Protein structure prediction with energy minimization and deep learning approaches.

In this paper we discuss the advantages and problems of two alternatives for ab initio protein structure prediction. On one hand, recent approaches based on deep learning, which have significantly improved prediction results for a wide variety of proteins, are discussed. On the other hand, methods based on protein conformational energy minimization and with different search strategies are analyzed. In this latter case, our methods based on a memetic combination between differential evolution and the fragment replacement technique are included, incorporating also the possibility of niching in the evolutionary search. Different proteins have been used to analyze the pros and cons in both approaches, proposing possibilities of integration of both alternatives.

Economics and outcomes of sotalol in-patient dosing approaches in patients with atrial fibrillation.

INTRODUCTION: There exists variability in the administration of in-patient sotalol therapy for symptomatic atrial fibrillation (AF). The impact of this variability on patient in-hospital and 30-day posthospitalization costs and outcomes is not known. Also, the cost impact of intravenous sotalol, which can accelerate drug loading to therapeutic levels, is unknown. METHODS: One hundred and thirty-three AF patients admitted for oral sotalol initiation at an Intermountain Healthcare Hospital from January 2017 to December 2018 were included. Patient and dosing characteristics were described descriptively and the impact of dosing schedule was correlated with daily hospital costs/clinical outcomes during the index hospitalization and for 30 days. The Centers for Medicare and Medicaid Services reimbursement for 3-day sotalol initiation is $9263.51. Projections of cost savings were made considering a 1-day load using intravenous sotalol that costs $2500.00 to administer. RESULTS: The average age was 70.3 ± 12.3 years and 60.2% were male with comorbidities of hypertension (83%), diabetes (36%), and coronary artery disease (53%). The mean ejection fraction was 59.9 ± 7.8% and the median corrected QT interval was 453.7 ± 37.6 ms before sotalol dosing. No ventricular arrhythmias developed, but bradycardia (<60 bpm) was observed in 37.6% of patients. The average length of stay was 3.9 ± 4.6 (median: 2.2) days. Postdischarge outcomes and rehospitalization rates stratified by length of stay were similar. The cost per day was estimated at $2931.55 (1. $2931.55, 2. $5863.10, 3. $8794.65, 4. $11 726.20). CONCLUSIONS: In-patient oral sotalol dosing is markedly variable and results in the potential of both cost gain and loss to a hospital. In consideration of estimated costs, there is the potential for $871.55 cost savings compared to a 2-day oral load and $3803.10 compared to a 3-day oral load.

Synthesis and In Vitro Characterization of Glycopeptide Drug Candidates Related to PACAP1-23.

The search for efficacious treatment of neurodegenerative and progressive neuroinflammatory diseases continues, as current therapies are unable to halt or reverse disease progression. PACAP represents one potential therapeutic that provides neuroprotection effects on neurons, and also modulates inflammatory responses and circulation within the brain. However, PACAP is a relatively long peptide hormone that is not trivial to synthesize. Based on previous observations that the shortened isoform PACAP1-23 is capable of inducing neuroprotection in vitro, we were inspired to synthesize shortened glycopeptide analogues of PACAP1-23. Herein, we report the synthesis and in vitro characterization of glycosylated PACAP1-23 analogues that interact strongly with the PAC1 and VPAC1 receptors, while showing reduced activity at the VPAC2 receptor.

A diagnostic screening tool for identifying safe drivers among dialysis patients.

INTRODUCTION: Studies have shown that adverse effects of dialysis are associated with increased risk of driving impairment. While recommendations have been made that physicians should place an increased focus on detecting risks for driving impairment among patients on dialysis, there are currently no diagnostic tools designed to help physicians assess driving impairment among this patient population. In addition to driver self-assessment tools provided by AAA (American Automobile Association), one of the only tools specifically designed to help physicians assess driver safety is the "Am I a Safe Driver?" checklist, originally designed to assess for driving impairment among geriatric patients. This study aimed to determine the utility of this checklist in detecting dialysis patients at risk for driving impairment. METHODS: The checklist was administered to dialysis patients who were predetermined to either be at risk or not at risk for driving impairment. The checklist was used to identify patients who test positive for driving impairment. ROC (receiver operationg characteristic) analysis was done to identify the best cut off to consider as a positive test. RESULTS: The study found that the checklist is very good in detecting risk for driving impairment among dialysis patients. ROC analysis determined that answering “yes” to at least two statements in the "Am I a Safe Driver?" checklist gives the highest sensitivity and specificity combination (Youden's index = 0.42). DISCUSSION: Higher sensitivity and lower specificity of the "Am I Safe Driver" checklist implies that it is effective only as a preliminary screening test for ruling out risk of driving impairment among dialysis patients.

Congenital Absence of Left Circumflex Presenting After an Emotional Stressor.

BACKGROUND: Absence of the left circumflex artery (LCX) is an extremely rare congenital anomaly of the coronary circulation. While some coronary circulation anomalies are associated with significant complications, including sudden cardiac death and premature atherosclerosis, absence of the LCX is largely considered benign, though it has been associated with exertional chest pain, which may mimic acute coronary syndrome. Diagnosis is made when heart catheterization is performed in the work up for acute coronary syndrome or when computed tomography coronary angiography is performed during evaluation of coronary artery disease. CASE REPORT: We report a 55 year old female who presented with non-exertional chest pain in the setting of an emotional stressor. The initial work up was only significant for elevated troponins, and subsequent left heart catheterization revealed findings consistent with congenital absence of the LCX. No significant stenosis was appreciated, and no intervention was performed. Following catheterization, the patient's troponins began to trend down, and her chest pain resolved. CONCLUSIONS: Congenitally absent LCX is a rare entity detected when work up is performed to rule out acute coronary syndrome in patients presenting with exertional chest pain. This is the first reported case of chest pain unrelated to physical activity reported in a patient with an absent LCX. There is no specific treatment for an absent LCX; however, proper identification of this anomaly and differentiation from complete occlusion of the LCX is important in making an accurate diagnosis of myocardial ischemia and for choosing the best intervention when ischemia is present.

Development and validation of the Atri-Risk Conduction Index risk score to predict risk of atrial fibrillation after typical atrial flutter ablation.

BACKGROUND: Identification of patients at risk for atrial fibrillation (AF) after typical atrial flutter (tAFL) ablation is important to guide monitoring and treatment. OBJECTIVE: The purpose of this study was to create and validate a risk score to predict AF after tAFL ablation METHODS: We identified patients who underwent tAFL ablation with no AF history between 2017 and 2022 and randomly allocated to derivation and validation cohorts. We collected clinical variables and measured conduction parameters in sinus rhythm on an electrophysiology recording system (CardioLab, GE Healthcare). Univariate and multivariate logistic regressions (LogR) were used to evaluate association with AF development. RESULTS: A total of 242 consecutive patients (81% male; mean age 66 ± 11 years) were divided into derivation (n =142) and validation (n = 100) cohorts. Forty-two percent developed AF over median follow-up of 330 days. In multivariate LogR (derivation cohort), proximal to distal coronary sinus time (pCS-dCS) ≥70 ms (odds ratio [OR] 16.7; 95% confidence interval [CI] 5.6-49), pCS time ≥36 ms (OR 4.5; 95% CI 1.5-13), and CHADS2-VASc score ≥3 (OR 4.3; 95% CI 1.6-11.8) were independently associated with new AF during follow-up. The Atri-Risk Conduction Index (ARCI) score was created with 0 as minimal and 4 as high-risk using pCS-dCS ≥70 ms = 2 points; pCS ≥36 ms = 1 point; and CHADS2-VASc score ≥3 = 1 point. In the validation cohort, 0% of patients with ARCI score = 0 developed AF, whereas 89% of patients with ARCI score = 4 developed AF. CONCLUSION: We developed and validated a risk score using atrial conduction parameters and clinical risk factors to predict AF after tAFL ablation. It stratifies low-, moderate-, and high-risk patients and may be helpful in individualizing approaches to AF monitoring and anticoagulation.

Primary central nervous system lymphoma in elderly: An illustrative case of the new role of surgery and integrative medical management.

Background: Primary central nervous system lymphoma (PCNSL) is a rare, aggressive non-Hodgkin lymphoproliferative neoplasm. Surgery is traditionally limited to biopsy due to past studies, but recent strong evidence continues to challenge this status quo in selected patients. Here, the authors characterize a case to illustrate the potential role of surgery and foster research on integrative medical management approaches for this disease. Case Description: A 73-year-old woman was admitted to the hospital with aphasia and confusion. Neuroimaging suggested a lymphoproliferative process. The patient underwent cytoreductive surgery to resect the lesion. Microscopically, large infiltrating lymphoid cells that induced brain tissue damage were observed, and a diagnosis of diffuse large B-cell lymphoma was made based on immunohistochemistry. The patient evolved clinically post surgery. A complete response to further chemotherapy maintained the patient's clinical recovery. Conclusion: This rare case highlights the potential of surgical intervention in the management of selected patients with PCNSL. The authors also underscore the recent, meta-analytic evidence on surgery followed by combined chemotherapy for the management of specific cases. The reported recovery in an elderly patient is noteworthy and adds to the literature on this rare subtype of brain tumors. Future research should consider investigating a potential profile of candidates for resection and combined chemotherapy in PCNSL.

Proteomic and toxicological analysis of the response of dinoflagellate Alexandrium catenella to changes in NaNO3 concentration.

Dinoflagellates of the genus Alexandrium cause Harmful Algal Blooms (HABs) in coastal waters worldwide, damaging marine environments, aquaculture, and human health. They synthesize potent neurotoxic alkaloids known as PSTs (i.e., Paralytic Shellfish Toxins), the etiological agents of PSP (i.e., Paralytic Shellfish Poisoning). In recent decades, the eutrophication of coastal waters with inorganic nitrogen (e.g., nitrate, nitrite, and ammonia) has increased the frequency and scale of HABs. PSTs concentrations within Alexandrium cells can increase by up to 76% after a nitrogen enrichment event; however, the mechanisms that underlie their biosynthesis in dinoflagellates remains unclear. This study combines mass spectrometry, bioinformatics, and toxicology and investigates the expression profiles of PSTs in Alexandrium catenella grown in 0.4, 0.9 and 1.3 mM NaNO3. Pathway analysis of protein expression revealed that tRNA amino acylation, glycolysis, TCA cycle and pigment biosynthesis were upregulated in 0.4 mM and downregulated in 1.3 mM NaNO3 compared to those grown in 0.9 mM NaNO3. Conversely, ATP synthesis, photosynthesis and arginine biosynthesis were downregulated in 0.4 mM and upregulated in 1.3 mM NaNO3. Additionally, the expression of proteins involved in PST biosynthesis (sxtA, sxtG, sxtV, sxtW and sxtZ) and overall PST production like STX, NEO, C1, C2, GTX1-6 and dcGTX2 was higher at lower nitrate concentrations. Therefore, increased nitrogen concentrations increase protein synthesis, photosynthesis, and energy metabolism and decrease enzyme expression in PST biosynthesis and production. This research provides new clues about how the changes in the nitrate concentration can modulate different metabolic pathways and the expression of PST biosynthesis in toxigenic dinoflagellates.

The intracellular helical bundle of human glucose transporter GLUT4 is important for complex formation with ASPL.

Glucose transporters (GLUTs) are responsible for transporting hexose molecules across cellular membranes. In adipocytes, insulin stimulates glucose uptake by redistributing GLUT4 to the plasma membrane. In unstimulated adipose-like mouse cell lines, GLUT4 is known to be retained intracellularly by binding to TUG protein, while upon insulin stimulation, GLUT4 dissociates from TUG. Here, we report that the TUG homolog in human, ASPL, exerts similar properties, i.e., forms a complex with GLUT4. We describe the structural details of complex formation by combining biochemical assays with cross-linking mass spectrometry and computational modeling. Combined, the data suggest that the intracellular domain of GLUT4 binds to the helical lariat of ASPL and contributes to the regulation of GLUT4 trafficking by cooperative binding.

Protocol Development and Initial Experience With Intravenous Sotalol Loading for Atrial Arrhythmias.

BACKGROUND: Oral sotalol is a class III antiarrhythmic commonly used for the maintenance of sinus rhythm in patients with atrial fibrillation (AF). Recently, the Food and Drug Administration (FDA) approved the use of IV sotalol loading, based primarily on modeling data for the infusion. We aimed to describe a protocol and experience with IV sotalol loading for elective treatment of adult patients with AF and atrial flutter (AFL). METHODS: We present our institutional protocol and retrospective review of initial patients treated with IV sotalol for AF/AFL at the University of Utah Hospital between September 2020 and April 2021. RESULTS: Eleven patients received IV sotalol for initial loading or dose escalation. All patients were male, aged 56-88 years (median 69). Mean QT interval (QTc) intervals increased from baseline (mean 384 ms) immediately after infusion of IV sotalol (mean change 42ms), but no patient required discontinuation of the medication. Six patients were discharged after 1 night; 4 patients were discharged after 2 nights; and 1 patient was discharged after 4 nights. Nine patients underwent electrical cardioversion prior to discharge (2 prior to load; 7 post-load on the day of discharge). There were no adverse events during the infusion or within 6 months of discharge. Persistence of therapy was 73% (8 of 11) at mean 9.9 weeks to follow up, with no discontinuations for adverse effects. CONCLUSIONS: We employed a streamlined protocol that was successfully implemented to facilitate the use of IV sotalol loading for atrial arrhythmias. Our initial experience suggests feasibility, safety, and tolerability while reducing hospitalization duration. Additional data are needed to augment this experience as IV sotalol use is broadened across different patient populations.

A memetic algorithm enables efficient local and global all-atom protein-protein docking with backbone and side-chain flexibility.

Protein complex formation is encoded by specific interactions at the atomic scale, but the computational cost of modeling proteins at this level often requires use of simplified energy models and limited conformational flexibility. In particular, use of all-atom energy functions and backbone and side-chain flexibility results in rugged energy landscapes that are difficult to explore. In this study, we develop a protein-protein docking algorithm, EvoDOCK, that combines the strength of a differential evolution algorithm for efficient exploration of the global search space with the benefits of a local optimization method to refine detailed atomic interactions. EvoDOCK enabled accurate and fast local and global protein-protein docking using an all-atom energy function with side-chain flexibility. Comparison with a standard method built on Monte Carlo optimization demonstrated improved accuracy and increases in computational speed of up to 35 times. The evolutionary algorithm also enabled efficient atomistic docking with backbone flexibility.

Increased incidence of cavotricuspid isthmus atrial flutter following slow pathway ablation.

PURPOSE: The incidence of atrial flutter following radiofrequency ablation of supraventricular tachycardias is poorly understood. Ablation of atrioventricular nodal reentry tachycardia may place patients at risk of flutter because ablation of the slow pathway is in close proximity to the cavotricuspid isthmus. This study aims to evaluate the risk of atrial flutter following ablation of atrioventricular nodal reentry tachycardia relative to ablation of other supraventricular tachycardias. METHODS: A single-center retrospective analysis was completed for all supraventricular tachycardia ablations performed between July 2006 and July 2016. Patient and procedural details were collected for 544 patients who underwent atrioventricular nodal reentry tachycardia ablation (n = 342), atrioventricular reentry tachycardia ablation (n = 125), or atrial tachycardia ablation (n = 60). Follow-up for flutter after ablation of their incident arrhythmia was assessed. RESULTS: Patients who underwent atrioventricular nodal reentry tachycardia ablation were more likely to develop CTI-dependent flutter than patients who underwent ablation of other supraventricular tachycardias (4.97% vs. 0%; p = 0.002). Compared with patients who did not develop flutter, patients who developed flutter after atrioventricular nodal reentry tachycardia ablation were more likely to have undergone ablation of atypical atrioventricular nodal reentry tachycardia (11.8% vs. 2.15%; p = 0.016). CONCLUSIONS: We identified an association between atrioventricular nodal reentry tachycardia ablation and development of CTI-dependent atrial flutter. This finding may have implications for the management and follow-up after atrioventricular nodal reentry tachycardia ablation.

Modelling the Spatial and Temporal Dynamics of Paralytic Shellfish Toxins (PST) at Different Scales: Implications for Research and Management.

Harmful algal blooms, in particular recurrent blooms of the dinoflagellate Alexandrium catenella, associated with paralytic shellfish poisoning (PSP), frequently limit commercial shellfish harvests, resulting in serious socio-economic consequences. Although the PSP-inducing species that threaten the most vulnerable commercial species of shellfish are very patchy and spatially heterogeneous in their distribution, the spatial and temporal scales of their effects have largely been ignored in monitoring programs and by researchers. In this study, we examined the spatial and temporal dynamics of PSP toxicity in the clam (Ameghinomya antiqua) in two fishing grounds in southern Chile (Ovalada Island and Low Bay). During the summer of 2009, both were affected by an intense toxic bloom of A. catenella (up to 1.1 × 106 cells L-1). Generalized linear models were used to assess the potential influence of different environmental variables on the field detoxification rates of PSP toxins over a period of 12 months. This was achieved using a four parameter exponential decay model to fit and compare field detoxification rates per sampling site. The results show differences in the spatial variability and temporal dynamics of PSP toxicity, given that greater toxicities (+10-fold) and faster detoxification (20% faster) are observed at the Ovalada Island site, the less oceanic zone, and where higher amounts of clam are annually produced. Our observations support the relevance of considering different spatial and temporal scales to obtain more accurate assessments of PSP accumulation and detoxification dynamics and to improve the efficacy of fisheries management after toxic events.

Impact of Catheter Ablation on Stroke, Cognitive Decline and Dementia.

AF has been consistently associated with multiple forms of dementia, including idiopathic dementia. Outcomes after catheter ablation for AF are favourable and patients experience a better quality of life, arrhythmia-free survival, and lower rates of hospitalisation compared to patients treated with antiarrhythmic drugs. Catheter ablation is consistently associated with lower rates of stroke compared to AF management without ablation in large national and healthcare system databases. Multiple observational trials have shown that catheter ablation is also associated with a lower risk of cognitive decline, dementia and improved cognitive testing that can be explained through a variety of pathways. Long-term, adequately powered, randomised trials are required to define the role of catheter ablation in the management of AF as a means to lower the risk of cognitive decline, stroke and dementia.

Latitudinal Variation in the Toxicity and Sexual Compatibility of Alexandrium catenella Strains from Southern Chile.

The bloom-forming toxic dinoflagellate Alexandrium catenella was first detected in southern Chile (39.5-55° S) 50 years ago and is responsible for most of the area's cases of paralytic shellfish poisoning (PSP). Given the complex life history of A. catenella, which includes benthic sexual cysts, in this study, we examined the potential link between latitude, toxicity, and sexual compatibility. Nine clones isolated from Chilean Patagonia were used in self- and out-crosses in all possible combinations (n = 45). The effect of latitude on toxicity, reproductive success indexes, and cyst production was also determined. Using the toxin profiles for all strains, consisting of C1, C2, GTX4, GTX1, GTX3, and NeoSTX, a latitudinal gradient was determined for their proportions (%) and content per cell (pg cell-1), with the more toxic strains occurring in the north (-40.6° S). Reproductive success also showed a latitudinal tendency and was lower in the north. None of the self-crosses yielded resting cysts. Rather, the production of resting cysts was highest in pairings of clones separated by distances of 1000-1650 km. Our results contribute to a better understanding of PSP outbreaks in the region and demonstrate the importance of resting cysts in fueling new toxic events. They also provide additional evidence that the introduction of strains from neighboring regions is a cause for concern.

Prevalence of multiple sclerosis in key cities of Brazil: a study in Passo Fundo, Southern Brazil.

BACKGROUND: To improve the comparability of multiple sclerosis (MS) prevalence across Brazilian regions, the Brazilian Committee for Treatment and Research in MS has implemented a standardized approach to assess the prevalence of the disease in five key cities, which were deemed representative of their regions in terms of socio-geographical features and where in-person revision of each case was feasible. OBJECTIVE: To report the point-prevalence of MS in Passo Fundo, one of the key cities in Southern Brazil. METHODS: We sought to identify all MS patients who were living in Passo Fundo on July 1st, 2015. The primary source for case ascertainment was records from the offices of neurologists and neurosurgeons practicing in the city. Multiple secondary sources were used to maximize identification of cases. All patients underwent in-person review of the diagnosis by a panel of neurologists with experience in MS. RESULTS: We identified 52 MS patients living in Passo Fundo on July 1st, 2015. The point-prevalence rate for MS was 26.4/100,000 population (95% confidence interval, 19.7 to 34.6/100,000). Among the MS cases, 42 (80.8%) were female, for a sex ratio of 4.2:1. Forty-six cases (88.5%) were categorized as relapsing-remitting MS, and the remaining 6 cases, as secondary progressive MS (11.5%). Other epidemiological and clinical features were comparable to national and international MS populations. CONCLUSIONS: The prevalence of MS in Passo Fundo is one of the highest reported in Brazil so far. Studies in other key Brazilian cities, using the same methodology, are currently being carried out.

Recommendations by the Scientific Department of Neuroimmunology of the Brazilian Academy of Neurology (DCNI/ABN) and the Brazilian Committee for Treatment and Research in Multiple Sclerosis and Neuroimmunological Diseases (BCTRIMS) on vaccination in general and specifically against SARS-CoV-2 for patients with demyelinating diseases of the central nervous system.

The Scientific Department of Neuroimmunology of the Brazilian Academy of Neurology (DCNI/ABN) and Brazilian Committee for Treatment and Research in Multiple Sclerosis and Neuroimmunological Diseases (BCTRIMS) provide recommendations in this document for vaccination of the population with demyelinating diseases of the central nervous system (CNS) against infections in general and against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes COVID-19. We emphasize the seriousness of the current situation in view of the spread of COVID-19 in our country. Therefore, reference guides on vaccination for clinicians, patients, and public health authorities are particularly important to prevent some infectious diseases. The DCNI/ABN and BCTRIMS recommend that patients with CNS demyelinating diseases (e.g., MS and NMOSD) be continually monitored for updates to their vaccination schedule, especially at the beginning or before a change in treatment with a disease modifying drug (DMD). It is also important to note that vaccines are safe, and physicians should encourage their use in all patients. Clearly, special care should be taken when live attenuated viruses are involved. Finally, it is important for physicians to verify which DMD the patient is receiving and when the last dose was taken, as each drug may affect the induction of immune response differently.

Endovascular Management of Femoropopliteal In-Stent Restenosis: A Systematic Review.

Despite the development of new therapies for the treatment of femoropopliteal disease, nitinol stents remain a mainstay of therapy following balloon angioplasty. Consequently, femoropopliteal in-stent restenosis (FP-ISR) remains an important clinical problem. Interventions used to treat de novo lesions of the femoropopliteal segment have been used to treat ISR lesions, with disappointing outcomes. Early interventions focused on repeat balloon angioplasty, cryoplasty, and various debulking therapies. Recently, treatment has shifted towards the use of stent-grafts, drug-eluting therapies, and combination therapies. This review analyzes the evidence behind each treatment modality and provides insight into future directions for optimal endovascular management of FP-ISR.