Elevated Cardiac Troponin I Level associated to Cardiac Dysfunction in Burned Patients.

Severely burned patients often developed cardiac dysfunction and heart failure. The purpose of this retrospective study is to evaluate the role of Cardiac Troponin I (cTI) and its association to patients with burns. Patients deidentified data were collected from a national database in May 2023. Adult burn patients who had cTnI lab counted were enrolled in this study. Patients were grouped by the cTnI mean level within 72 hours including patients with elevated cTnI levels at >0.3 ng/mL (n= 2188 patients), and patients with non-elevated cTnI level (< 0.04 ng/mL) (n= 3200). The cohorts were further stratified by less than 20% TBSA mild burn population and >20% TBSA severe burn population to replicate the severity of burns. The 30-days incidences of acute myocardial infarction (MI), sepsis, and mortality were investigated after the cohorts were propensity matching balanced. The odds ratios (ORs) with 95%CI for MI were (9.829/7.081-13.645), sepsis (1.527/1.269-1.959) and mortality (2.586/2.110- 3.170) respectively (p<0.05). The groups that were further stratified into mild burn and severe burn had the following results: The mild burn ORs and 95% CI for MI was (6.237/3.986-9.785), sepsis (1.603/1.132-2.270), and mortality was (2.298/1.629-3.242). The severe burn cohort had ORs and 95% CI for MI (3.145/1.469-6.732), sepsis (0.993/0.555-1.777), mortality (2.934/1.924-4.475). In conclusion, the patients with earlier elevated cTnI level had worse outcomes of MI and mortality in both severe and mild burns.

Structural basis for nuclear import of hepatitis B virus (HBV) nucleocapsid core.

Nuclear import of the hepatitis B virus (HBV) nucleocapsid is essential for replication that occurs in the nucleus. The ~360-angstrom HBV capsid translocates to the nuclear pore complex (NPC) as an intact particle, hijacking human importins in a reaction stimulated by host kinases. This paper describes the mechanisms of HBV capsid recognition by importins. We found that importin α1 binds a nuclear localization signal (NLS) at the far end of the HBV coat protein Cp183 carboxyl-terminal domain (CTD). This NLS is exposed to the capsid surface through a pore at the icosahedral quasi-sixfold vertex. Phosphorylation at serine-155, serine-162, and serine-170 promotes CTD compaction but does not affect the affinity for importin α1. The binding of 30 importin α1/ß1 augments HBV capsid diameter to ~620 angstroms, close to the maximum size trafficable through the NPC. We propose that phosphorylation favors CTD externalization and prompts its compaction at the capsid surface, exposing the NLS to importins.

Structure of the Hepatitis B virus capsid quasi-6-fold with a trapped C-terminal domain reveals capsid movements associated with domain exit.

Many viruses undergo transient conformational change to surveil their environments for receptors and host factors. In Hepatitis B virus (HBV) infection, after the virus enters the cell, it is transported to the nucleus by interaction of the HBV capsid with an importin α/ß complex. The interaction between virus and importins is mediated by nuclear localization signals on the capsid protein's C-terminal domain (CTD). However, CTDs are located inside the capsid. In this study, we asked where does a CTD exit the capsid, are all quasi-equivalent CTDs created equal, and does the capsid structure deform to facilitate CTD egress from the capsid? Here, we used Impß as a tool to trap transiently exposed CTDs and examined this complex by cryo-electron microscopy. We examined an asymmetric reconstruction of a T = 4 icosahedral capsid and a focused reconstruction of a quasi-6-fold vertex (3.8 and 4.0 Å resolution, respectively). Both approaches showed that a subset of CTDs extended through a pore in the center of the quasi-6-fold complex. CTD egress was accompanied by enlargement of the pore and subtle changes in quaternary and tertiary structure of the quasi-6-fold. When compared to molecular dynamics simulations, structural changes were within the normal range of capsid flexibility. Although pore diameter was enlarged in the Impß-bound reconstruction, simulations indicate that CTD egress does not exclusively depend on enlarged pores. In summary, we find that HBV surveillance of its environment by transient exposure of its CTD requires only modest conformational change of the capsid.

Primary Sjögren syndrome and development of another autoimmune rheumatic disease during the follow-up.

BACKGROUND: Primary Sjögren syndrome (pSS) is a chronic autoimmune disease with its main target being exocrine glands, and is the connective tissue disease more frequently associated with other autoimmune diseases. The aim of this study was to assess the frequency of another autoimmune rheumatic disease (ARD) developed in primary Sjögren syndrome (pSS) patients and to describe it's clinical, serological and histologic characteristics. MATERIALS AND METHODS: This is a retrospective cohort study. Data of patients with pSS diagnosis (American-European criteria 2002), included in the GESSAR database (Grupo de Estudio Síndrome de Sjögren, Sociedad Argentina de Reumatología) were analyzed. The development of a second ARD was registered during the follow up. RESULTS: 681 patients were included, 94.8% female. The mean age was 54 (SD 14) years and mean age at diagnosis of 50 (SD 13) years. The mean follow-up was 4.7 (SD 4.9) years; 30 patients (4.41%, CI 95%: 3.1-5.7) developed a second ARD during the follow up, incidence rate was 9.1/1000 patients-year (IR 95%: 5.8-12.4/1000 patients-year), the most frequent being rheumatoid arthritis (RA). 96% out of these 30 patients had xerophthalmia, 86.2% xerostomia, 92% positive Schirmer test, 88.24% positive Rosa Bengala test, lisamine green or Ocular Staining Score, 81.2% positive unstimulated salivary flow, 82.1% Ro(+) and 33.33% La(+). Minor salivary gland biopsy had been performed in 14 of the 30 patients, 12 with positive results. There were no statistically significant differences respect baseline characteristics when comparing the patients who developed another ARD to the ones that did not. CONCLUSIONS: Of all the patients analyzed, 4.4% presented another ARD during their follow-up. It is important to be aware of this, to make an early and proper diagnosis and treatment of our patients.

Implementing COVID-19 surveillance through inter-organizational coordination: a qualitative study of three cities in Colombia.

Introducing comprehensive surveillance is recommended as an urgent public health measure to control and mitigate the spread of coronavirus disease 2019 (COVID-19) worldwide. However, its implementation has proven challenging as it requires inter-organizational coordination among multiple healthcare stakeholders. The purpose of this study was to examine the role of soft and hard mechanisms in the implementation of inter-organizational coordination strategies for COVID-19 surveillance within Colombia, drawing on evidence from the cities of Bogotá, Cali and Cartagena. The study used a case study approach to understand the perspectives of local and national authorities, insurance companies and health providers in the implementation of inter-organizational coordination strategies for COVID-19 surveillance. Eighty-one semi-structured interviews were conducted between June and November 2020. The data were analysed by codes and categorized using New NVivo software. The study identified inter-organizational coordination strategies that were implemented to provide COVID-19 surveillance in the three cities. Both soft (e.g. trust and shared purpose) and hard mechanisms (e.g. formal agreements and regulations) acted as mediators for collaboration and helped to address existing structural barriers in the provision of health services. The findings suggest that soft and hard mechanisms contributed to promoting change among healthcare system stakeholders and improved inter-organizational coordination for disease surveillance. The findings contribute to evidence regarding practices to improve coordinated surveillance of disease, including the roles of new forms of financing and contracting between insurers and public and private health service providers, logistics regarding early diagnosis in infectious disease and the provision of health services at the community level regardless of insurance affiliation. Our research provides evidence to improve disease surveillance frameworks in fragmented health systems contributing to public health planning and health system improvement.

Primary Sjögren syndrome and development of another autoimmune rheumatic disease during the follow-up

Abstract Background: Primary Sjögren syndrome (pSS) is a chronic autoimmune disease with its main target being exocrine glands, and is the connective tissue disease more frequently associated with other autoimmune diseases. The aim of this study was to assess the frequency of another autoimmune rheumatic disease (ARD) developed in primary Sjögren syndrome (pSS) patients and to describe it's clinical, serological and histologic characteristics. Materials and methods: This is a retrospective cohort study. Data of patients with pSS diagnosis (American-European criteria 2002), included in the GESSAR database (Grupo de Estudio Síndrome de Sjögren, Sociedad Argentina de Reumatología) were analyzed. The development of a second ARD was registered during the follow up. Results: 681 patients were included, 94.8% female. The mean age was 54 (SD 14) years and mean age at diagnosis of 50 (SD 13) years. The mean follow-up was 4.7 (SD 4.9) years; 30 patients (4.41%, CI 95%: 3.1-5.7) developed a second ARD during the follow up, incidence rate was 9.1/1000 patients-year (IR 95%: 5.8-12.4/1000 patients-year), the most frequent being rheumatoid arthritis (RA). 96% out of these 30 patients had xerophthalmia, 86.2% xerostomia, 92% positive Schirmer test, 88.24% positive Rosa Bengala test, lisamine green or Ocular Staining Score, 81.2% positive unstimulated salivary flow, 82.1% Ro(+) and 33.33% La(+). Minor salivary gland biopsy had been performed in 14 of the 30 patients, 12 with positive results. There were no statistically significant differences respect baseline characteristics when comparing the patients who developed another ARD to the ones that did not. Conclusions: Of all the patients analyzed, 4.4% presented another ARD during their follow-up. It is important to be aware of this, to make an early and proper diagnosis and treatment of our patients. Key points Patients with primary Sjögren's Syndrome may develop another connective tissue disease during follow-up. The most frequently connective tissue disease developed during follow-up in the population of patients with primary Sjogren's Syndrome studied was rheumatoid arthritis. It is important to be aware of this to make an early and proper diagnosis.

Subset of Fluorophores Is Responsible for Radiation Brightening in Viromimetic Particles.

In certain conditions, dye-conjugated icosahedral virus shells exhibit suppression of concentration quenching. The recently observed radiation brightening at high fluorophore densities has been attributed to coherent emission, i.e., to a cooperative process occurring within a subset of the virus-supported fluorophores. Until now, the distribution of fluorophores among potential conjugation sites and the nature of the active subset remained unknown. With the help of mass spectrometry and molecular dynamics simulations, we found which conjugation sites in the brome mosaic virus capsid are accessible to fluorophores. Reactive external surface lysines but also those at the lumenal interface where the coat protein N-termini are located showed virtually unrestricted access to dyes. The third type of labeled lysines was situated at the intercapsomeric interfaces. Through limited proteolysis of flexible N-termini, it was determined that dyes bound to them are unlikely to be involved in the radiation brightening effect. At the same time, specific labeling of genetically inserted cysteines on the exterior capsid surface alone did not lead to radiation brightening. The results suggest that lysines situated within the more rigid structural part of the coat protein provide the chemical environments conducive to radiation brightening, and we discuss some of the characteristics of these environments.

Organisational responses to mitigate the effects of COVID-19 on healthcare workers: a qualitative case study from Bogotá, Colombia.

BACKGROUND: Healthcare organisations have undergone organisational change to respond to COVID-19. This pandemic has presented challenges for employee adjustment, with impacts on the availability and coordination of human resources in healthcare. This study aimed to characterise the organisational actions regarding the coordination of human resources in healthcare within Bogotá, Colombia, to respond to the COVID-19 pandemic. METHODS: We followed a case study approach to understand the response to the emergency taking into account the narratives of managerial actors who have been directly involved in the planning of guidelines oriented to face the pandemic or in the implementation of health services for COVID-19. Twenty-two interviews with multiple health system organisations within Bogotá were conducted between May and September 2020 and analysed thematically. RESULTS: Three themes emerged from the analysis of the interview data: to retain human resources, to implement actions to improve the mental and physical health of the healthcare workers, and to enhance healthcare workers knowledge, skills and availability to respond to COVID-19. CONCLUSIONS: Organisational actions led by hospital managers to retain, protect, and train human health resources in the dynamic context of the COVID-19 pandemic were identified. Other system-wide organisations like scientific associations contributed to the coordination of human resources across hospitals to respond to COVID-19 in Bogotá, Colombia. The actions of hospital managers, and roles of system-wide intermediary organisations, in coordinating human resources need to be explored in other health system contexts facing COVID-19.

Molecular dynamics of the viral life cycle: progress and prospects.

Molecular dynamics (MD) simulations across spatiotemporal resolutions are widely applied to study viruses and represent the central technique uniting the field of computational virology. We discuss the progress of MD in elucidating the dynamics of the viral life cycle, including the status of modeling intact extracellular virions and leveraging advanced simulations to mimic active life cycle processes. We further remark on the prospects of MD for continued contributions to the basic science characterization of viruses, especially given the increasing availability of high-quality experimental data and supercomputing power. Overall, integrative computational methods that are closely guided by experiments are unmatched in the level of detail they provide, enabling-now and in the future-new discoveries relevant to thwarting viral infection.

Endonasal Endoscopic and Hybrid Surgery Techniques for Blunt Trauma Fractures of the Skull Base With Cerebrospinal Fluid Leaks.

ABSTRACT: Cerebrospinal fluid (CSF) leakage caused by skull base fracture represents high risks of bacterial meningitis, and a rate of mortality of 8.9%. Endoscopic endonasal repair of CSF leaks is quite safe and effective procedure with high rates of success. The aim of this study is to describe our technique for management of skull base CSF leaks secondary to craniofacial trauma based on the anatomic location of the leak. This is a retrospective case series of 17 patients with diagnosis of craniofacial trauma, surgically treated with sole endonasal endoscopic and combined endonasal/transcranial approaches with diagnosis of CSF leak secondary to skull base fractures. Seventeen patients met inclusion criteria for this study. Mean age was 46 years old. Most common etiology was motor vehicle. Early surgery was performed in 8 patients, and late surgery in 9 patients. The most common site of CSF leak was at ethmoid cells or at the fronto-ethmoid junction in 9 patients. Thirteen patients (76.4%) were treated only with endonasal endoscopic technique, and 4 (23.5%) with hybrid surgery, combining endonasal endoscopic and cranial bicoronal approaches with nasal and pericranial vascularized flaps, and nasal mucosal free flaps. Mean hospital stay was 23.7 days.The mean follow-up time was 25.6 months. When surgical reconstruction is indicated for CSF leaks secondary to skull base fractures, endonasal endoscopic techniques should be part of the surgical management either as a sole procedure, or in combination with classical transcranial approaches with high rates of success and low morbidity.

All-Atom MD Simulations of the HBV Capsid Complexed with AT130 Reveal Secondary and Tertiary Structural Changes and Mechanisms of Allostery.

The hepatitis B virus (HBV) capsid is an attractive drug target, relevant to combating viral hepatitis as a major public health concern. Among small molecules known to interfere with capsid assembly, the phenylpropenamides, including AT130, represent an important antiviral paradigm based on disrupting the timing of genome packaging. Here, all-atom molecular dynamics simulations of an intact AT130-bound HBV capsid reveal that the compound increases spike flexibility and improves recovery of helical secondary structure in the spike tips. Regions of the capsid-incorporated dimer that undergo correlated motion correspond to established sub-domains that pivot around the central chassis. AT130 alters patterns of correlated motion and other essential dynamics. A new conformational state of the dimer is identified, which can lead to dramatic opening of the intradimer interface and disruption of communication within the spike tip. A novel salt bridge is also discovered, which can mediate contact between the spike tip and fulcrum even in closed conformations, revealing a mechanism of direct communication across these sub-domains. Altogether, results describe a dynamical connection between the intra- and interdimer interfaces and enable mapping of allostery traversing the entire core protein dimer.

Experimental Characterization of the Hepatitis B Virus Capsid Dynamics by Solid-State NMR.

Protein plasticity and dynamics are important aspects of their function. Here we use solid-state NMR to experimentally characterize the dynamics of the 3.5 MDa hepatitis B virus (HBV) capsid, assembled from 240 copies of the Cp149 core protein. We measure both T 1 and T 1ρ relaxation times, which we use to establish detectors on the nanosecond and microsecond timescale. We compare our results to those from a 1 microsecond all-atom Molecular Dynamics (MD) simulation trajectory for the capsid. We show that, for the constituent residues, nanosecond dynamics are faithfully captured by the MD simulation. The calculated values can be used in good approximation for the NMR-non-detected residues, as well as to extrapolate into the range between the nanosecond and microsecond dynamics, where NMR has a blind spot at the current state of technology. Slower motions on the microsecond timescale are difficult to characterize by all-atom MD simulations owing to computational expense, but are readily accessed by NMR. The two methods are, thus, complementary, and a combination thereof can reliably characterize motions covering correlation times up to a few microseconds.

The origin of the regiospecificity of acrolein dimerization.

Acrolein dimerization is a intriguing case since the reaction does not occur to form the electronically preferred regioisomeric adduct. Various explanations have been suggested to rationalize this experimental regioselectivity, however, none of these arguments had been convincing enough. In this work, the hetero Diels-Alder acrolein dimerization was theoretically investigated using DFT and MP2 methods. The influence of nucleophilic/electrophilic interactions and non-covalent interactions (NCI) in the regiospecificity of the reaction were analyzed. Our results show that the NCI at the transition state are the key factor controlling the regiospecificity in this reaction. Besides, we found that the choice of calculation method can have an effect on the prediction of the mechanism in the reaction, as all DFT methods forecast a one-step hetero Diels-Alder acrolein dimerization, while MP2 predicts a stepwise description for the lower energy reaction channel.

Effect of a High-Intensity Tandem Bicycle Exercise Program on Clinical Severity, Functional Magnetic Resonance Imaging, and Plasma Biomarkers in Parkinson's Disease.

Rationale: The optimal modality, intensity, duration, frequency, and dose-response of exercise as a therapy for Parkinson's Disease (PD) are insufficiently understood. Objective: To assess the impact of a high-intensity tandem bicycle program on clinical severity, biomarkers, and functional MRI (fMRI) in PD. Methods: A single-center, parallel-group clinical trial was conducted. Thirteen PD patients aged 65 or younger were divided in two groups: a control group and an intervention group that incorporated a cycling program at 80% of each individual's maximum heart rate (HR) (≥80 rpm), three times a week, for 16 weeks. Both groups continued their conventional medications for PD. At baseline and at the end of follow-up, we determined in all participants the Unified Parkinson's Disease Rating Scale, anthropometry, VO2max, PD biomarkers, and fMRI. Results: VO2max improved in the intervention group (IG) (+5.7 ml/kg/min), while it slightly deteriorated in the control group (CG) (-1.6 ml/kg/min) (p = 0.041). Mean Unified Parkinson's Disease Rating Scale (UPDRS) went down by 5.7 points in the IG and showed a small 0.9-point increase in the CG (p = 0.11). fMRI showed activation of the right fusiform gyrus during the motor task and functional connectivity between the cingulum and areas of the frontal cortex, and between the cerebellar vermis and the thalamus and posterior temporal gyrus. Plasma brain-derived neurotrophic factor (BDNF) levels increased more than 10-fold in the IG and decreased in the CG (p = 0.028). Larger increases in plasma BDNF correlated with greater decreases in UPDRS (r = -0.58, p = 0.04). Conclusions: Our findings suggest that high-intensity tandem bicycle improves motor function and biochemical and functional neuroimaging variables in PD patients. Trial registration number: ISRCTN 13047118, Registered on February 8, 2018.

The Integrity of the Intradimer Interface of the Hepatitis B Virus Capsid Protein Dimer Regulates Capsid Self-Assembly.

During the hepatitis B virus lifecycle, 120 copies of homodimeric capsid protein assemble around a copy of reverse transcriptase and viral RNA and go on to produce an infectious virion. Assembly needs to be tightly regulated by protein conformational change to ensure symmetry, fidelity, and reproducibility. Here, we show that structures at the intradimer interface regulate conformational changes at the distal interdimer interface and so regulate assembly. A pair of interacting charged residues, D78 from each monomer, conspicuously located at the top of a four-helix bundle that forms the intradimer interface, were mutated to serine to disrupt communication between the two monomers. The mutation slowed assembly and destabilized the dimer to thermal and chemical denaturation. Mutant dimers showed evidence of transient partial unfolding based on the appearance of new proteolytically sensitive sites. Though the mutant dimer was less stable, the resulting capsids were as stable as the wildtype, based on assembly and thermal denaturation studies. Cryo-EM image reconstructions of capsid indicated that the subunits adopted an "open" state more usually associated with a free dimer and that the spike tips were either disordered or highly flexible. Molecular dynamics simulations provide mechanistic explanations for these results, suggesting that D78 stabilizes helix 4a, which forms part of the intradimer interface, by capping its N-terminus and hydrogen-bonding to nearby residues, whereas the D78S mutation disrupts these interactions, leading to partial unwinding of helix 4a. This in turn weakens the connection from helix 4 and the intradimer interface to helix 5, which forms the interdimer interface.

Coronavirus through Delaware's Computational Microscope.

The Perilla/Hadden-Perilla research team at the University of Delaware presents an overview of computational structural biology, their efforts to model the SARS-CoV-2 viral particle, and their perspective on how their work and training endeavors can contribute to public health.

Biosynthesis of Grandione: An Example of Tandem Hetero Diels-Alder/Retro-Claisen Rearrangement Reaction?

Mechanistic theoretical studies about the feasibility of the traditional proposed mechanism of formation for icetexane diterpene dimer grandione were assessed using density functional method at the M06-2X/6-31G(d,p) level of theory. Bulk water solvent effects were taken into account implicitly using the polarizable continuum model (SCI-PCM). The results were compared with the selectivity found in the biomimetic synthesis performed by experimental research groups. The relative free energy calculation shows that the one-step H-DA formation mechanism nominated in the literature is not a viable mechanism. We found that an alternative competing Tandem pathway is consistent with the experimental trends. Thus, our results suggested that the compound grandione is formed via a H-DA/retro-Claisen rearrangement and not by the traditional H-DA mechanism proposed early in the experimental studies. The H-DA initial step produce a biecyclic adduct followed by a domino retro-Claisen rearrangement that releases the energy strain of the bicyclic intermediary. Steric issues and hyperconjugation interactions are the mainly factors driving the reaction nature and the selectivity in the formation reaction. Finally, the enzymatic assistance for dimer formation was analyzed in terms of the calculated transition state energy barrier.

Endolymphatic Sac Surgery for Ménière's Disease - Current Opinion and Literature Review

Abstract Introduction The endolymphatic sac is thought to maintain the hydrostatic pressure and endolymph homeostasis for the inner ear, and its dysfunction may contribute to the pathophysiology of Ménière's disease. Throughout the years, different surgical procedures for intractable vertigo secondary to Ménière's disease have been described, and though many authors consider these procedures as effective, there are some who question its long-term efficacy and even those who think that vertigo control is achieved more due to a placebo effect than because of the procedure itself. Objective To review the different surgical procedures performed in the endolymphatic sac for the treatment of Ménière's disease. Data Sources PubMed, MD consult and Ovid-SP databases. Data Synthesis We focus on describing the different surgical procedures performed in the endolymphatic sac, such as endolymphatic sac decompression, endolymphatic sac enhancement, endolymphatic sac shunting and endolymphatic duct blockage, their pitfalls and advantages, their results in vertigo control and the complication rates. The senior author also describes his experience after 30 years of performing endolymphatic sac surgery. Conclusions The endolymphatic sac surgery, with all its variants, is a good option for patients with incapacitating endolymphatic hydrops, providing a high percentage of vertigo control and hearing preservation.

Endolymphatic Sac Surgery for Ménière's Disease - Current Opinion and Literature Review.

Introduction The endolymphatic sac is thought to maintain the hydrostatic pressure and endolymph homeostasis for the inner ear, and its dysfunction may contribute to the pathophysiology of Ménière's disease. Throughout the years, different surgical procedures for intractable vertigo secondary to Ménière's disease have been described, and though many authors consider these procedures as effective, there are some who question its long-term efficacy and even those who think that vertigo control is achieved more due to a placebo effect than because of the procedure itself. Objective To review the different surgical procedures performed in the endolymphatic sac for the treatment of Ménière's disease. Data Sources PubMed, MD consult and Ovid-SP databases. Data Synthesis We focus on describing the different surgical procedures performed in the endolymphatic sac, such as endolymphatic sac decompression, endolymphatic sac enhancement, endolymphatic sac shunting and endolymphatic duct blockage, their pitfalls and advantages, their results in vertigo control and the complication rates. The senior author also describes his experience after 30 years of performing endolymphatic sac surgery. Conclusions The endolymphatic sac surgery, with all its variants, is a good option for patients with incapacitating endolymphatic hydrops, providing a high percentage of vertigo control and hearing preservation.