Defining dyssynchrony: The ongoing search for cardiac resynchronization therapy “response”Chinmaya Mareddy, MD and Pamela K. Mason, MDUniversity of Virginia Health System, Charlottesville, VACorresponding Author:Pamela K. Mason, MDProfessor of MedicineUniversity of Virginia Health SystemBox 800158Charlottesville, VA 22908434-924-2465Pkm5f@virginia.eduThere are no relevant disclosures.There are no sources of financial support.The first trial to demonstrate the benefits of cardiac resynchronization therapy (CRT) was published in 2001. The single-blind crossover study demonstrated significant improvement in quality of life, NYHA class, and 6 minute walk test for patients with a left ventricular ejection fraction less than 35%, NYHA class III, an enlarged left ventricle, and a QRS duration greater than 150 ms.1 CRT represented an exciting advancement in cardiac implantable electronic device (CIED) therapy. While implantable cardioverter defibrillators (ICDs) had been in use for decades and represented a reliable, life-saving measure to treat fatal ventricular arrhythmias, for the first time, there was a device therapy that could improve quality of life for heart failure patients. The CARE-HF trial went on to demonstrate reduction in hospitalization and mortality in a similar population, and subsequent studies, such as MADIT-CRT suggested that the benefits extended to patients with NYHA class I or II.2,3While there was quick adoption of CRT and over the years and many patients have benefitted, it quickly became clear that there were unresolved issues and questions.4 First, there were patients who could not receive a coronary sinus pacing lead. This was predominantly due to variation in the coronary sinus anatomy and phrenic nerve stimulation. Developments such as quadripolar left ventricular pacing leads and improved sheath design have certainly reduced the number of failed implants, however, they will never be completely eliminated. Second, despite successful implants in “good” locations, some patients simply did not have clinical improvement. Further work identified subgroups that were more likely to respond, particularly those with a wide left bundle branch block (LBBB); however, even now, only about 70% of patients who meet generally accepted criteria for CRT experience improvement after a successful implant. Finally, while symptom improvement was the standard measure for most studies, there were patients who were “super responders” who actually developed improvement in their left ventricular ejection fraction after CRT, and it is difficult to predict which patients might receive this advantage.5As the data increasingly have shown that patients with LBBB are more likely to benefit from CRT compared to right bundle branch block or non-specific intraventricular conduction delays, most society guidelines require a true LBBB to meet a class I indication for CRT.6,7 The difficulty with using LBBB as a metric for CRT candidacy is that defining it has been controversial. Multiple criteria have been proposed. In their 2021 guidelines statement for pacing and CRT, the European Society of Cardiology (ESC) altered their definition of LBBB.8 Specifically, they added the requirement of notching or slurring in 2 adjacent leads to define a true LBBB, thus making the definition of LBBB more restrictive. In addition, the 2021 guidelines also moved patients with narrower LBBB (120-149 ms) to a Class IIa recommendation. This obviously has important implications as to guidelines recommendations and benefits of CRT.In this edition of the Journal of Cardiovascular Electrophysiology, Rijik, et al present a retrospective analysis of 1202 consecutive patients from a registry who received a CRT device between 2000 and 2015. They applied the 2013 European Society of Cardiology (ESC) definition of left bundle branch block (LBBB) to the population and then the 2021 ESC definition of LBBB and assessed how patients would have qualified for CRT based upon those criteria. In addition, the authors reviewed the actual patient response to CRT in comparison to the guidelines recommendation for CRT implantation by 2013 and 2021 guidelines. Applying the more stringent 2021 criteria dramatically reduced the number of patients with a true LBBB from 80.9% of the population to 31.6%. This moved many patients out of a class I indication for CRT. In addition, they found that the 2013 criteria better discriminated the patients who actually did respond to CRT therapy. When evaluating a combined end point of transplantation, left ventricular assist device implantation, and mortality, the patients with a LBBB by the 2013 criteria and a QRS duration > 150 ms had significant benefit and those without did not. The same was true for echocardiographic response. When applying the 2021 criteria, differences were not seen between the two groups, implying that many patients who no longer had LBBB by 2021 guidelines still benefitted from CRT.The authors should be congratulated for adding important understanding to how we think about CRT and patient selection. These data show that employing a more strict definition of LBBB does not discriminate those who are most likely to benefit from CRT and might discourage implantation in patients who may benefit. The ESC is not the only society that has supported a more restrictive definition of LBBB.9 It is difficult to know how these definitions and guidelines directly influence practice, but we don’t want to risk denying patients an important therapy that could improve their quality and quantity of life. It is also difficult not to reflect that this paper shows both how far we have come with device therapy for our heart failure patients and how much further we have to go. We have been implanting CRT devices for over 20 years. Many patients have benefitted from this novel therapy, and yet there is so much that we don’t know.We must consider what the role for CRT will be in the future. Novel methods of leadless left ventricular pacing are being developed.10 There are observational and retrospective data suggesting that left bundle branch area pacing may be as good or better than CRT in improving clinical outcomes and heart function.11,12 Further, with experience, it is potentially faster to implant a left bundle area lead compared to a coronary sinus lead, and there has been wide early adoption of the technique compared to His bundle pacing. A multi-center, randomized controlled trial evaluating conduction system pacing compared to CRT should start enrolling soon and we should have more information in the coming years.13 It is possible to envision a future where coronary sinus pacing leads are no longer the norm in this patient population. It is also unlikely that the need for successful coronary sinus lead placement will be completely eliminated. Regardless of what the future holds, the insights from CRT studies, the effects on hemodynamics, electrical function, and outcomes will inform new directions.ReferencesCazeau S, Leclercq C, Lavergne T, et al. Affects of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay. N Engl J Med2001;344:873-80.Cleland JGF, Daubert JC, Erdmann E, Freemantle N, et al. The effective cardiac resynchronization on morbidity and mortality and heart failure. N Engl J Med 2005;352:1539-1549.Moss AJ, Hall WJ, Cannom DS, et al. Cardiac resynchronization therapy for prevention of heart failure events. N Engl J Med2009;361:1329-1338.Sieniewicz BJ, Gould J, Porter B, et al. Understanding nonresponse to cardiac resynchronisation therapy: common problems and potential solutions. Heart Fail Rev 2019;24:41-54.Liang Y, Wang Q, Zhang M, et al. Cessation of pacing in super-responders of cardiac resynchronization therapy: a randomized controlled trial. J Cardiovasc Electrophysiol 2018; 29:1548-1555.Brignole M, Auricchio A, Baron-Esquivias G, et al. 2013 ESC guidelines on cardiac pacing and cardiac resynchronization therapy: The task force on cardiac pacing and resynchronization therapy of the European society of Cardiology (ESC). Developed in collaboration with European heart rhythm Association (EHRA). Eur Heart J 2013;34:2281-329.Tracy CM, Epstein AE, Barbar D, et al. 2012 ACCF/AHA/HRS focused update of the 2008 guidelines for device based therapy of cardiac rhythm abnormalities. Circulation 2012;126:1784-1800.Glikson M, Nielsen JC, Kronborg MB, et al. 2021 ESC guidelines on cardiac pacing and cardiac resynchronization therapy: developed by the task for sudden cardiac pacing and cardiac resynchronization therapy of the European Society of Cardiology (ESC) with a special contribution of the European Heart Rhythm Association (EHRA).Eur Heart J 2021;42:3427-3520.Surawicz B, Childers R, Deal BJ, et al. AHA/ACCF/HRS recommendations for the standardization and interpretation of the electrocardiogram: Part 3: intraventricular conduction disturbances: A scientific statement from the American Heart Association Electrophysiology and Arrhythmias Committee, Council on Clinical Cardiology; the American College of Cardiology Foundation; and the Heart rhythm Society: Endorsed by the International Society for Computerized Electrocardiography. Circulation 2009; 119:e235-40.Okabe O, Hummel JD, Bank AJ, et al. Leadless left ventricular stimulation with a WISE-CRT system: Initial experience results from the phase 1 of the SOLVE-CRT study (non randomized, role in phase).Heart Rhythm 2020; S1547-5271(21)01808-7.Vijayaraman P, Zalavadia D, Haseeb A, et al. Clinical outcomes of conduction system pacing compared to biventricular pacing in patients requiring cardiac resynchronization therapy. Heart Rhythm. 2022;19(8):1263-1271.Ezzeddine FM, Pistiolis SM, Pujol-Lopez M, et al. Outcomes of Conduction System Pacing for Cardiac Resynchronization Therapy in Patients with Heart Failure: A Multicenter Experience. Heart Rhythm. Published online February 24, 2023. doi:10.1016/j.hrthm.2023.02.018.Wang Y, Zhu H, Hou X, et al. Randomized trial of left bundle branch vs biventricular pacing for cardiac resynchronization therapy. J Am Coll Cardiol 2022;80:1205-1216.
Commentary:Herpes simplex virus and SLE: though uncommon yet with significant implicationsNaim Mahroum1, Abdulrahman Elsalti1, Yehuda Shoenfeld21International School of Medicine, Istanbul Medipol University, Istanbul, Turkey.2Zabludowicz Center for autoimmune diseases, Sheba Medical Center, Ramat-Gan, Israel.Running title : Commentary: Herpes simplex virus and SLE: though uncommon yet with significant implicationsKeywords – Autoimmunity, infection and autoimmunity, systemic lupus erythematosus, human herpes viruses, herpes simplex virus
Evaluating Serum HE4: Some Serious ConsiderationsAimen Waqar Khana, Hussain Haider Shahba: Department of Medicine, Jinnah Sindh Medical University, Karachi, Pakistan.b: Department of Medicine, Dow University of Health Sciences, Karachi, Pakistan.Dear Dr Papageorghiou,We have perused with great interest the scholarly article ”Serum HE4 predicts progestin treatment response in endometrial cancer and atypical hyperplasia: A prognostic study” by Chloe Barr et al. . We applaud the authors’ diligent efforts in investigating a biomarker that could independently predict the response to conservative therapy. However, we wish to draw attention to certain noteworthy aspects upon a comprehensive evaluation.Firstly, it is noteworthy that all the women who participated in the study underwent a preliminary endometrial biopsy before the initiation of progestin. However, there is no mention of whether women with relative contraindications such as cervical stenosis, coagulopathy or obstructive cervical lesions were sampled if they were included in the study. It is essential to consider these factors as they can significantly affect the accuracy and reliability of the biopsy results. Furthermore, it is necessary to note that insufficient tissue sampling is a common complication of endometrial biopsy, with an average of 31% of tissues obtained requiring improvement . Considering that this is typically more prevalent in postmenopausal women, and 61% of the participants were 50 years or older, it is crucial to standardize the volume of tissue obtained to ensure fair and precise results. As outlined in the study, the primary form of progestin therapy was levonorgestrel-releasing intrauterine system (LNG-IUS). Still, for women whose devices had been misplaced more than once, an alternative treatment of oral medroxyprogesterone acetate 500mg was administered twice daily. This raises a concern regarding whether these women were closely monitored for compliance with the prescribed treatment regimen. This is particularly important as non-compliance, particularly with extended oral therapies, is a common issue that, if present, could skew the study’s findings. The prognostic potential of pretreatment serum HE4 in predicting therapeutic response has been extensively researched; however, studies have also reported elevated serum HE4 levels in various other cancers, including ovarian, pancreatic, breast, lung, and stomach . Therefore, it is crucial to exclude such patients thoroughly, as their inclusion could lead to inaccurate results by falsely accounting for the non-responder count.Moreover, serum HE4 levels are also known to be influenced by renal function and status, necessitating adjustment . It is, therefore, essential to consider and standardize these factors when analyzing the serum HE4 levels to obtain reliable and valid results. Lastly, it should be noted that a CLEIA technique was employed for analysis, which has been reported to significantly overestimate serum HE4 as compared to EIA . This may raise concerns regarding the validity of the reported findings, and hence, caution must be exercised when interpreting the results.The study focused on endometrial biopsy in women receiving progestin therapy, but potential complications such as insufficient tissue sampling and the inclusion of women with contraindications were not addressed. The study primarily used LNG-IUS but also administered oral medroxyprogesterone acetate, and compliance monitoring was not discussed. Serum HE4 levels were examined, but patients with other cancers or renal issues were not excluded, and the CLEIA technique used for analysis may have overestimated results. Therefore, caution is necessary when interpreting the findings of this study.
TITLE PAGETitle: Comment on: evaluating age and sex-specific rates of gall bladder disease in children with sickle cell diseaseArticle type: Letter to the editorCorrespondence : 1. Ifra Eeman Ahmed contact : 03335890003 Email : firstname.lastname@example.orgInstitution : Federal medical & dental college,IslamabadAddress: House#2,Street#15g,Sector A,Bahria Enclave,IslamabadCo-author : 2. Satesh KumarContact: +92-3325252902 Email:Institute: Shaheed Mohtarma Benazir Bhutto Medical College Liyari, KarachiAddress: Parsa citi Garden east, KarachiWord count: 391Conflict of interest : NoneDeclaration : NoneAcknowledgment : None
Daratumumab induced Minimal Residual Disease Negative Remission in CD 38 (dim) Positive Pediatric Acute Myeloid LeukemiaPronamee Borah1, Dinah Ng1, Nitin Dayal2, Sangeeta Pathak3, Rahul Naithani11Hematology and Bone Marrow Transplant Division, Max Superspecialty Hospital, Delhi, India2Department of Lab Medicine, Max Superspecialty Hospital, Delhi, India3Department of Transfusion medicine, Max Superspecialty Hospital, Delhi, IndiaConflicts of interest: None to declare.No financial support was obtained in this study.Text word count 815Brief running title: Daratumumab in Pediatric AMLKey Words: Daratumumab, AML, ChildrenTables: 0; Figures: 0
Pelvic dimensions and hypotheses on duration of active second stage of labourTilde Broach OstborgStavanger University HospitalTM EggeboTrondheium University HospitalWe would like to thank Jan Novák and Petr Sedlak for their interest and comments to our manuscript. We found that increasing BMI was associated with shorter estimated median duration of the active second stage of labour.1We could not find any obvious causal mechanism for our findings; but suggested some possible explanations. The shorter active second stage may be related to increased abdominal pressure with increasing BMI, or perhaps increased strength when pushing.2, 3 Increased infiltration of fat in the muscular pelvic floor may decrease its strength and resistance.4 The presence of fat in the birth canal of obese women may delay the urge to bear down, thereby postponing active pushing until the head is lower in the maternal pelvis.Novak et al. measured the bi-ilac and bi-cristal diameters of the greater pelvis and found a broader pelvis in individuals with a history of obesity from adolescence.5 We supposed that there would be an association between the size of the greater pelvis and the size of the birth canal. We agree to the limitations commented by Novák and Sedlak. However, our proposed causal mechanisms are merely hypotheses, and cannot be accepted nor rejected based on current knowledge.1. Ostborg TB, Sande RK, Kessler J, Tappert C, von Brandis P, Eggebo TM. Put your weight behind it-Effect of body mass index on the active second stage of labour: A retrospective cohort study. BJOG. 2022;129:2166-2174.2. Lambert DM, Marceau S, Forse RA. Intra-abdominal pressure in the morbidly obese. Obes Surg. 2005;15:1225-1232.3. Tomlinson DJ, Erskine RM, Morse CI, Winwood K, Onambele-Pearson G. The impact of obesity on skeletal muscle strength and structure through adolescence to old age. Biogerontology. 2016;17:467-483.4. Pomian A, Lisik W, Kosieradzki M, Barcz E. Obesity and Pelvic Floor Disorders: A Review of the Literature. Med Sci Monit. 2016;22:1880-1886.5. Novak JM, Bruzek J, Zamrazilova H, Vankova M, Hill M, Sedlak P. The relationship between adolescent obesity and pelvis dimensions in adulthood: a retrospective longitudinal study. PeerJ. 2020;8:e8951.
A 19 year-old adolescent girl with Dravet syndrome, characterized by complex seizure disorder and global developmental delay, presented with B-cell acute lymphoblastic leukemia. The genetic basis for her Dravet syndrome was a pathogenic variant in SCN1A, a sodium channel subunit. SCN1A is chiefly expressed in neuronal tissue, but bioinformatic analysis demonstrated its presence in B cell lineage. One estimate suggested that 10% of children with pediatric cancer have a germline predisposition involving proto-oncogenes or tumor suppressors. This number might be even higher should non-classical genetic variants, such as that encoding a sodium channel subunit, be considered.
Pd-catalyzed asymmetric allylic C−H functionalization has emerged as a powerful tool to access chiral, densely functionalized molecules from easily ac-cessible alkenes, enabling the increase of the step- or atom-economy by minimizing functional group manipulations for preparing allylating reagents. Due to the inadequacy of stereoselection strategies, the asymmetric allylic C-H functionalization is still in the early stage. In this essay, we will describe our journey to identification of asymmetric catalytic systems, mechanism of allylic C−H activation, control of stereo- and regioselectivity, and applica-tions in asymmetric synthesis.
Dear Editor, We read with great interest the article recently published in Journal of Cardiovascular Electrophysiology, “Left atrial appendage dimension predicts elevated brain natriuretic peptide in nonvalvular atrial fibrillation” by Cook JA. et al. 1 The authors have studied the relation between Brain natriuretic peptide (BNP) elevations and left atrial appendage measurements in patients who referred for left atrial appendage (LAA) occlusion in patients with nonvalvular atrial fibrillation (AF). BNP release is largely from the ventricles and it is also dynamically dependent on myocardial stretch and fluid volume status. However, it seems difficult to prove that BNP levels are directly related to the LAA measurements. Correlating BNP elevation only with left atrial or LAA measurements means ignoring left ventricular strain. Considering that these patients were referred for LAA occlusion and had a high CHA 2DS 2-VASc score, and not taking heart failure with preserved ejection fraction into account may lead to errors in interpreting the results. Moreover, it should be evaluated that the left atrial appendage may undergo remodeling or enlargement as a result of the left ventricular end-diastolic pressure increase. In this case, although the study is valuable, remains a cross-sectional study and a snapshot of the correlation of BNP and LAA. Second, it should be disclosed whether patients have paroxysmal or chronic AF and how long the patient has had AF. A relationship was established between LAA dimensions and BNP in the study, it is essential that the duration of AF should be considered and subgroup analyses should be evaluated if possible, since AF has a significant effect on BNP release. We appreciate this study and believe that a more detailed evaluation including left ventricular evaluation and prospectively monitored LAA and BNP would yield more realistic results. In addition, we think that it would be useful to evaluate midregional pro-A-type natriuretic (MR-proANP) in LAA studies, which is specific to the left atrial enlargement and similar physiology to BNP. 2
Purpose: Poly-medicated patients, especially those over 65, have increased. Multiple drug use and inappropriate prescribing increase drug-drug interactions, adverse drug reactions, morbidity, and mortality. This issue was addressed with several CDSS alerts. Health professionals have not followed these systems due to their poor alert quality and incomplete databases. Methods: Recent research shows a growing interest in using Text Mining via NLP to extract drug-drug interactions from unstructured data sources to support clinical prescribing decisions. NLP text mining and machine learning classifier training for drug relation extraction were used in this process. Results: In this context, the proposed solution allows to develop an extraction system for drug-drug interactions from unstructured data sources. The system produces structured information, which can be inserted into a database that contains information acquired from three different data sources. Conclusion: The architecture outlined for the drug-drug interaction extraction system is capable of receiving unstructured text, identifying drug entities sentence by sentence, and determining whether or not there are interactions between them.
The conflict in Ukraine, which started when Russia invaded and violated its sovereignty, has led to the country's worst war since the annexation of Crimea in 2014. The war has resulted in a significant number of casualties, displaced millions of people, and damaged the healthcare system, which was already struggling before the conflict. The neurosurgical field, in particular, has been severely affected, with infrastructure and healthcare systems routinely demolished or interrupted in conflict zones, making fundamental medical operations unavailable to victims of armed conflict. As a result, neurosurgeons have been compelled to conduct surgeries outside of their areas of competence, in makeshift settings or under challenging conditions, with limited access to materials and equipment. The war has also severely damaged specialized neurosurgery facilities, causing a severe shortage of crucial supplies and equipment. To address the challenges facing neurosurgery care in Ukraine, it is essential to rebuild and repair the damaged neurosurgical centers and provide them with the necessary equipment and supplies to successfully administer neurosurgical treatments. Training programs for neurosurgeons and other medical specialists must also be organized to manage complex neurosurgical problems under difficult conditions.
In the production of biopharmaceuticals depth filters followed by sterile filters are often employed to remove residual cell debris present in the feed stream. In the back drop of a global pandemic, supply chains associated with the production of biopharmaceuticals have been constrained. These constraints have limited the available amount of depth filters for the manufacture of biologics. This has placed manufacturing facilities in a difficult position having to choose between running processes with reduced number of depth filters and risking a failed batch or the prospect of plants going into temporary shutdown until the depth filter resources are replenished. This communication describes a modeling based method that leverages manufacturing scale filtration data to predict the depth filter performance with a reduced number of filters and an increased operational flux. This method can be used to quantify the acceptable level of area reduction before which the filtration process performance is affected. This enables facilities to manage their filter inventory avoiding potential plant shutdowns and reduces the risks of negative depth filter performance.
Osteogenesis imperfecta (OI) is a rare disorder of bone fragility. Gravid patients with OI usually need cesarean and may present multiple challenges. We present a case of an OI patient with severe scoliosis and an anticipated difficult airway undergoing cesarean section, with details on perioperative assessment and strategy of anesthesia.
Protein glycosylation is the most complex and diverse form of post-translational modification in human body. Meanwhile, glycosylation of peptides and proteins emerges as a promising strategy to improve the pharmacokinetic profile of peptide- and protein-based therapeutics. Owing to the importance of protein glycosylation, rigorous evaluation of the relationship between the precise structure and biological function of glycoproteins has to be per-formed. Recently, chemical synthesis, chemoenzymatic synthesis and semisynthesis strategy have attracted extensive attentions towards the prepara-tion of structurally defined glycopeptides and glycoproteins; the obtained synthetic glycoforms thus enable the thorough investigation of specific effects of protein glycosylation. This review highlights the recent progress in the development of novel strategies, preparation of homogeneous glycoproteins and exploration of structure-activity relationships. On this basis, the challenges and prospects are discussed.
The ancient Greeks took the entertainment of their crowds very seriously and used drama as a way of investigating the world they lived in. The theatrical re-enactment of suffering and grief in front of a large audience was to foster compassion, as well as a cathartic release of emotion that was restorative through a deeply felt interconnection between actors and audience. When our patients encounter tragedy, we are also drawn into their ordeal and experience it first hand. Such it was with Rose.
One hundred fecal samples from hooded vultures in the Gambia (Banjul area) were investigated for the presence of bacteria with extended-spectrum cephalosporin- (ESBL/AmpC), carbapenemases, and colistin resistance. No Enterobacteriales carrying carbapenemases or resistance against colistin were detected. Fifty-four ESBL-producing Escherichia coli and five ESBL-producing Klebsiella pneumoniae isolates were identified in 52 of the samples, of which 52 E. coli and 4 K. pneumoniae yielded passed sequencing results. Fifty of the E. coli had ESBL phenotype and genotype harboring blaCTX-M genes, of which 88.5% (n=46) were the blaCTX-M-15 gene, commonly found on the African continent. Furthermore, the genetic context around blaCTX-M-15 was similar between isolates, being co-localized with ISKpn19. In contrast, cgMLST analysis of the E. coli harboring ESBL genes revealed a genetic distribution over a large fraction of the currently known existing E. coli populations in the Gambia. Hooded vultures in the Gambia thus have a high ESBL E. coli-prevalence (>50%) with low diversity regarding key resistance genes. Furthermore, given the urban presence and frequent interactions between hooded vultures and humans, data from this study implies hooded vultures as potential vectors contributing to the further dissemination of antibiotic-resistance genes.
SARS-CoV-2 causes COVID-19 pandemic and continues to pose a threat to global public health through genetic mutation. In this study, we have found that an ACE2-specific monoclonal antibody at low concentration was able to greatly enhance SARS-CoV-2 infection and growth in cell culture. Strikingly, it promotes SARS-CoV-2 plaque formation, resulting in accurate titration of different SARS-CoV-2 variants, particularly the newly emerged Omicron variants, which otherwise cannot be determined by standard plaque assays. Quantification of infectious titers of the newly emerged variants will facilitate the development and evaluation of vaccines and antiviral drugs against SARS-CoV-2.