doses of oral treprostinil for the treatment of pulmonary arterial hypertension. METHODS: Parenteral treprostinil was titrated for 2-8 weeks, followed by cross-titration of oral treprostinil. The primary endpoint was percentage of patients reaching ≥12 mg daily of oral treprostinil at Week 16. Secondary endpoints included clinical changes from baseline to Week 16. RESULTS: Twenty-nine prostacyclin-naïve patients were included in efficacy analyses. At Week 16, the mean daily oral treprostinil dose was 16.4 mg; 79% of patients met the primary endpoint. From baseline to Week 16, median REVEAL Lite 2 score improved (decreased) from 6 to 3.5 (p = 0.0006). Statistically significant improvements were also seen in World Health Organization Functional Class, N-terminal-pro brain natriuretic peptide levels, 6-minute walk distance, right atrial area, Borg Dyspnea Score, and emPHasis-10 score. Favorable trends were seen in risk stratification, echocardiography parameters, disease symptoms, and treatment satisfaction. CONCLUSION: Short-course parenteral treprostinil induction resulted in oral treprostinil doses over twice those reported in de novo initiations and may be a useful approach to quickly achieve the therapeutic benefits of oral treprostinil.

Implementing the EXPEDITE parenteral induction protocol: Rapid parenteral treprostinil titration and transition to oral treprostinil.

Treprostinil is a prostacyclin analogue that targets multiple cellular receptors to treat pulmonary arterial hypertension (PAH). In certain scenarios, patients may require aggressive treprostinil titration. Several studies have demonstrated that higher doses of treprostinil lead to greater clinical benefit. Data supports successful transitions from parenteral to oral treprostinil; however, administration routes, transition duration, and transition setting vary in the real-world. The EXPEDITE clinical trial (NCT03497689) prospectively studied whether rapid parenteral treprostinil induction can be used to achieve high doses of oral treprostinil (total daily dose: ≥12 mg) in prostacyclin naïve PAH patients. Parenteral prostacyclin induction may be more appropriate for patients who need to reach therapeutic dosing more urgently than longer titration durations reported with conventional de novo oral treprostinil initiation. This summary provides strategies utilized in EXPEDITE. Parenteral treprostinil was initiated at 2 ng/kg/min intravenously or subcutaneously; clinicians determined the frequency and dose increment of up-titration. Two distinct transition schedules from parenteral to oral treprostinil were employed: rapid cross-titration in an inpatient setting (median: 2 days) or gradual cross-titration in an outpatient setting (median: 5 days). Patient status was closely monitored after transition; oral treprostinil dose was titrated to clinical effect and tolerability. Factors considered when individualizing dosing strategies included parenteral and oral treprostinil target doses, nursing support, patient education, medication counseling and adverse events management. EXPEDITE demonstrated the time to a therapeutic dose of oral treprostinil is significantly shorter when utilizing a short-term parenteral induction strategy and may be suitable for patients requiring aggressive titration of oral treprostinil.

Safety and efficacy of RT234 vardenafil inhalation powder on exercise parameters in pulmonary arterial hypertension: phase II, dose-escalation study design.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a progressive disease characterized by high mean pulmonary arterial pressure (≥ 20 mmHg) and remodeling of the vascular arteries. Approved therapies improve symptoms and delay clinical worsening in the long term, but they do not relieve acute exertional symptoms. RT234, a drug/device combination (Respira Therapeutics, Palo Alto, CA, USA) that delivers the phosphodiesterase 5 inhibitor vardenafil to the lungs via inhalation, has been shown to reduce pulmonary vascular resistance in patients with PAH. This study aims to evaluate whether RT234 can increase oxygen capacity during cardiopulmonary exercise testing (CPET) in patients with PAH. METHODS: This prospective, multi-center, open-label, two-cohort, dose-escalation, phase IIb trial in patients with PAH will evaluate the safety and efficacy of RT234 in improving exercise parameters. The trial began in September 2020 and is expected to be completed by early 2024. Patients eligible for enrollment will have a right heart catheterization-confirmed diagnosis of PAH, a 6-minute walking distance of ≥ 150 m, a minute ventilation/carbon dioxide production slope of ≥ 36, and will be on up to three stable oral and/or inhaled (not parenteral) PAH-specific background therapies. The estimated sample size is 86 patients, who will be divided into two dose cohorts. Cohort 1 will receive 0.5 mg RT234, and cohort 2 will receive 1.0 mg RT234. Each cohort will contain two subgroups based on the number of PAH background medications (up to two vs three). The trial will assess patients' changes from baseline in peak oxygen consumption (VO2) during CPET 30 minutes after a single dose of 0.5 mg or 1.0 mg RT234, the change in the 6-minute walking distance, and the pharmacokinetics and safety profile of single doses of RT234. CONCLUSION: This is the first trial involving an as-needed medication for PAH. The trial will provide insights into the safety and efficacy of as-needed RT234 in treating the acute symptoms of PAH during exercise and will inform the design of further trials. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier NCT04266197.

ISHLT consensus statement: Perioperative management of patients with pulmonary hypertension and right heart failure undergoing surgery.

Pulmonary hypertension (PH) is a risk factor for morbidity and mortality in patients undergoing surgery and anesthesia. This document represents the first international consensus statement for the perioperative management of patients with pulmonary hypertension and right heart failure. It includes recommendations for managing patients with PH being considered for surgery, including preoperative risk assessment, planning, intra- and postoperative monitoring and management strategies that can improve outcomes in this vulnerable population. This is a comprehensive document that includes common perioperative patient populations and surgical procedures with unique considerations.

Chemical Diversity of Citrus Leaf Essential Oils.

The essential oils from leaves of 20 commercial citrus accessions maintained by the University of California, Riverside Givaudan Citrus Variety Collection and selected on the basis of their odor profile were analyzed by GCMS/FID. The main components were quantified while the semi-quantitative percentage composition data was compiled with data from other publications for sample visualization, classification and comparison with leaf oils from other citrus accessions. Some compositional clusters aligned closely with the taxonomic clades of sweet orange, bitter orange, and C. hystrix while other clades like the mandarins and lemons showed distinct chemical sub-groups. Characteristic compounds for the clusters included linalyl acetate and linalool (bitter orange leaf), sabinene (sweet orange leaf), methyl N-methyl anthranilate (mandarin leaf), γ-terpinene (yuzu leaf), citronellal (C. hystrix), limonene, citronellal and citral (lemons and citrons). A chemometric approach combined with t-SNE cluster plots can be more informative than taxonomic assignments when considering flavor and fragrance characteristics.

Safety of direct oral anticoagulants in solid organ transplant recipients: A meta-analysis.

There is limited evidence comparing direct oral anticoagulants (DOACs) and warfarin in solid organ transplant (SOT) recipients. We performed a pooled analysis to study the safety and efficacy of DOACs in this patient population. We searched PubMed, Embase, and Scopus databases using the search terms "heart transplant" or "lung transplant" or "liver transplant" or "kidney transplant" or "pancreas transplant" and "direct oral anticoagulant" for literature search. Random effects model with Mantel-Haenszel method was used to pool the outcomes. Pooled analysis included 489 patients, of which 259 patients received DOACs and 230 patients received warfarin. When compared to warfarin, the use of DOACs was associated with decreased risk of composite bleed (RR .49, 95% CI .32-.76, p = .002). There were no differences in rates of major bleeding (RR .55, 95% CI .20-1.49, p = .24) or venous thromboembolism (RR .65, 95% CI .25-1.70, p = .38) between the two groups. Evidence from pooled analysis suggests that DOACs are comparable to warfarin in terms of safety in SOT recipients. Further research is warranted to conclusively determine whether DOACs are safe alternatives to warfarin for anticoagulation in SOT recipients.

ISHLT consensus document on lung transplantation in patients with connective tissue disease: Part II: Cardiac, surgical, perioperative, operative, and post-operative challenges and management statements.

Patients with connective tissue disease (CTD) present unique surgical, perioperative, operative, and postoperative challenges related to the often underlying severe pulmonary hypertension and right ventricular dysfunction. The International Society for Heart and Lung Transplantation-supported consensus document on lung transplantation in patients with CTD standardization addresses the surgical challenges and relevant cardiac involvement in the perioperative, operative, and postoperative management in patients with CTD.

Pulmonary vasodilators: beyond the bounds of pulmonary arterial hypertension therapy in COVID-19.

Pulmonary arterial hypertension (PAH) and novel coronavirus (SARS-CoV-2) disease COVID-19 are characterized by extensive endothelial dysfunction and inflammation leading to vascular remodeling and severe microthrombi and microvascular obliterative disease. It is hypothesized that those patients with underlying lung disease, like PAH, represent a high-risk cohort in this pandemic. However, reports of COVID-19 in this cohort of patient have been scaring and an observational survey showed that the disease was relatively well tolerated. We postulate that specific PAH vasodilator may offer some protection and/or advantage in the case of concomitant COVID-19. Here we review the literature describing mechanisms of action for each of the broad categories of PAH therapy, and offer potential hypothesis about why this therapy may impact outcomes in COVID-19.

Monitoring Pulmonary Arterial Hypertension Using an Implantable Hemodynamic Sensor.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a chronic disease that ultimately progresses to right-sided heart failure (HF) and death. Close monitoring of pulmonary artery pressure (PAP) and right ventricular (RV) function allows clinicians to appropriately guide therapy. However, the burden of commonly used methods to assess RV hemodynamics, such as right heart catheterization, precludes frequent monitoring. The CardioMEMS HF System (Abbott) is an ambulatory implantable hemodynamic monitor, previously only used in patients with New York Heart Association (NYHA) class III HF. In this study, we evaluate the feasibility and early safety of monitoring patients with PAH and right-sided HF using the CardioMEMS HF System. METHODS: The CardioMEMS HF sensors were implanted in 26 patients with PAH with NYHA class III or IV right-sided HF (51.3 ± 18.3 years of age, 92% women, 81% NYHA class III). PAH therapy was tracked using a minimum of weekly reviews of CardioMEMS HF daily hemodynamic measurements. Safety, functional response, and hemodynamic response were tracked up to 4 years with in-clinic follow-ups. RESULTS: The CardioMEMS HF System was safely used to monitor PAH therapy, with no device-related serious adverse events observed and a single preimplant serious adverse event. Significant PAP reduction and cardiac output elevation were observed as early as 1 month postimplant using trends of CardioMEMS HF data, coupled with significant NYHA class and quality of life improvements within 1 year. CONCLUSIONS: The CardioMEMS HF System provided useful information to monitor PAH therapy, and demonstrated short- and long-term safety. Larger clinical trials are needed before its widespread use to guide therapy in patients with severe PAH with right-sided HF.

Pulmonary Hypertension in Women.

Prevalence of pulmonary arterial hypertension (PAH) is higher in women, and the mechanism remains unclear. Prognosis is overall better for female compared with male patients with PAH. Pregnancy is associated with significant risk, mortality, and morbidity in patients with PAH; consensus guidelines recommend against pregnancy and counsel about early termination in these patients. Recent advances in treatment showed improvement in prognosis in small case reports of pregnant patients with PAH, particularly with the early use of parental prostacyclin. Education remains fundamental for women with PAH of childbearing age for pregnancy prevention as well as discussion about birth control methods.

Management of Pulmonary Hypertension: Associated with Left Heart Disease.

Pulmonary hypertension (PH) due to left heart disease, or WHO group 2 PH, is the most frequent cause of PH. It affects approximately 50% to 60% of patients with heart failure with preserved ejection fraction as well as 60% of those with heart failure with reduced ejection fraction and contributes significantly to disease progression and unfavorable outcomes. The diagnosis of PH is associated with poor prognosis and significant morbidity and mortality.

Pilot Randomized Controlled Trial to Reduce Readmission for Heart Failure Using Novel Tablet and Nurse Practitioner Education.

BACKGROUND: Heart failure education programs are not standardized. The best form of education is unclear. We evaluated whether addition of a novel tablet application to nurse practitioner (NP) education was superior to NP education alone in reducing 30-day readmission after heart failure hospitalization. METHODS: From February 2015-March 2016, patients admitted to a quaternary academic center with primary diagnosis of heart failure were randomized to 1) treatment - NP education plus tablet application (interactive conditional logic program that flags patient questions to medical staff), or 2) control - NP education. The primary outcome was reduction in 30-day readmission rate. Secondary outcomes included satisfaction and education assessed via survey. RESULTS: Randomization included 60 patients to treatment and 66 to control. A total of 13 patients withdrew prior to intervention (treatment n = 4, control n = 1) or were lost to follow-up (treatment n = 3, control n = 5). The 30-day readmission rate trended lower for treatment compared with control, but results were not statistically significant (13.2% [7/53], 26.7% [16/60], respectively, P = .08). Similarly, satisfaction trended higher with treatment than control (P = .08). Treatment patients rated explanations from their physicians higher than control (Always: 83.7%, 55.8%, respectively, P = .01). CONCLUSIONS: NP education plus tablet use was not associated with significantly lower 30-day readmission rates in comparison with NP alone, but a positive trend was seen. Patient satisfaction trended higher and heart failure explanations were better with NP education plus tablet. A larger study is needed to determine if NP education plus tablet reduces readmission rates following heart failure admission.

Cardiopulmonary exercise testing in the MRI environment.

Maximal oxygen consumption ([Formula: see text]max) measured by cardiopulmonary exercise testing (CPX) is the gold standard for assessment of cardiorespiratory fitness. Likewise, cardiovascular magnetic resonance (CMR) is the gold standard for quantification of cardiac function. The combination of CPX and CMR may offer unique insights into cardiopulmonary pathophysiology; however, the MRI-compatible equipment needed to combine these tests has not been available to date. We sought to determine whether CPX testing in the MRI environment, using equipment modified for MRI yields results equivalent to those obtained in standard exercise physiology (EP) lab. Ten recreationally trained subjects completed [Formula: see text]max tests in different locations; an EP laboratory and an MRI laboratory, using site specific equipment. CMR cine images of the heart were acquired before and immediately after maximal exercise to measure cardiac function. Subjects in all tests met criteria indicating that peak exercise was achieved. Despite equipment modifications for the MRI environment, [Formula: see text]max was nearly identical between tests run in the different labs (95% lower confidence limit (LCL) = 0.8182). The mean difference in [Formula: see text]max was less than 3.40 ml (kg/min)(-1), within the variability expected for tests performed on different days, in different locations, using different metabolic carts. MRI performed at rest and following peak exercise stress indicated cardiac output increased from 5.1 ± 1.0 l min(-1) to 16.4 ± 5.6 l min(-1), LVEF increased from 65.2 ± 3.3% to 78.4 ± 4.8%, while RVEF increased from 52.8 ± 5.3% to 63.4 ± 5.3%. Regression analysis revealed a significant positive correlation between [Formula: see text]max and stroke volume (R = 0.788, P = 0.006), while the correlation with cardiac output did not reach statistical significance (R = 0.505, P = 0.137). [Formula: see text]max CPX testing can be effectively performed in the MRI environment, enabling direct combination of physiological data with advanced post-exercise imaging in the same test session.

Assessing protein kinase target similarity: Comparing sequence, structure, and cheminformatics approaches.

In just over two decades, structure based protein kinase inhibitor discovery has grown from trial and error approaches, using individual target structures, to structure and data driven approaches that may aim to optimize inhibition properties across several targets. This is increasingly enabled by the growing availability of potent compounds and kinome-wide binding data. Assessing the prospects for adapting known compounds to new therapeutic uses is thus a key priority for current drug discovery efforts. Tools that can successfully link the diverse information regarding target sequence, structure, and ligand binding properties now accompany a transformation of protein kinase inhibitor research, away from single, block-buster drug models, and toward "personalized medicine" with niche applications and highly specialized research groups. Major hurdles for the transformation to data driven drug discovery include mismatches in data types, and disparities of methods and molecules used; at the core remains the problem that ligand binding energies cannot be predicted precisely from individual structures. However, there is a growing body of experimental data for increasingly successful focussing of efforts: focussed chemical libraries, drug repurposing, polypharmacological design, to name a few. Protein kinase target similarity is easily quantified by sequence, and its relevance to ligand design includes broad classification by key binding sites, evaluation of resistance mutations, and the use of surrogate proteins. Although structural evaluation offers more information, the flexibility of protein kinases, and differences between the crystal and physiological environments may make the use of crystal structures misleading when structures are considered individually. Cheminformatics may enable the "calibration" of sequence and crystal structure information, with statistical methods able to identify key correlates to activity but also here, "the devil is in the details." Examples from specific repurposing and polypharmacology applications illustrate these points. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases.

Conversion from sildenafil to tadalafil: results from the sildenafil to tadalafil in pulmonary arterial hypertension (SITAR) study.

PURPOSE: Among phosphodiesterase type 5 inhibitors, tadalafil offers clinicians a once-daily alternative to 3 times daily sildenafil for the treatment of pulmonary arterial hypertension (PAH). This study assessed the safety and patient satisfaction with conversion from sildenafil to tadalafil. METHODS: In this multicenter, prospective, 6-month study, patients with PAH were instructed to take their last dose of sildenafil in the evening and initiate tadalafil 40 mg/d the next morning. Patients completed the Treatment Satisfaction Questionnaire for Medication at baseline and 30, 90, and 180 days after transition to assess PAH symptoms and patient satisfaction. Safety was assessed on the basis of recorded adverse events (AEs). RESULTS: Of the 35 patients who met the study criteria, 56% were receiving ≥2 PAH therapies. At the time of transition, the sildenafil dose ranged from 40 to 300 mg/d, with 20% of the patients on >20 mg of sildenafil 3 times daily. Transition to tadalafil was generally well tolerated, and the incidence of common AEs, except for myalgia, appeared to decrease over time on tadalafil therapy. Five (14%) patients switched back to sildenafil. A greater percentage of patients were satisfied than were dissatisfied after conversion to tadalafil (55% vs 19% at 90 days), while 26% felt about the same degree of satisfaction. Conversion to tadalafil resulted in significant improvement in patient ratings of therapy convenience. CONCLUSIONS: Transition of patients from sildenafil to tadalafil was usually well tolerated, with improved convenience and may enhance treatment satisfaction.

Immune responses in Ugandan women infected with subtypes A and D HIV using the BED capture immunoassay and an antibody avidity assay.

INTRODUCTION: Analysis of samples from Uganda using serologic HIV incidence assays reveal that individuals with subtype D infection often have weak humoral immune responses to HIV infection. It is unclear whether this reflects a poor initial response to infection or a waning antibody response later in infection. MATERIALS AND METHODS: Samples (N = 2614) were obtained from 114 women aged 18-45 years in the Ugandan Genital Shedding and Disease Progression Study cohort (2001-2009; 82 subtype A, 32 subtype D; median 23 samples/women, range 3-41 samples, median follow-up of 6.6 years). Samples were analyzed using the BED capture immunoassay (cutoff, 0.8 OD-n) and the avidity assay (cutoff, 90% Avidity Index). Antibody maturation was assessed by having the BED capture enzyme immunoassay (BED-CEIA) or avidity value exceed the assay cutoff 1 or 2 years after infection. The waning antibody response was measured by having the BED-CEIA or avidity value fall >20% below the maximum value. RESULTS: For the BED-CEIA, 8 women with subtype A infection and 3 women with subtype D infection never progressed previously the cutoff value (median, 5.9 years follow-up after infection). Six women with subtype D infection never achieved an avidity index >90%. Subtype did not impact the proportion of women whose assay values regressed by >20% of the maximal value (for BED-CEIA: 33% for A, 41% for D, P = 0.51; for avidity: 1% for A, 6% for D, P = 0.19). DISCUSSION: The higher frequency of misclassification of individuals with long-term subtype D infection as recently infected using serologic incidence assays reflects a weak initial antibody response to HIV infection that is sustained over time.