The Polyanalgesic Consensus Conference (PACC)®: Updates on Clinical Pharmacology and Comorbidity Management in Intrathecal Drug Delivery for Cancer Pain.

INTRODUCTION: The International Neuromodulation Society convened a multispecialty group of physicians based on expertise with international representation to establish evidence-based guidance on using intrathecal drug delivery in chronic pain treatment. This Polyanalgesic Consensus Conference (PACC)® project's scope is to provide evidence-based guidance for clinical pharmacology and best practices for intrathecal drug delivery for cancer pain. MATERIALS AND METHODS: Authors were chosen on the basis of their clinical expertise, familiarity with the peer-reviewed literature, research productivity, and contributions to the neuromodulation literature. Section leaders supervised literature searches using Medline, EMBASE, Cochrane CENTRAL, BioMed Central, Web of Science, Google Scholar, PubMed, Current Contents Connect, Meeting Abstracts, and Scopus from 2017 (when the PACC last published guidelines) to the present. Identified studies were graded using the United States Preventive Services Task Force criteria for evidence and certainty of net benefit. Recommendations were based on the strength of evidence, and when evidence was scant, recommendations were based on expert consensus. RESULTS: The PACC evaluated the published literature and established evidence- and consensus-based expert opinion recommendations to guide best practices in treating cancer pain. Additional guidance will occur as new evidence is developed in future iterations of this process. CONCLUSIONS: The PACC recommends best practices regarding the use of intrathecal drug delivery in cancer pain, with an emphasis on managing the unique disease and patient characteristics encountered in oncology. These evidence- and consensus-based expert opinion recommendations should be used as a guide to assist decision-making when clinically appropriate.

External validation of the natriuretic response prediction equation to discriminate diuretic response in heart failure.

AIMS: Incomplete decongestion due to lack of titration of diuretics to effective doses is a common reason for readmission in patients with acute decompensated heart failure (ADHF). The natriuretic response prediction equation (NRPE) is a novel tool that proved to be rapid and accurate to predict natriuretic response and does not need urine collection. However, the NRPE has not been externally validated. The goal of this study was to externally validate the discrimination capacity of the NRPE in patients with ADHF and fluid overload. METHODS AND RESULTS: Patients admitted with ADHF who required intravenous loop diuretics were included. A spot urine sample was obtained ~2 h following diuretic administration, and a timed 6-h urine collection by study staff was carried out. Urine sodium and urine creatinine from the spot urine sample were used to predict the 6-h natriuretic response using the NRPE. The primary goal was to validate the NRPE to discriminate poor loop diuretic natriuretic response (sodium output <50 mmol in the 6 h following diuretic administration). The NRPE was compared with urine sodium and measured urine output which are the methods currently recommended by international guidelines to assess diuretic response. Eighty-seven diuretic administrations from 49 patients were analysed. Mean age of patients was 57 ± 17 years and 67% were male. Mean estimated glomerular filtration rate was 65 ± 28 mL/min/1.73 m2, and ejection fraction was 35 ± 15%. Median dose of intravenous furosemide equivalents administered the day of the study was 80 mg (IQR 40 - 160). Poor natriuretic response occurred in 39% of the visits. The AUC of the NRPE to predict poor natriuretic response during the 6-h urine collection was 0.91 (95% CI 0.85-0.98). Compared with the NRPE, spot urine sodium concentration (AUC 0.75) and urine output during the corresponding nursing shift (AUC 0.74) showed lower discrimination capacity. CONCLUSIONS: In this cohort of patients with ADHF, the NRPE outperformed spot urine sodium concentration and all other metrics related to diuretic response to predict poor natriuretic response. Our findings support the use of this equation at other settings to allow rapid and accurate prediction of natriuretic response.

Removal of endothelial surface-associated von villebrand factor suppresses accelerate datherosclerosis after myocardial infarction.

BACKGROUND: Thromboinflammation involving platelet adhesion to endothelial surface-associated von Willebrand factor (VWF) has been implicated in the accelerated progression of non-culprit plaques after MI. The aim of this study was to use arterial endothelial molecular imaging to mechanistically evaluate endothelial-associated VWF as a therapeutic target for reducing remote plaque activation after myocardial infarction (MI). METHODS: Hyperlipidemic mice deficient for the low-density lipoprotein receptor and Apobec-1 underwent closed-chest MI and were treated chronically with either: (i) recombinant ADAMTS13 which is responsible for proteolytic removal of VWF from the endothelial surface, (ii) N-acetylcysteine (NAC) which removes VWF by disulfide bond reduction, (iii) function-blocking anti-factor XI (FXI) antibody, or (iv) no therapy. Non-ischemic controls were also studied. At day 3 and 21, ultrasound molecular imaging was performed with probes targeted to endothelial-associated VWF A1-domain, platelet GPIbα, P-selectin and vascular cell adhesion molecule-1 (VCAM-1) at lesion-prone sites of the aorta. Histology was performed at day 21. RESULTS: Aortic signal for P-selectin, VCAM-1, VWF, and platelet-GPIbα were all increased several-fold (p < 0.01) in post-MI mice versus sham-treated animals at day 3 and 21. Treatment with NAC and ADAMTS13 significantly attenuated the post-MI increase for all four molecular targets by > 50% (p < 0.05 vs. non-treated at day 3 and 21). On aortic root histology, mice undergoing MI versus controls had 2-4 fold greater plaque size and macrophage content (p < 0.05), approximately 20-fold greater platelet adhesion (p < 0.05), and increased staining for markers of platelet transforming growth factor-ß1 signaling. Accelerated plaque growth and inflammatory activation was almost entirely prevented by ADAMTS13 and NAC. Inhibition of FXI had no significant effect on molecular imaging signal or plaque morphology. CONCLUSIONS: Plaque inflammatory activation in remote arteries after MI is strongly influenced by VWF-mediated platelet adhesion to the endothelium. These findings support investigation into new secondary preventive therapies for reducing non-culprit artery events after MI.

Transposon DNA sequences facilitate the tissue-specific gene transfer of circulating tumor DNA between human cells.

The exchange of genes between cells is known to play an important physiological and pathological role in many organisms. We show that circulating tumor DNA (ctDNA) facilitates cell-specific gene transfer between human cancer cells and explain part of the mechanisms behind this phenomenon. As ctDNA migrates into the nucleus, genetic information is transferred. Cell targeting and ctDNA integration require ERVL, SINE or LINE DNA sequences. Chemically manufactured AluSp and MER11C sequences replicated multiple myeloma (MM) ctDNA cell targeting and integration. Additionally, we found that ctDNA may alter the treatment response of MM and pancreatic cancer models. This study shows that retrotransposon DNA sequences promote cancer gene transfer. However, because cell-free DNA has been detected in physiological and other pathological conditions, our findings have a broader impact than just cancer. Furthermore, the discovery that transposon DNA sequences mediate tissue-specific targeting will open up a new avenue for the delivery of genes and therapies.

P53 and BCL-2 family proteins PUMA and NOXA define competitive fitness in pluripotent cell competition.

Cell Competition is a process by which neighboring cells compare their fitness. As a result, viable but suboptimal cells are selectively eliminated in the presence of fitter cells. In the early mammalian embryo, epiblast pluripotent cells undergo extensive Cell Competition, which prevents suboptimal cells from contributing to the newly forming organism. While competitive ability is regulated by MYC in the epiblast, the mechanisms that contribute to competitive fitness in this context are largely unknown. Here, we report that P53 and its pro-apoptotic targets PUMA and NOXA regulate apoptosis susceptibility and competitive fitness in pluripotent cells. PUMA is widely expressed specifically in pluripotent cells in vitro and in vivo. We found that P53 regulates MYC levels in pluripotent cells, which connects these two Cell Competition pathways, however, MYC and PUMA/NOXA levels are independently regulated by P53. We propose a model that integrates a bifurcated P53 pathway regulating both MYC and PUMA/NOXA levels and determines competitive fitness.

Incidental Carcinoid Tumor of the Appendix After Appendectomy During Pregnancy.

Neuroendocrine tumors comprise a range of neoplasms with varying spectra of origin, biological activity, clinical features, and histological appearance. In this case report, we present a pregnant 33-year-old female who was brought to the emergency department (ED) complaining of acute right iliac fossa pain accompanied by diarrhea and vomiting. Initial management showed no improvement. Lab results, clinical history, and physical exam were suggestive of appendicitis, so an exploratory minimally invasive laparoscopic exam was performed. The histopathological analysis of the excised appendix confirmed the diagnosis of acute appendicitis and periappendicitis. Incidentally, a 0.6 cm neuroendocrine tumor (carcinoid tumor) was identified on the wall of the appendiceal tip. The tumor extended at multiple points into the subserosal fat, and the serous surface and the resection margin were negative for the tumor. After seven days of the initial procedure, the patient presented with abdominal pain and a fever. An abdominal ultrasound was performed, revealing the presence of free fluid. A second exploratory laparoscopy revealed adhesions between the fallopian tubes and cecum, as well as a collection of purulent fluid. The management consisted of adhesiolysis, cavity lavage, and drainage, along with antibiotic therapy, pain management, and close monitoring of the mother's and fetus's status. The patient had a successful recovery and was discharged home a week after surgery. She gave birth to a full-term, healthy baby and remains free of tumor relapse. This case highlights the importance of obtaining histopathological interpretation of any extracted tissue during surgery. Guidelines regarding the management of carcinoids during pregnancy are not available, and when considering surgical intervention, an open or laparoscopic approach must be carefully evaluated.

Elevated LDL Cholesterol Increases Microvascular Endothelial VWF and Thromboinflammation After Myocardial Infarction.

BACKGROUND: In reperfused myocardial infarction, VWF (von Willebrand factor)-mediated platelet adhesion contributes to impaired microvascular reflow and possibly also to postmyocardial infarction inflammation. We hypothesized that postischemic thromboinflammatory processes are worsened by elevated LDL (low-density lipoprotein) cholesterol. METHODS: Myocardial ischemia-reperfusion or sham procedure was performed in wild-type mice and hyperlipidemic mice deficient for the LDL receptor and Apobec-1 (apolipoprotein-B mRNA editing enzyme catalytic polypeptide-1; DKO [double knockout]). DKO subgroups were treated with N-acetylcysteine, which inhibits pro-adhesive VWF multimers or with recombinant ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin motifs-13), which enzymatically cleaves endothelial surface-associated VWF. Myocardial contrast echocardiography perfusion imaging and molecular imaging for VWF, platelet glycoprotein Ibα, and leukocyte CD18 (cluster of differentiation) were performed 30 minutes post-reperfusion. Histology, infarct sizing, and echocardiography were performed at 1.5 or 72 hours; late echocardiography was performed at day 21. RESULTS: After ischemia-reperfusion, DKO compared with wild-type mice had ≈2-fold higher (P<0.05) risk area signal for microvascular platelet adhesion, VWF, and CD18; greater impairment in microvascular reflow, and 2-fold larger infarct size. Treatment of DKO mice with N-acetylcysteine and ADAMTS13 reduced molecular imaging signal for microvascular platelet adhesion, VWF, and CD18; improved early microvascular reflow; and reduced eventual infarct size. ADAMTS13 suppressed the postmyocardial infarction neutrophil and monocyte infiltration, enhanced the time-dependent recovery of left ventricular systolic function, and prevented late left ventricular remodeling. CONCLUSIONS: In reperfused myocardial infarction, elevated LDL cholesterol promotes thromboinflammation through excess microvascular endothelial VWF and platelet adhesion, resulting in less microvascular reflow and larger infarct size. In the presence of elevated LDL cholesterol, therapies that suppress endothelial-associated VWF can promote recovery of left ventricular function and protect against remodeling.

Plasma Interleukin-6 (IL-6), Angiopoietin-2, and C-Reactive Protein Levels Predict Subsequent Type 1 Myocardial Infarction in Persons With Treated HIV Infection.

BACKGROUND: HIV infection leads to endothelial activation, promoting platelet adhesion, and accelerating atherosclerosis. Our goal was to determine whether biomarkers of endothelial activation and hemostasis/thrombosis were elevated in people with treated HIV (PWH) before myocardial infarction (MI). METHODS: In a case-control study nested within the CFAR Network of Integrated Clinical Systems (CNICS) cohort, we compared 69 adjudicated cases with type 1 MI with 138 controls matched for antiretroviral therapy regimen. We measured angiopoietin-1, angiopoietin-2 (ANG-2), intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13), von Willebrand factor, C-reactive protein (CRP), interleukin-6 (IL-6), plasminogen activation inhibitor-1, P-selectin, serum amyloid-A, soluble CD14, and apolipoprotein A1 in stored plasma. Conditional logistic regression identified associations with subsequent MI, with and without adjustment for Atherosclerotic Cardiovascular Disease (ASCVD) and Veterans Aging Cohort Study (VACS) scores. RESULTS: Higher IL-6 was associated with MI after adjustment for ASCVD score (adjusted odds ratio [AOR] 1.51, 95% confidence interval [95% CI]: 1.05 to 2.17 per standard-deviation-scaled log 2 increment). In a separate model adjusting for VACS score, higher ANG-2 (AOR 1.49, 95% CI: 1.04 to 2.14), higher CRP (AOR 1.45, 95% CI: 1.06 to 2.00), and higher IL-6 (AOR 1.68, 95% CI: 1.17 to 2.41) were associated with MI. In a sensitivity analysis excluding PWH with viral load ≥400 copies/mL, higher IL-6 remained associated with MI after adjustment for ASCVD score and after adjustment for VACS score. CONCLUSIONS: Among PWH, higher levels of plasma IL-6, CRP, and ANG-2 predict subsequent type 1 MI, independent of conventional risk scores. IL-6 had the most consistent associations with type 1 MI, regardless of viral load suppression.

Clinical and paraclinical characteristics in pediatric patients with acute recurrent and chronic pancreatitis: a cohort in Mexico / Características clínicas y paraclínicas en pacientes pediátricos con pancreatitis aguda recurrente y crónica: una cohorte en México

Abstract Background: Acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP) are infrequent clinical entities in pediatric patients, as less than 8% of the literature mentions this population. This study aimed to describe the clinical and paraclinical profile, and the etiology related to patients with ARP and CP attended at a tertiary-level healthcare institute in Mexico. Methods: We conducted a retrospective study from medical records of patients with ARP and CP attended between 2010 and 2020, analyzing the clinical characteristics, imaging studies, and the etiology associated with each patient. Results: We analyzed 25 patients: 17 were diagnosed with ARP, and eight with CP. The main etiology identified was an anatomical alteration of the pancreatic duct (32%); pancreas divisum was the most prevalent condition. In 48% of the population, the etiology was not identified. The group with CP was higher in frequency for calcifications and dilation of the pancreatic duct (p < 0.005) compared to the ARP group. Conclusions: The main etiology for ARP and CP was an anatomical alteration of the pancreatic duct; however, in almost half of the cases, no established cause was identified. Although comparing our results with those offered by large cohorts such as the INSPPIRE group can be complex, we found relevant similarities. Currently, the data obtained from this first descriptive study are the foundation for future research in the field of Mexican pediatric pancreatology.

Resumen Introducción: La pancreatitis aguda recurrente (PAR) y crónica (PC) son entidades poco frecuentes en la edad pediátrica; sin embargo, menos del 8% de la literatura hace referencia a esta población. El objetivo de este estudio fue describir el perfil clínico, paraclínico y etiologías vinculadas en los pacientes con PAR y PC atendidos en una institución de tercer nivel de atención en México. Métodos: Se realizó un estudio retrospectivo de los expedientes de los pacientes con PAR y PC atendidos entre 2010 a 2020, analizando las características clínicas, estudios de imagen y etiologías asociadas en cada uno de los pacientes. Resultados: Se analizaron 25 pacientes, 17 con diagnóstico de PAR y ocho con PC. La principal etiología identificada correspondió a las alteraciones anatómicas del conducto pancreático (32%); el páncreas divisum fue la entidad más prevalente. En el 48% de la población no se pudo identificar una etiología. El grupo con PC presentó mayor frecuencia de calcificaciones y dilatación ductal pancreática (p < 0.005) en comparación al grupo de PAR. Conclusiones: La principal etiología de PAR y PC identificada en nuestro estudio corresponde a las alteraciones anatómicas del conducto pancreático; sin embargo, en casi la mitad de los casos, no se tiene una causa establecida. Aunque es complicado comparar nuestros resultados con los ofrecidos por las grandes cohortes del grupo INSPPIRE, sí encontramos similitudes relevantes. Los datos obtenidos en este primer estudio descriptivo son la base para futuras investigaciones en el ámbito de la pancreatología pediátrica mexicana.

The Awake Craniotomy: A Patient's Experience and A Literature Review.

We present a case report and a literature review of the awake craniotomy procedure for mass resection, with emphasis on the historical aspects, anatomical and surgical considerations, and, uniquely, a patient's experience undergoing this procedure. This procedure is a safe and effective method for lesion resection when working in and around eloquent brain. We have described our process of guiding a patient through an awake craniotomy procedure and detailed the patient's experience in this study. We also conducted a systematic literature review of studies involving awake craniotomy over three years, 2018-2021. Lastly, we compared the methodology used by our institution and the current mostly used methods within the neurosurgical community. Several studies were identified using PubMed and Google Scholar. Awake craniotomy is a safe and effective method of achieving a high rate of resection of lesions located in and around the eloquent cortex with a low degree of postoperative neurological deficit.

Avances en tumores del estroma gastrointestinal: ¿hacia dónde vamos?

Gastrointestinal Stromal Sarcomas (GIST) are mesenchymal neoplasms whose incidence accounts for 1-2% of digestive tumors, being located in the stomach (55-60%) and small intestine (30%). The advances in its knowledge and management succeeded in the last years have being spectacular. This review aims to summarize the most important of them for surgeons. We identified four areas of interest: molecular oncology, laparoscopic approach, management of GIST located at unusual locations, and management of advanced GIST. Advances in the field of molecular oncology lead to the discovery of new oncogenic mutations making the term Wil Type GIST obsolete. Moreover, these advances allow for the development of 2 new drugs: Avapritinib and Ripretinib, that added to the previous 3 commercially available drugs (imatinib, sunitinib and regorafenib) make possible the management of GIST with resistant mutations. The principles of the surgical management of primary GIST are well stablished which laparoscopic approach must accomplish. This approach is limited by 2 main factors: location and size. The diagnosis of GIST in unusual locations as esophagus, duodenum, rectum of out of the gastrointestinal tract (EGIST), implies an extraordinary therapeutic challenge, being imperative to manage them by surgeons and oncologist among others in the setting of a multidisciplinary team. The management of advanced/metastatic GIST has changed in a revolutionary fashion because surgery is now part of its treatment as adjuvant to tyrosine kinase inhibitors.

Los tumores del estroma gastrointestinal (GIST) suponen el 1-2% de los tumores digestivos, siendo su localización más frecuente el estómago (55-60%) y el intestino delgado (30%). Los avances más importantes sucedidos en los últimos años se centran en cuatro áreas: biología molecular, abordaje quirúrgico laparoscópico, manejo técnico del GIST en localizaciones inusuales y tratamiento e integración de la cirugía en el manejo del GIST avanzado. Los avances en el conocimiento de la biología molecular del GIST han dado lugar a la progresiva identificación de nueva mutaciones oncogénicas que hacen del concepto wild type obsoleto. Estos avances han permitido el desarrollo de dos nuevos fármacos, avapritinib y ripretinib, lo que permite el tratamiento de pacientes con mutaciones resistentes a las tres líneas terapéuticas clásicas. El tratamiento quirúrgico del GIST se rige por unos principios técnicos bien establecidos que el abordaje laparoscópico debe cumplir, abordaje que queda limitado por dos factores clave: localización y tamaño. El GIST de localización infrecuente (esófago, duodeno o recto, o extradigestivo) supone un reto terapéutico. Estos pacientes deben ser manejados en un contexto multidisciplinario. La cirugía queda integrada en el manejo del GIST avanzado, considerándose como adyuvante a los inhibidores de la tirosina cinasa.

Comparative clinical effectiveness and safety of tobacco cessation pharmacotherapies and electronic cigarettes: a systematic review and network meta-analysis of randomized controlled trials.

AIM: To determine how varenicline, bupropion, nicotine replacement therapy (NRT) and electronic cigarettes compare with respect to their clinical effectiveness and safety. METHOD: Systematic reviews and Bayesian network meta-analyses of randomized controlled trials, in any setting, of varenicline, bupropion, NRT and e-cigarettes (in high, standard and low doses, alone or in combination) in adult smokers and smokeless tobacco users with follow-up duration of 24 weeks or greater (effectiveness) or any duration (safety). Nine databases were searched until 19 February 2019. Primary outcomes were sustained tobacco abstinence and serious adverse events (SAEs). We estimated odds ratios (ORs) and treatment rankings and conducted meta-regression to explore covariates. RESULTS: We identified 363 trials for effectiveness and 355 for safety. Most monotherapies and combination therapies were more effective than placebo at helping participants to achieve sustained abstinence; the most effective of these, estimated with some imprecision, were varenicline standard [OR = 2.83, 95% credible interval (CrI) = 2.34-3.39] and varenicline standard + NRT standard (OR = 5.75, 95% CrI = 2.27-14.88). Estimates were higher in smokers receiving counselling than in those without and in studies with higher baseline nicotine dependence scores than in those with lower scores. Varenicline standard + NRT standard showed a high probability of being ranked best or second-best. For safety, only bupropion at standard dose increased the odds of experiencing SAEs compared with placebo (OR = 1.27, 95% CrI = 1.04-1.58), and we found no evidence of effect modification. CONCLUSIONS: Most tobacco cessation monotherapies and combination therapies are more effective than placebo at helping participants to achieve sustained abstinence, with varenicline appearing to be most effective based on current evidence. There does not appear to be strong evidence of associations between most tobacco cessation pharmacotherapies and adverse events; however, the data are limited and there is a need for improved reporting of safety data.

Smoking cessation medicines and e-cigarettes: a systematic review, network meta-analysis and cost-effectiveness analysis.

BACKGROUND: Cigarette smoking is one of the leading causes of early death. Varenicline [Champix (UK), Pfizer Europe MA EEIG, Brussels, Belgium; or Chantix (USA), Pfizer Inc., Mission, KS, USA], bupropion (Zyban; GlaxoSmithKline, Brentford, UK) and nicotine replacement therapy are licensed aids for quitting smoking in the UK. Although not licensed, e-cigarettes may also be used in English smoking cessation services. Concerns have been raised about the safety of these medicines and e-cigarettes. OBJECTIVES: To determine the clinical effectiveness, safety and cost-effectiveness of smoking cessation medicines and e-cigarettes. DESIGN: Systematic reviews, network meta-analyses and cost-effectiveness analysis informed by the network meta-analysis results. SETTING: Primary care practices, hospitals, clinics, universities, workplaces, nursing or residential homes. PARTICIPANTS: Smokers aged ≥ 18 years of all ethnicities using UK-licensed smoking cessation therapies and/or e-cigarettes. INTERVENTIONS: Varenicline, bupropion and nicotine replacement therapy as monotherapies and in combination treatments at standard, low or high dose, combination nicotine replacement therapy and e-cigarette monotherapies. MAIN OUTCOME MEASURES: Effectiveness - continuous or sustained abstinence. Safety - serious adverse events, major adverse cardiovascular events and major adverse neuropsychiatric events. DATA SOURCES: Ten databases, reference lists of relevant research articles and previous reviews. Searches were performed from inception until 16 March 2017 and updated on 19 February 2019. REVIEW METHODS: Three reviewers screened the search results. Data were extracted and risk of bias was assessed by one reviewer and checked by the other reviewers. Network meta-analyses were conducted for effectiveness and safety outcomes. Cost-effectiveness was evaluated using an amended version of the Benefits of Smoking Cessation on Outcomes model. RESULTS: Most monotherapies and combination treatments were more effective than placebo at achieving sustained abstinence. Varenicline standard plus nicotine replacement therapy standard (odds ratio 5.75, 95% credible interval 2.27 to 14.90) was ranked first for sustained abstinence, followed by e-cigarette low (odds ratio 3.22, 95% credible interval 0.97 to 12.60), although these estimates have high uncertainty. We found effect modification for counselling and dependence, with a higher proportion of smokers who received counselling achieving sustained abstinence than those who did not receive counselling, and higher odds of sustained abstinence among participants with higher average dependence scores. We found that bupropion standard increased odds of serious adverse events compared with placebo (odds ratio 1.27, 95% credible interval 1.04 to 1.58). There were no differences between interventions in terms of major adverse cardiovascular events. There was evidence of increased odds of major adverse neuropsychiatric events for smokers randomised to varenicline standard compared with those randomised to bupropion standard (odds ratio 1.43, 95% credible interval 1.02 to 2.09). There was a high level of uncertainty about the most cost-effective intervention, although all were cost-effective compared with nicotine replacement therapy low at the £20,000 per quality-adjusted life-year threshold. E-cigarette low appeared to be most cost-effective in the base case, followed by varenicline standard plus nicotine replacement therapy standard. When the impact of major adverse neuropsychiatric events was excluded, varenicline standard plus nicotine replacement therapy standard was most cost-effective, followed by varenicline low plus nicotine replacement therapy standard. When limited to licensed interventions in the UK, nicotine replacement therapy standard was most cost-effective, followed by varenicline standard. LIMITATIONS: Comparisons between active interventions were informed almost exclusively by indirect evidence. Findings were imprecise because of the small numbers of adverse events identified. CONCLUSIONS: Combined therapies of medicines are among the most clinically effective, safe and cost-effective treatment options for smokers. Although the combined therapy of nicotine replacement therapy and varenicline at standard doses was the most effective treatment, this is currently unlicensed for use in the UK. FUTURE WORK: Researchers should examine the use of these treatments alongside counselling and continue investigating the long-term effectiveness and safety of e-cigarettes for smoking cessation compared with active interventions such as nicotine replacement therapy. STUDY REGISTRATION: This study is registered as PROSPERO CRD42016041302. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 59. See the NIHR Journals Library website for further project information.

Cigarette smoking is one of the main causes of early death both in the UK and worldwide. Three medicines, varenicline, bupropion and nicotine replacement therapy, are licensed in the UK to help people stop smoking. E-cigarettes can also be used as a stop smoking aid. We combined information from previous studies, including clinical trials, to determine which product was the safest, most effective and best value for money for the NHS. We compared treatments that were given alone as well as treatments that were combined with others, such as combination nicotine replacement therapy, varenicline combined with nicotine replacement therapy, varenicline combined with bupropion and bupropion combined with nicotine replacement therapy. The last three combined treatments are not currently licensed in the UK for smoking cessation. We also compared different treatment doses (low, high and standard doses). We found that most treatments were more effective than placebo in helping people to quit smoking. One of the combination treatments (varenicline at standard dose combined with nicotine replacement therapy at standard dose) was the most effective at getting people to quit smoking, followed by e-cigarette at low dose, varenicline at standard dose combined with bupropion at standard dose, and e-cigarette at high dose. We also found that smokers with higher tobacco dependence and smokers treated with counselling alongside medicines achieved a higher proportion of continuous quitting. We also found evidence that the standard dose of bupropion was associated with an increased risk of serious side effects compared with placebo. There was inconclusive evidence that any of the treatments increased the risk of major cardiovascular side effects. There was some evidence that smokers who received a standard dose of varenicline had an increased risk of major neurological and psychiatric side effects compared with those receiving a standard dose of bupropion. E-cigarette at low dose, varenicline standard plus nicotine replacement therapy standard and varenicline standard plus bupropion standard were the best value for money interventions, but further clinical trials comparing treatments against each other are needed to increase confidence in these findings.

Cost-Effectiveness Analysis of Smoking Cessation Interventions in the United Kingdom Accounting for Major Neuropsychiatric Adverse Events.

OBJECTIVES: Smoking is a leading cause of death worldwide. Cessation aids include varenicline, bupropion, nicotine replacement therapy (NRT), and e-cigarettes at various doses (low, standard and high) and used alone or in combination with each other. Previous cost-effectiveness analyses have not fully accounted for adverse effects nor compared all cessation aids. The objective was to determine the relative cost-effectiveness of cessation aids in the United Kingdom. METHODS: An established Markov cohort model was adapted to incorporate health outcomes and costs due to depression and self-harm associated with cessation aids, alongside other health events. Relative efficacy in terms of abstinence and major adverse neuropsychiatric events was informed by a systematic review and network meta-analysis. Base case results are reported for UK-licensed interventions only. Two sensitivity analyses are reported, one including unlicensed interventions and another comparing all cessation aids but removing the impact of depression and self-harm. The sensitivity of conclusions to model inputs was assessed by calculating the expected value of partial perfect information. RESULTS: When limited to UK-licensed interventions, varenicline standard-dose and NRT standard-dose were most cost-effective. Including unlicensed interventions, e-cigarette low-dose appeared most cost-effective followed by varenicline standard-dose + bupropion standard-dose combined. When the impact of depression and self-harm was excluded, varenicline standard-dose + NRT standard-dose was most cost-effective, followed by varenicline low-dose + NRT standard-dose. CONCLUSION: Although found to be most cost-effective, combined therapy is currently unlicensed in the United Kingdom and the safety of e-cigarettes remains uncertain. The value-of-information analysis suggested researchers should continue to investigate the long-term effectiveness and safety outcomes of e-cigarettes in studies with active comparators.

Prognostic Biomarkers for Thrombotic Microangiopathy after Acute Graft-versus-Host Disease: A Nested Case-Control Study.

Transplantation-associated thrombotic microangiopathy (TA-TMA) is a complication of allogeneic hematopoietic cell transplantation (HCT) that often occurs following the development of acute graft-versus-host disease (aGVHD). In this study, we aimed to identify early TMA biomarkers among patients with aGVHD. We performed a nested-case-control study from a prospective cohort of allogeneic HCT recipients, matching on the timing and severity of antecedent aGVHD. We identified 13 TMA cases and 25 non-TMA controls from 208 patients in the cohort. Using multivariable conditional logistic regression, the odds ratio for TMA compared with non-TMA was 2.65 (95% confidence interval [CI], 1.00 to 7.04) for every 100 ng/mL increase in terminal complement complex sC5b9 and 2.62 (95% CI, 1.56 to 4.38) for every 1000 pg/mL increase in angiopoietin-2 (ANG2) at the onset of aGVHD. ADAMTS13 and von Willebrand factor (VWF) antigens were not appreciably associated with TMA. Using a Cox regression model incorporating sC5b9 >300 ng/mL and ANG2 >3000 pg/mL at the onset of aGVHD, the adjusted hazard ratio for mortality was 5.33 (95% CI, 1.57 to 18.03) for the high-risk group (both elevated) and 4.40 (95% CI, 1.60 to 12.07) for the intermediate-risk group (one elevated) compared with the low-risk group (neither elevated). In conclusion, we found that elevated sC5b9 and ANG2 levels at the onset of aGVHD were associated with the development of TMA and possibly mortality after accounting for the timing and severity of aGVHD. The results suggest important roles of complement activation and endothelial dysfunction in the pathogenesis of TMA. Measurement of these biomarkers at the onset of aGVHD may inform prognostic enrichment for preventive trials and improve clinical care.

Echocardiographic Molecular Imaging of the Effect of Anticytokine Therapy for Atherosclerosis.

BACKGROUND: Echocardiographic molecular imaging techniques are beginning to be applied to evaluate preclinical efficacy of new drugs. In a large clinical trial, anti-interleukin-1ß (IL-1ß) immunotherapy reduced atherosclerotic events, yet treatment effects were modest, and the mechanisms of action were not fully elucidated. We tested the hypothesis that echocardiographic molecular imaging can assess changes in vascular thromboinflammatory status in response to anti-IL-1ß therapy. METHODS: In wild-type and atherosclerotic mice deficient for the low-density lipoprotein-receptor and Apobec-1, closed-chest myocardial infarction (MI) was performed to mimic high-risk clinical cohorts. Control animals had sham surgery. Post-MI animals were randomized to either no therapy or anti-IL-1ß immunotherapy, which was continued weekly. At post-MI day 3 or 21, in vivo ultrasound molecular imaging of aortic VCAM-1, P-selectin, von Willebrand factor A1-domain, and platelet GPIbα in the thoracic aorta was performed. Aortic histology and NF-κB activity were assessed in atherosclerotic mice. RESULTS: In both atherosclerotic and wild-type mice, MI produced a several-fold increase (P < .05) in aortic molecular signals for P-selectin, VCAM-1, von Willebrand factor, and GPIbα. In atherosclerotic mice, signal remained elevated at day 21. Anti-IL-1ß therapy completely abolished the post-MI increase in signal for all endothelial targets (P < .05 vs nontreated) at day 3 and 21. In atherosclerotic mice, MI triggered an increase in aortic plaque growth and macrophage content, a decrease in plaque collagen, and elevated aortic NF-κB (P < .05 for all changes). All of these remote plaque adverse changes were inhibited by anti-IL-1ß therapy. CONCLUSIONS: Echocardiographic molecular imaging of the vascular endothelium can quantify the beneficial effects of therapies designed to suppress the proatherosclerotic arterial thromboinflammatory effects of alarmins such as IL-1ß. This approach could potentially be used to evaluate the biologic variables that influence response in preclinical studies, and possibly to select patients most likely to benefit from therapy.

Excerpts from the documents of Mexican positions and recommendations in cardiovascular diseases and COVID-19.

The recommendations in which the Mexican Society of Cardiology (SMC) in conjunction with the National Association of Cardiologists of Mexico (ANCAM) as well as different Mexican medical associations linked to cardiology are presented, after a comprehensive and consensual review and analysis of the topics related to cardiovascular diseases in the COVID-19 pandemic. Scientific positions are analyzed and responsible recommendations on general measures are given to patients, with personal care, healthy eating, regular physical activity, actions in case of cardio-respiratory arrest, protection of the patient and health personnel as well as precise indications in the use of non-invasive cardiovascular imaging, prescription of medications, care in specific topics such as systemic arterial hypertension, heart failure, arrhythmias and acute coronary syndromes, in addition to emphasizing electrophysiology, interventionism, cardiac surgery and in cardiac rehabilitation. The main interest is to provide the medical community with a general orientation on what to do in daily practice and patients with cardiovascular diseases in the setting of this unprecedented epidemiological crisis of COVID-19.

Se presentan las recomendaciones en las cuales la Sociedad Mexicana de Cardiología (SMC) en conjunto con la Asociación Nacional de Cardiólogos de México (ANCAM), así como diferentes asociaciones médicas mexicanas vinculadas con la cardiología, después de una revisión y análisis exhaustivo y consensuado sobre los tópicos relacionados con las enfermedades cardiovasculares en la pandemia de COVID-19, se analizan posturas científicas y se dan recomendaciones responsables sobre medidas generales a los pacientes, con cuidados personales, alimentación saludable, actividad física regular, acciones en caso de paro cardiorrespiratorio, la protección del paciente y del personal de salud así como las indicaciones precisas en el uso de la imagen cardiovascular no invasiva, la prescripción de medicamentos, cuidados en tópicos específicos como en la hipertensión arterial sistémica, insuficiencia cardiaca, arritmias y síndromes coronarios agudos, además de hacer énfasis en los procedimientos de electrofisiología, intervencionismo, cirugía cardiaca y en la rehabilitación cardiaca. El interés principal es brindar a la comunidad médica una orientación general sobre el quehacer en la práctica cotidiana y pacientes con enfermedades cardiovasculares en el escenario esta crisis epidemiológica sin precedentes de COVID-19.

Recomendaciones para la atención de pacientes con insuficiencia cardiaca y COVID-19 / Recommendations for the care of patients with heart failure and COVID-19

Resumen La pandemia por COVID-19 decretada por la Organización Mundial de la Salud (OMS) desde el 12 de marzo de 2020 está produciendo estragos a nivel mundial y es un verdadero reto económico, social y sanitario. Aunque las manifestaciones clínicas del COVID-19 son síntomas respiratorios, algunos pacientes también tienen síntomas cardiológicos. Dentro de los pacientes con afecciones cardiológicas2 suponen un grupo de mayor riesgo y que de hecho son un grupo especialmente vulnerable, por su mayor riesgo de contagio y mayor gravedad en caso de adquirir la enfermedad1 aquellos con insuficiencia cardiaca (IC), incluyendo al trasplante cardiaco (TC) y las asistencias ventriculares, así como los pacientes con hipertensión arterial pulmonar (HAP). La IC es la principal patología cardiovascular crónica y los pacientes en este grupo son los más vulnerables para el desarrollo de cuadros clínicos más graves tras sufrir la infección, y en mayor medida los casos con IC avanzada3. De hecho, la IC es unas de las complicaciones más frecuentes en los pacientes con COVID-194. De igual forma, los pacientes trasplantados que requieren de los inmunosupresores para evitar el rechazo del injerto, constituyen una población especialmente susceptible a la infección y a desarrollar procesos más graves. Esta situación ha hecho que la Asociación Nacional de Cardiólogos de México (ANCAM) y la Sociedad Mexicana de Cardiología (SMC) junto con sus respectivos capítulos, hayan elaborado las siguientes recomendaciones para el personal médico, que participa en la atención de este grupo especial de pacientes en los diferentes escenarios clínicos, que padezcan o no, COVID-19.

Abstract The COVID-19 pandemic decreed by the World Health Organization (WHO) since March 12, 2020 is wreaking havoc globally and it is a true economic, social and health challenge. Although the clinical manifestations of COVID-19 are respiratory symptoms, some patients also have cardiological symptoms. Among patients with cardiological conditions2 they represent a group of higher risk and, in fact, they are a particularly vulnerable group, due to their higher risk of contagion and greater severity in case of acquiring the disease1 those with heart failure (HF), including heart transplant (CT) and ventricular assists, as well as patients with pulmonary arterial hypertension (PAH). HF is the main chronic cardiovascular disease and patients in this group are the most vulnerable for the development of more serious clinical symptoms after suffering the infection, and to a greater extent cases with advanced HF3. In fact, HF is one of the most frequent complications in patients with COVID-194. Likewise, transplant patients who require immunosuppressants to avoid graft rejection, constitute a population especially susceptible to infection and to develop more serious processes. This situation has made the National Association of Cardiologists of Mexico (ANCAM) and the Mexican Society of Cardiology (SMC) together with their respective chapters, have prepared the following recommendations for medical personnel, who participate in the care of this special group of patients in the different clinical settings, who suffer or not, of COVID-19.