Interactions of circadian clock genes with the hallmarks of cancer.

The molecular machinery of the circadian clock regulates the expression of many genes and processes in the organism, allowing the adaptation of cellular activities to the daily light-dark cycles. Disruption of the circadian rhythm can lead to various pathologies, including cancer. Thus, disturbance of the normal circadian clock at both genetic and environmental levels has been described as an independent risk factor for cancer. In addition, researchers have proposed that circadian genes may have a tissue-dependent and/or context-dependent role in tumorigenesis and may function both as tumor suppressors and oncogenes. Finally, circadian clock core genes may trigger or at least be involved in different hallmarks of cancer. Hence, expanding the knowledge of the molecular basis of the circadian clock would be helpful to identify new prognostic markers of tumorigenesis and potential therapeutic targets.

Epidemiological, Clinical, and Microbiological Characteristics in a Large Series of Patients Affected by Dermacentor-Borne-Necrosis-Erythema-Lymphadenopathy from a Unique Centre from Spain.

During recent decades, a tick-borne rickettsial syndrome, characterized by eschar and painful lymphadenopathy after Dermacentor marginatus-bite, has been described as an emerging rickettsiosis in Europe. Our group named it DEBONEL (Dermacentor-borne-necrosis-erythema-lymphadenopathy), regarding the vector and the main infection signs. Other groups called it TIBOLA (tick-borne-lymphadenophathy) and, later, SENLAT (scalp-eschar-and-neck-lymphadenopathy-after-tick-bite), expanding, in the latter, the etiological spectrum to other pathogens. Objective: To investigate the etiology of DEBONEL agents in our area, and to compare their epidemiological/clinical/microbiological characteristics. During 2001-2020, 216 patients clinically diagnosed of DEBONEL (the largest series from one center) in La Rioja (northern Spain) were examined. Rickettsia spp. were amplified in 14/104 (13.46%) blood samples, 69/142 (48.59%) eschar swabs, 7/7 (100%) biopsies, and 71/71 (100%) D. marginatus from patients. For samples in which Rickettsia was undetected, no other microorganisms were found. 'Candidatus Rickettsia rioja', Rickettsia slovaca, Rickettsia raoultii, and Rickettsia DmS1 genotype were detected in 91, 66, 4, and 3 patients, respectively. DEBONEL should be considered in patients with clinical manifestations herein described in areas associated to Dermacentor. The most frequently involved agent in our environment is 'Ca. R. rioja'. The finding of Rickettsia sp. DmS1 in ticks attached to DEBONEL patients suggests the implication of other rickettsia genotypes.

Structural mechanism for tyrosine hydroxylase inhibition by dopamine and reactivation by Ser40 phosphorylation.

Tyrosine hydroxylase (TH) catalyzes the rate-limiting step in the biosynthesis of dopamine (DA) and other catecholamines, and its dysfunction leads to DA deficiency and parkinsonisms. Inhibition by catecholamines and reactivation by S40 phosphorylation are key regulatory mechanisms of TH activity and conformational stability. We used Cryo-EM to determine the structures of full-length human TH without and with DA, and the structure of S40 phosphorylated TH, complemented with biophysical and biochemical characterizations and molecular dynamics simulations. TH presents a tetrameric structure with dimerized regulatory domains that are separated 15 Å from the catalytic domains. Upon DA binding, a 20-residue α-helix in the flexible N-terminal tail of the regulatory domain is fixed in the active site, blocking it, while S40-phosphorylation forces its egress. The structures reveal the molecular basis of the inhibitory and stabilizing effects of DA and its counteraction by S40-phosphorylation, key regulatory mechanisms for homeostasis of DA and TH.

Analyzing the impact of preoperative interrogation of cardiac implantable electronic devices.

Background: Cardiac implantable electronic devices (CIED) are becoming more common for the management of underlying of cardiac dysrhythmias, and more patients with these devices are presenting for cardiac and noncardiac procedures. Methods: We performed a retrospective, cohort, single-center study at a tertiary teaching medical center, gathering 151 patients with CIED undergoing elective and emergent surgeries for the time period between November 2013 and December 2016. We aimed to determine whether patients with CIED had the device interrogated before surgery as recommended by the Heart Rhythm Society (HRS)/American Society of Anesthesiologists (ASA) consensus, whether this lack of compliance led to delay in the holding area before surgery and determine the presence of intra- or postoperative cardiac events in these patients. Results: A total of 76% of patients had interrogation of the device before surgery. Emergent cases were not interrogated as much as elective cases preoperatively (43% vs. 18%, respectively; P < 0.05). In total, 6% of cases had a CIED-related average holding area delay time of 54 minutes. Patients without preoperative device interrogation had more perioperative cardiac events than those who had the device checked (25% vs. 8%, respectively; odds ratio [OR] 0.26; 95% CI, 0.09-0.7, P < 0.013). Conclusions: Our findings suggest that preoperative interrogation of the device plays a significant role to minimize the incidence of perioperative cardiac adverse events. Institutional providers show a lack of compliance with HRS/ASA recommendations for preoperative CIED management. Further research is required to determine if improved compliance to recommendations will lead to enhanced outcomes.

Maraviroc Prevents HCC Development by Suppressing Macrophages and the Liver Progenitor Cell Response in a Murine Chronic Liver Disease Model.

Maraviroc (MVC), a CCR5 antagonist, reduces liver fibrosis, injury and tumour burden in mice fed a hepatocarcinogenic diet, suggesting it has potential as a cancer therapeutic. We investigated the effect of MVC on liver progenitor cells (LPCs) and macrophages as both have a role in hepatocarcinogenesis. Mice were fed the hepatocarcinogenic choline-deficient, ethionine-supplemented diet (CDE) ± MVC, and immunohistochemistry, RNA and protein expression were used to determine LPC and macrophage abundance, migration and related molecular mechanisms. MVC reduced LPC numbers in CDE mice by 54%, with a smaller reduction seen in macrophages. Transcript and protein abundance of LPC-associated markers correlated with this reduction. The CDE diet activated phosphorylation of AKT and STAT3 and was inhibited by MVC. LPCs did not express Ccr5 in our model; in contrast, macrophages expressed high levels of this receptor, suggesting the effect of MVC is mediated by targeting macrophages. MVC reduced CD45+ cells and macrophage migration in liver and blocked the CDE-induced transition of liver macrophages from an M1- to M2-tumour-associated macrophage (TAM) phenotype. These findings suggest MVC has potential as a re-purposed therapeutic agent for treating chronic liver diseases where M2-TAM and LPC numbers are increased, and the incidence of HCC is enhanced.

Supra-systemic pulmonary hypertension after complicated percutaneous mitral balloon valvuloplasty: a case report and review of literature.

BACKGROUND: The World Symposium of Pulmonary Hypertension in 2018, updated the definition of pulmonary hypertension (PH) as mean pulmonary artery pressures (PAP) > 20 mmHg. Pulmonary venous hypertension secondary to left-heart disease, constitutes the most common cause of PH, and the determination of a co-existent pre-capillary (primary) PH becomes paramount, particularly at the moment of evaluating and managing patients with heart failure. Pulmonary artery pressures above the systemic pressures define supra-systemic PH and generally leads to frank right ventricular failure and high mortality. CASE PRESENTATION: We present the perioperative management of a patient with rheumatic mitral valve disease, initially found to have severe PH due to pulmonary venous hypertension, who underwent percutaneous mitral balloon valvuloplasty complicated with mitral chordae rupture, severe mitral regurgitation and supra-systemic PH. Multiple medical therapies and an intra-aortic balloon pump were used as means of non-surgical management of this complication. CONCLUSIONS: This case report illustrates the perioperative implications of combined pre- and post-capillary PH and supra-systemic PH, as this has not been widely discussed in previous literature. A thorough literature review of the clinical characteristics of PH, methods to determine co-existent pre- and post-capillary PH components, as well as concomitant right ventricular failure is presented. Severe PH has known detrimental effects on the hemodynamic status of patients, which can ultimately lead to a decrease in effective cardiac output and poor tissue perfusion.

Dynamic anterior mediastinal mass compression of the superior vena cava during airway stent deployment.

Mediastinal masses carry the intrinsic potential for life-threatening perioperative complications that directly impact anesthetic management, since well-recognized cardiopulmonary failure either chronic or acute may occur. A 48-year-old patient with known airway collapse due to an anterior mediastinal mass presents for airway stent insertion, that upon manipulation of the airway, a sudden and reproducible cardiovascular collapse ensued, due to dynamic compression of the superior vena cava, witnessed via endobronchial ultrasound. Close communication with the procedural team before and during manipulation of the patient's airway plays a paramount role to assure positive clinical outcomes.

COVID-19 in hospitalized HIV-positive and HIV-negative patients: A matched study.

OBJECTIVES: We compared the characteristics and clinical outcomes of hospitalized individuals with COVID-19 with [people with HIV (PWH)] and without (non-PWH) HIV co-infection in Spain during the first wave of the pandemic. METHODS: This was a retrospective matched cohort study. People with HIV were identified by reviewing clinical records and laboratory registries of 10 922 patients in active-follow-up within the Spanish HIV Research Network (CoRIS) up to 30 June 2020. Each hospitalized PWH was matched with five non-PWH of the same age and sex randomly selected from COVID-19@Spain, a multicentre cohort of 4035 patients hospitalized with confirmed COVID-19. The main outcome was all-cause in-hospital mortality. RESULTS: Forty-five PWH with PCR-confirmed COVID-19 were identified in CoRIS, 21 of whom were hospitalized. A total of 105 age/sex-matched controls were selected from the COVID-19@Spain cohort. The median age in both groups was 53 (Q1-Q3, 46-56) years, and 90.5% were men. In PWH, 19.1% were injecting drug users, 95.2% were on antiretroviral therapy, 94.4% had HIV-RNA < 50 copies/mL, and the median (Q1-Q3) CD4 count was 595 (349-798) cells/µL. No statistically significant differences were found between PWH and non-PWH in number of comorbidities, presenting signs and symptoms, laboratory parameters, radiology findings and severity scores on admission. Corticosteroids were administered to 33.3% and 27.4% of PWH and non-PWH, respectively (P = 0.580). Deaths during admission were documented in two (9.5%) PWH and 12 (11.4%) non-PWH (P = 0.800). CONCLUSIONS: Our findings suggest that well-controlled HIV infection does not modify the clinical presentation or worsen clinical outcomes of COVID-19 hospitalization.

PRO: The pulmonary artery catheter has a paramount role in current clinical practice.

Ever since its clinical introduction, the utilization of the pulmonary artery catheter (PAC) has been surrounded by multiple controversies, mostly related to imprecise clinical indications and the complications derived from its placement. Currently, one of the most important criticisms of the PAC is the ambiguity in the interpretation of its hemodynamic measurements and therefore, in the translation of this data into specific therapeutic interventions. The popularity of the PAC stems from the fact that it provides hemodynamic data that cannot be obtained from clinical examination. The assumption is that this information would allow better understanding of the individual's hemodynamic profile which would trigger therapeutic interventions that improve patient outcomes. Nevertheless, even with the current diversity of hemodynamic devices available, the PAC remains a valuable tool in a wide variety of clinical settings. The authors present a review exposing the benefits of the PAC, current clinical recommendations for its use, mortality and survival profile, its role in goal-directed therapy, and other applications of the PAC beyond cardiac surgery and the intensive care unit.

CON: Pulmonary artery catheter use should be forgone in modern clinical practice.

The pulmonary artery catheter (PAC) and its role in the practice of modern medicine remains to be questioned and has experienced a substantial decline in its use in the most recent decades. The complications associated to its use, the lack of consistency of the interpretation provided by the PAC among clinicians, the development of new hemodynamic methods, and the deleterious cost profile associated to the PAC are some of the reasons behind the decrease in its use. Since its introduction into clinical practice, the PAC and the data obtained from its use became paramount in the management of critically ill patients as well as for the high-risk/invasive procedures. Initially, many clinicians were under the impression that regardless the clinical setting, acquiring the information provided by the PAC justified its use, until a growing body of evidence demonstrated its lack of mortality and morbidity improvement, as well as several reports of the presence of difficulties-some of them fatal-during its insertion. The authors present an updated review discussing the futility of the PAC in current clinical practice, the complications associated to its insertion, the lack of mortality benefit in critically ill patients and cardiac surgery, as well as present alternative hemodynamic methods to the PAC.

Leveraging copper import by yersiniabactin siderophore system for targeted PET imaging of bacteria.

There is an emerging need for accurate and rapid identification of bacteria in the human body to achieve diverse biomedical objectives. Copper homeostasis is vital for the survival of bacterial species owing to the roles of the metal as a nutrient, respiratory enzyme cofactor, and a toxin. Here, we report the development of a copper-64-labeled bacterial metal chelator, yersiniabactin, to exploit a highly conserved metal acquisition pathway for noninvasive and selective imaging of bacteria. Compared with traditional techniques used to manufacture probes, our strategy simplifies the process considerably by combining the function of metal attachment and cell recognition to the same molecule. We demonstrate, for the first time to our knowledge, how a copper-64 PET probe can be used to identify specific bacterial populations, monitor antibiotic treatment outcomes, and track bacteria in diverse niches in vivo.

Perioperative care of heart transplant recipients undergoing non-cardiac surgery.

The life expectancy of patients with end-stage heart disease undergoing Orthotopic Heart Transplantation (OHT) has increased significantly in the recent decades since its original introduction into the medical practice in 1967. Substantial advances in post-operative intensive care, surgical prophylaxis, and anti-rejection drugs have clearly impacted survivability after OHT, therefore the volume of patients presenting for non-cardiac surgical procedures is expected to continue to escalate in the upcoming years. There are a number of caveats associated with this upsurge of post-OHT patients requiring non-cardiac surgery, including presenting to healthcare facilities without the resources and technology necessary to manage potential perioperative complications or that may not be familiar with the care of these patients, facilities in which a cardiac anesthesiologist is not available, patients presenting for emergency procedures and so forth. The perioperative care of patients after OHT introduces several challenges to the anesthesiologist including preoperative risk assessments different to the general population and intraoperative management of a denervated organ with altered response to medications and drug-drug interactions. The present review aims to synopsize current data of patients presenting for non-cardiac surgery after OHT, surgical aspects of the transplant that may impact perioperative care, physiology of the transplanted heart as well as anesthetic considerations.

Failure to Clear Intermediate Lactate Levels in Ward Patients With Admission Blood Cultures Did Not Increase the Risk of Intensive Care Unit Transfer or In-Hospital Mortality: A Retrospective Cohort Study.

Introduction A sepsis bundle instituted by the Centers for Medicare and Medicaid Services, known as SEP-1, mandates remeasuring lactate concentrations in patients with suspected sepsis who have an initial lactate level ≥ 2.0 mmol/L to identify those at risk of mortality or clinical deterioration. However, in the group with an intermediate lactate level (2.0 - 3.9 mmol/L), evidence for the predictive utility for such practice is lacking. The objective of this retrospective cohort study was to evaluate the potential utility of repeating the blood lactate measurement for the premonitory detection of clinical deterioration in patients admitted to a ward with a diagnosis of suspected sepsis and an initial intermediate lactate level. Methods Using electronic health records, we retrospectively evaluated all non-hospice adult patients admitted from the emergency department to a ward of an academic medical center between October 1, 2017, and November 30, 2019, in whom a blood culture was obtained on admission as part of their workup for suspected sepsis. Patient demographics, the times and values of lactate concentrations, the occurrence of subsequent intensive care unit (ICU) transfer during the admission, and hospital mortality were determined. We computed the relative risk of ICU transfer (i.e., clinical deterioration) and hospital mortality in patients whose initial lactate was in the intermediate range who failed to reduce their lactate concentration by at least 10% within six hours. We hypothesized that failure to clear the lactate would be associated with an increased risk of ICU transfer and hospital mortality. Results We studied 12,157 patients, of whom 25 hospice patients were excluded. Of the remaining 12,132 patients, 1,416 (11.7%) were initially admitted to an intensive care unit, and 10,716 (88.3%) were admitted to a ward. Repeat lactate determinations were performed in 10.7%, 77.1%, and 90.2% of the ward patients with initial normal (< 2.0 mmol/L), intermediate (2.0 - 3.99 mmol/L), and high (≥ 4.0 mmol/L) admission lactate concentrations, respectively. There was no increase in the relative risk of ICU transfer (relative risk [RR] = 0.90, 95% CI, 0.53 - 1.28, P = 0.55) or hospital mortality (RR = 1.23, 95% CI, 0.85 - 1.79, P = 0.27) within the intermediate lactate level group among those whose lactate remained within 10% of the initial value (i.e., no change) or increased by more than 10%, compared to those in whom the level decreased by more than 10%. Conclusions Failure to reduce lactate concentrations in ward patients admitted with possible sepsis and an intermediate lactate level was not associated with an increased risk of ICU transfer or mortality. These results call into question the mandate in SEP-1 to routinely repeat the lactate determination in patients presenting with an intermediate concentration.

Parallel veno-venous and veno-arterial extracorporeal membrane circuits for coexisting refractory hypoxemia and cardiovascular failure: a case report.

BACKGROUND: The complexity of extracorporeal membrane oxygenation (ECMO) techniques continues to evolve. Different cannulation methods and configurations have been proposed as a response to a challenging cardiovascular and pulmonary physiology of the patients. The use of parallel ECMO circuits represents a unique and novel approach for patients with refractory respiratory failure and cardiovascular collapse with very large body surface areas. CASE PRESENTATION: We present the case of a 25-year-old morbidly obese male patient admitted for severe acute respiratory distress syndrome (ARDS) and refractory hypoxemia, requiring institution of double cannulation for veno-venous ECMO. Since his hypoxemia persisted, likely due to insufficient flows given his large body surface area, an additional drainage venous cannula was implemented to provide higher flows, temporarily addressing his oxygenation status. Unfortunately, the patient developed concomitant cardiogenic shock refractory to inotropic support and extracorporeal fluid removal, further worsening his oxygenation status, thus the decision was to institute four-cannulation/parallel-circuits veno-venous and veno-arterial ECMO, successfully controlling both refractory hypoxemia and cardiogenic shock. CONCLUSIONS: Our case illustrates a novel and complex approach for combined severe ARDS and cardiovascular collapse through the use of parallel veno-venous and veno-arterial ECMO circuits, and exemplifies the expansion of ECMO techniques and its life-saving capabilities when conservative approaches are futile.

Expert Consensus Decision Pathway of the American College of Cardiology on Management of Bleeding in Patients With Oral Anticoagulants: A Review of the 2020 Update for Perioperative Physicians.

The use and evolution of oral anticoagulation therapies continue to advance for multiple reasons, including a growing segment of older patients with associated chronic prothrombotic illnesses including cardiovascular, pulmonary, hematologic and oncologic conditions. Correlated to this increased use of oral anticoagulants is bleeding complications associated with their use. Based on these trends, it is expected that perioperative physicians will be facing more and more of these patients requiring scheduled, urgent or emergent surgical procedures During May 2020, the American College of Cardiology updated its Expert Consensus Decision Pathway devoted to the approach of bleeding in patients on oral anticoagulants. This updated version emphasized the expanding role of the direct-acting oral anticoagulants in other conditions beyond nonvalvular atrial fibrillation, such as venous thromboembolism. Several details discussed within this most recent update are pertinent to perioperative physicians, who frequently deal with bleeding in the setting of anticoagulation. The purpose of this narrative review is to highlight and expand on these salient points because they relate to perioperative management.

Cyclotron Production and Separation of Scandium Radionuclides from Natural Titanium Metal and Titanium Dioxide Targets.

Theranostic strategies involve select radionuclides that allow diagnostic imaging and tailored radionuclide therapy in the same patient. An example of a Food and Drug Administration-approved theranostic pair is the 68Ga- and 177Lu-labeled DOTATATE peptides, which are used to image neuroendocrine tumors, predict treatment response, and treat disease. However, when using radionuclides of 2 different elements, differences in the pharmacokinetic and pharmacodynamic profile of the agent can occur. Theranostic agents that incorporate the matched-pair radionuclides of scandium-43Sc/47Sc or 44Sc/47Sc-would guarantee identical chemistries and pharmacologic profiles. The aim of this study was to investigate production of 43,44,47Sc via proton-induced nuclear reactions on titanium nuclei using a 24-MeV cyclotron. Methods: Aluminum, niobium, and tantalum target holders were used with titanium foils and pressed TiO2 to produce scandium radionuclides with proton energies of up to 24 MeV. Irradiated targets were digested using NH4HF2 and HCl in a closed perfluoroalkoxy alkane vessel in 90 min. Scandium radionuclides were purified via ion-exchange chromatography using branched N,N,N',N'-tetra-2-ethylhexyldiglycolamide. The titanium target material was recovered via alkali precipitation with ammonia solution. Results: Titanium foil and TiO2 were digested with an average efficiency of 98% ± 3% and 95% ± 1%, respectively. The typical digestion time was 45 min for titanium foil and 75 min for TiO2 The average scandium recovery was 94% ± 3%, and the average titanium recoveries from digested titanium foil and TiO2 after precipitation as TiO2 were 108% ± 8% and 104% ± 5% of initial mass, respectively. Conclusion: This work demonstrated a robust method for the cyclotron production of scandium radionuclides that could be used with natural or enriched TiO2 target material.

Intraoperative Focused Cardiac Ultrasound for Assessment of Hypotension: A Systematic Review.

Focused cardiac ultrasound (FoCUS) has become a valuable tool to assess unexplained hypotension in critically ill patients. Due to increasing availability of transthoracic echocardiography (TTE) equipment in the operating room, there is a widespread interest in its usefulness for intraoperative diagnosis of hypotension as an alternative to transesophageal echocardiography (TEE). The objective of this systematic review is to evaluate the utility of intraoperative FoCUS to assess patients experiencing unexplained hypotension while undergoing noncardiac surgery. We performed a systematic literature search of multiple publication databases for studies that evaluated the utility of intraoperative FoCUS for assessment and management of unexplained hypotension in patients undergoing noncardiac surgery, including retro- and prospective clinical studies. A summary of the study findings, study quality, and assessment of level of evidence is presented. We identified 2227 unique articles from the literature search, of which 27 were potentially relevant, and 9 were included in this review. The number of patients pooled from these studies was 255, of whom 228 had intraoperative diagnoses with the aid of intraoperative FoCUS. The level of evidence of all studies included was very low according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) guidelines. This systematic review has demonstrated that FoCUS may be a useful, noninvasive method to differentiate causes of intraoperative hypotension and guide correcting interventions, although the quality of evidence is very low. Further prospective high-quality studies are needed to investigate whether intraoperative FoCUS has a diagnostic utility that is associated with improved outcomes.