First-in-human study of alpibectir (BVL-GSK098), a novel potent anti-TB drug.

BACKGROUND: The clinical candidate alpibectir augments the activity of, and overcomes resistance to, the anti-TB drug ethionamide in vitro and in vivo. OBJECTIVES: A Phase 1, double-blind, randomized, placebo-controlled study to investigate the safety, tolerability, pharmacokinetics (PK) and food effect of alpibectir administered as single and multiple oral doses in healthy volunteers (NCT04654143). METHODS: Eighty participants were randomized. In single ascending dose (SAD), a total of six dose levels of alpibectir (0.5 to 40 mg) were tested under fasted and fed (10 mg) conditions as single daily doses in sequential cohorts. In multiple ascending dose (MAD), repeat doses (5 to 30 mg) were administered once daily for 7 days in three sequential cohorts. RESULTS: No serious adverse event was reported. Thirteen participants across groups experienced a total of 13 mild or moderate treatment-emergent adverse events. Alpibectir showed rapid absorption after single dose (mean Tmax range of 0.88 to 1.53 h). Food affected the PK of alpibectir, characterized by a slower absorption (mean Tmax 3.87 h), a lower Cmax (-17.7%) and increased AUC0-t (+19.6%) compared with the fasted condition. Following repeat dosing, dose proportionality was shown for both Cmax and AUC0-tau. Accumulation of alpibectir was observed across all doses, with a more profound effect on AUC during a dosing interval (AUC0-tau) compared with Cmax (1.8- and 1.3-fold on average), respectively. Steady state was considered to have been achieved by Day 7 of dosing. CONCLUSIONS: Alpibectir was generally well tolerated, and no clinically relevant safety findings were identified in the participants treated during SAD or MAD. The PK is dose-proportional and affected by food.

Advanced esophageal neuroendocrine carcinoma.

Case report of an advanced esophageal neuroendocrine carcinoma with hepatic metastasis.

Are intracystic chromogranin A and neuron-specific enolase useful in the diagnosis of cystic pancreatic neuroendocrine tumors?

Value of Choromogranin A and neuron-specific enolase intracystic (EUS-FNB) in the preoperatory diagnosis of cystic pancreatic neuroendocrine tumors.

In Search of the Holy Grail of Artificial Hearts: Are We There Yet?

The total artificial heart (TAH) has a long and rich history, being the product of decades of innovation, hard work, and dedication. This review examines the history of the TAH, a device that has revolutionized the treatment of end-stage biventricular heart failure. It reviews the development of the device from early concepts to the current state-of-the-art device, the SynCardia TAH, which has been implanted in over 2,000 patients worldwide. The article also discusses the challenges and successes experienced by researchers, clinicians, and patients throughout the development of TAH devices. Our focus will also be on discussing the hemostatic alterations in patients implanted with TAH and anticoagulation strategies to decrease associated thromboembolic risks. The article concludes with a look at other novel TAH devices and the future of TAH as an increasingly viable treatment for end-stage heart failure.

Endoscopic management of gastric neuroendocrine tumors: an analysis of 50 cases.

Of 50 cases gastric neuroendocrine tumors, in 30 (60%) endoscopic treatment, with relapse rate of 25%, perforation 3,6% and bleeding 7,1%.

Heart Transplant Outcomes After Total Artificial Heart.

BACKGROUND: We sought to compare heart transplant (HTX) outcomes from patients with a total artificial heart (TAH), biventricular assist device (BiVAD), or left ventricular assist device (LVAD) as a bridge to transplant (BTT). Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS)-Scientific Registry of Transplant Recipients (SRTR) created a dataset with TAH or durable mechanical circulatory support (MCS) who reached HTX between 2006 and 2015. METHODS: The retrospective analysis compared TAH outcomes with those with a BiVAD or LVAD before HTX. The primary outcome was posttransplant survival at 1, 36, and 60 months. Secondary outcomes included simultaneous heart-kidney transplants, donor characteristics, and mortality risk factors. INTERMACS-SRTR cohort had, at the time of HTX, 2762 patients with LVAD; 205 BiVAD (139 durable and 66 temporary RVAD); 176 TAH (6 prior HeartMate II). RESULTS: Sixty months after HTX, mortality rates were 16.5% in the total group: LVAD 15.2%, BiVAD 22.4%, and TAH 29%. Survival differed between the LVAD, the TAH, and BiVAD but not between the BiVAD and TAH groups. One-year survival and complication rates were similar across groups-there was no difference in survival by donor age in the overall cohort. There was a difference in TTD based on recipient age in the LVAD group but not in BiVAD or TAH groups. Occurrence of HTX-kidney and post-transplant dialysis were higher in the TAH versus LVAD and BiVAD groups. CONCLUSIONS: The TAH is an efficacious BTT. Refinements in technology and patient selection may improve outcomes.

Disordering two-dimensional magnet-particle configurations using bidispersity.

In various types of many-particle systems, bidispersity is frequently used to avoid spontaneous ordering in particle configurations. In this study, the relation between bidispersity and disorder degree of particle configurations is investigated. By using magnetic dipole-dipole interaction, magnet particles are dispersed in a two-dimensional cell without any physical contact between them. In this magnetic system, bidispersity is introduced by mixing large and small magnets. Then, the particle system is compressed to produce a uniform particle configuration. The compressed particle configuration is analyzed by using Voronoi tessellation for evaluating the disorder degree, which strongly depends on bidispersity. Specifically, the standard deviation and skewness of the Voronoi cell area distribution are measured. As a result, we find that the peak of standard deviation is observed when the numbers of large and small particles are almost identical. Although the skewness shows a non-monotonic behavior, a zero skewness state (symmetric distribution) can be achieved when the numbers of large and small particles are identical. In this ideally random (disordered) state, the ratio between pentagonal, hexagonal, and heptagonal Voronoi cells becomes roughly identical, while hexagons are dominant under monodisperse (ordered) conditions. The relation between Voronoi cell analysis and the global bond orientational order parameter is also discussed.

The small-molecule SMARt751 reverses Mycobacterium tuberculosis resistance to ethionamide in acute and chronic mouse models of tuberculosis.

The sensitivity of Mycobacterium tuberculosis, the pathogen that causes tuberculosis (TB), to antibiotic prodrugs is dependent on the efficacy of the activation process that transforms the prodrugs into their active antibacterial moieties. Various oxidases of M. tuberculosis have the potential to activate the prodrug ethionamide. Here, we used medicinal chemistry coupled with a phenotypic assay to select the N-acylated 4-phenylpiperidine compound series. The lead compound, SMARt751, interacted with the transcriptional regulator VirS of M. tuberculosis, which regulates the mymA operon encoding a monooxygenase that activates ethionamide. SMARt751 boosted the efficacy of ethionamide in vitro and in mouse models of acute and chronic TB. SMARt751 also restored full efficacy of ethionamide in mice infected with M. tuberculosis strains carrying mutations in the ethA gene, which cause ethionamide resistance in the clinic. SMARt751 was shown to be safe in tests conducted in vitro and in vivo. A model extrapolating animal pharmacokinetic and pharmacodynamic parameters to humans predicted that as little as 25 mg of SMARt751 daily would allow a fourfold reduction in the dose of ethionamide administered while retaining the same efficacy and reducing side effects.

An updated meta-analysis of TAVR in patients at intermediate risk for SAVR.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) has been approved for use in patients with severe aortic stenosis at intermediate, high and extreme surgical risk. This meta-analysis was performed to assess the safety and efficacy of TAVR compared to surgical aortic valve replacement (SAVR) in intermediate risk patients. METHODS: We searched PubMed, EMBASE, Web of science, and the Cochrane Central Register of Controlled Trials databases for studies comparing TAVR versus SAVR in patients at intermediate surgical risk, with a mean Society of Thoracic Surgeon score of 3-8% or a mean logistic European risk score of 10-20%. The primary endpoint was to assess the efficacy of TAVR compared to SAVR, defined as all-cause and cardiovascular mortality at 30-days, 1-year, and ≥2 years of follow-up. Secondary endpoints were the safety profile, comprising of cerebrovascular events, myocardial infarctions, permanent pacemaker placement, new onset atrial fibrillation, aortic regurgitation, vascular complications, major bleeding and acute kidney injury. RESULTS: This is the largest and most contemporary meta-analysis of 5647 intermediate risk patients in eleven studies published to date. There were no statistically significant differences in all-cause and cardiac mortality at 30 days, 1- year and >2-years of follow up. Acute kidney injury and atrial fibrillation occurred more frequently in patients treated with SAVR and permanent pacemaker implantation and aortic insufficiency were more frequent in patients treated with TAVR. CONCLUSION: This meta-analysis suggests that for intermediate risk patients with severe aortic stenosis, TAVR has similar efficacy as SAVR but with a different adverse event profile.

Tumores neuroendocrinos quísticos del páncreas / Cystic pancreatic neuroendocrine tumor. Pancreatic endocrine or neuroendocrine tumor. Endoscopic ultrasonography

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Cystic pancreatic neuroendocrine tumor. Pancreatic endocrine or neuroendocrine tumor. Endoscopic ultrasonography.

Cystic pancreatic neuroendocrine tumors (cPNETs) represent less than 8% of all pancreatic cysts and approximately 13% of pancreatic endocrine tumors (PNETs). According to a recent review, the percentage of non-functional (NF) PNETs is 85% and 44.6% are incidentalomas. In our series of 75 PNET cases, ten cPNET cases (13%) were identified which are discussed and summarized below.

Miniprobe Endoscopic Sonography for Gastrointestinal Tract Assessment: A Case Series of 1451 Procedures.

Conventional endoscopic sonography has allowed precise diagnostics without disturbances, and miniprobes can be easily introduced through the biopsy channel of the endoscope. Miniprobe endoscopic sonography has many benefits compared with conventional endoscopic sonography. Although there are well-known indications for miniprobe endoscopic sonography in endoscopic digestive tract assessment, there is still a need for this method to be widely spread among physicians and commonly used by most endoscopists. The aim of this series was to describe a multicenter retrospective experience with 1451 procedures using miniprobes, presenting examples and the applicability and usefulness of this technology in the daily activities of an endoscopy department.

Canalization technique to obtain deep tissue biopsy of gastrointestinal subepithelial tumors as an alternative to conventional known techniques.

BACKGROUND AND OBJECTIVES: The most accurate technology to detect and diagnose subepithelial tumors (SETs) is the endoscopic ultrasonography (EUS) combined with puncture techniques, such as the endoscopic ultrasonography-guided fine-needle aspiration (EUS-FNA) or the endoscopic ultrasonography-guided fine-needle biopsy. Going further in the improvement of the results of tumor samples obtained endoscopically to diagnose the SETs, the canalization technique guided by miniprobes (MPs) to obtain biopsies of SET could be an alternative to EUS-FNA. The objective of this study is to analyze the results of samples obtained by this procedure. MATERIALS AND METHODS: A multicenter, retrospective study of a review of a database of 32 consecutive patients with a SET in the digestive tract, from 2000 to 2015 was conducted. All patients underwent EUS-performed by MP, to define the size, internal echostructure, and layer of origin of tumor. Once the echostructure was defined, it proceeded to the canalization technique to arrive to the tumor tissue. RESULTS: The average diameter of SETs in this series (32 patients) was about 21.6±11 mm (range: 5-41 mm). The diagnostic accuracy was 28/32, 87.50% (Confidence interval 95%: 76.04%-98.99%), and there were no major complications. All procedures were performed on outpatients, none of which required additional hospitalization. The 50% of patients were operated or endoscopically resected and in all cases, the previous pathological diagnosis was confirmed. CONCLUSIONS: This is a feasible, safe, and effective procedure that allows to access to inside of SET to obtain deep biopsies. Tumor samples obtained by deep biopsy, with prior performing of the canalization technique guided by MP, were sufficient for histopathological and immunohistochemical diagnosis and similar to those obtained with other known methods (FNA Trucut, ProCore®, etc.). However, more prospective comparative studies with a larger number of patients and different specialists carrying out the procedure to reach a higher statistical significance are necessary.

Neoplasia neuroendocrina rectal / A rectal neuroendocrine neoplasm

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Enteropatía asociada a olmesartán: atención a un fenómeno iatrogénico emergente / Olmesartan-associated enteropathy: attention to an emerging iatrogenic phenomenon

El olmesartán es un antagonista del receptor tipo 1 de la angiotensina II utilizado habitualmente en el tratamiento de pacientes con hipertensión arterial. Recientemente se han descrito varios casos de enteropatía sprue-like asociados al uso de este fármaco, con afectación clínica importante y total remisión tras la retirada del mismo. Se presenta el caso de un varón de 64 años, con antecedentes de hipertensión arterial en tratamiento con olmesartan-amlodipino con clínica de diarrea y pérdida de peso severas, atrofia vellositaria en biopsia duodenal sin criterios de enfermedad celiaca y remisión completa del cuadro tras la supresión del olmesartán. Basado en los hallazgos del caso clínico presentado, se revisan las manifestaciones clínicas e histopatológicas así como el curso evolutivo de una posible causa de enteropatía farmacológica recientemente descrita (AU)

Olmesartan is an angiotensin II type 1 receptor blocker commonly used in the treatment of hypertension. Several cases of sprue-like enteropathy associated with the use of this drug have been described which, even with important signs and limitations for the patient, present a full recovery after discontinuing the use of olmesartan. The case of a 64 year-old patient is presented, diagnosed with hypertension, under treatment with olmesartan- amlodipine, with chronic diarrhoea and villous atrophy on intestinal biopsies without diagnostic criteria for celiac disease and with complete remission after suspending discontinuing the use of olmesartan. Based on the clinical features presented by the case reported, the clinical and anatomopathological findings are described as well as the evolution of drug-induced enteropathy (AU)

A rectal neuroendocrine neoplasm.

The incidence of gastric and rectal carcinoids is increasing. This is probably due to endoscopic screening. The prognosis is primarily dependent upon tumor size, aggressiveness (pathology, Ki-67), metastatic disease and stage. However, neuroendocrine carcinoma usually behaves as an adenocarcinoma.

Tumores neuroendocrinos pancreáticos / Pancreatic neuroendocrine tumors

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THPP target assignment reveals EchA6 as an essential fatty acid shuttle in mycobacteria.

Phenotypic screens for bactericidal compounds against drug-resistant tuberculosis are beginning to yield novel inhibitors. However, reliable target identification remains challenging. Here, we show that tetrahydropyrazo[1,5-a]pyrimidine-3-carboxamide (THPP) selectively pulls down EchA6 in a stereospecific manner, instead of the previously assigned target Mycobacterium tuberculosis MmpL3. While homologous to mammalian enoyl-coenzyme A (CoA) hydratases, EchA6 is non-catalytic yet essential and binds long-chain acyl-CoAs. THPP inhibitors compete with CoA-binding, suppress mycolic acid synthesis, and are bactericidal in a mouse model of chronic tuberculosis infection. A point mutation, W133A, abrogated THPP-binding and increased both the in vitro minimum inhibitory concentration and the in vivo effective dose 99 in mice. Surprisingly, EchA6 interacts with selected enzymes of fatty acid synthase II (FAS-II) in bacterial two-hybrid assays, suggesting essentiality may be linked to feeding long-chain fatty acids to FAS-II. Finally, our data show that spontaneous resistance-conferring mutations can potentially obscure the actual target or alternative targets of small molecule inhibitors.

A review of the dissociative disorders: from multiple personality disorder to the posttraumatic stress / Una revisión de los trastornos disociativos: de la personalidad múltiple al estrés postraumático

In this paper we review the idea of dissociation, dissociative disorders and their relationship with the processes of consciousness. We will deal specifically with multiple personality disorder and posttraumatic stress disorder. Both polarize the discussion of diagnostic categories with dissociative symptoms. This review compares the initial ideas (one century old) with the current scenario and emerging trends in research, which are relating cognitive processes and dissociative phenomena and disorders from a neuroscientific approach. We discuss the ideas on dissociation, hypnosis and suicide associated with these disorders. There seems to be a lack of consensus as to the nature of dissociation with theoretical, empirical and clinical implications

Este trabajo trata la idea de disociación, los trastornos disociativos y su relación con los procesos de conciencia. Se centra en el trastorno de personalidad múltiple y el trastorno de estrés postraumático, desde la perspectiva del diagnóstico y del tratamiento. Ambos grupos de trastornos polarizan el debate sobre las categorías diagnósticas con síntomas disociativos. Se revisan las ideas sobre disociación, hipnosis y suicidio asociadas a estos trastornos. Parece darse una falta de consenso en cuanto a la naturaleza misma de la disociación con implicaciones teóricas, empíricas y clínicas. Completa esta revisión la comparación desde sus inicios, hace poco más de un siglo, con el panorama actual y las nuevas tendencias en las investigaciones que desde las neurociencias están relacionando los procesos cognitivos con los fenómenos y trastornos disociativos