Mechanical dyssynchrony as a selection criterion for cardiac resynchronization therapy: Design of the AMEND-CRT trial.

AIMS: One third of patients do not improve after cardiac resynchronization therapy (CRT). Septal flash (SF) and apical rocking (ApRock) are deformation patterns observed on echocardiography in most patients eligible for CRT. These markers of mechanical dyssynchrony have been associated to improved outcome after CRT in observational studies and may be useful to better select patients. The aim of this trial is to investigate whether the current guideline criteria for selecting patients for CRT should be modified and include SF and ApRock to improve therapy success rate, reduce excessive costs and prevent exposure to device-related complications in patients who would not benefit from CRT. METHODS: The AMEND-CRT trial is a multicentre, randomized, parallel-group, double-blind, sham-controlled trial with a non-inferiority design. The trial will include 578 patients scheduled for CRT according to the 2021 ESC guidelines who satisfy all inclusion criteria. The randomization is performed 1:1 to an active control arm ('guideline arm') or an experimental arm ('echo arm'). All participants receive a device, but in the echo arm, CRT is activated only when SF or ApRock or both are present. The outcome of both arms will be compared after 1 year. The primary outcome measures are the average change in left ventricular end-systolic volume and patient outcome assessed using a modified Packer Clinical Composite Score. CONCLUSIONS: The findings of this trial will redefine the role of echocardiography in CRT and potentially determine which patients with heart failure and a prolonged QRS duration should receive CRT, especially in patients who currently have a class IIa or class IIb recommendation.

A Comprehensive Review of Nanomaterials as Potential Weapons against Multidrug-Resistant Staphylococcus aureus.

Multidrug-resistant Staphylococcus aureus is a serious public health problem with high fatality rates and difficult treatment. Conventional antimicrobials are limited in their effectiveness against MRSA due to developing resistance mechanisms and protective biofilms. Nanomaterials present a potential alternative since they offer targeted drug delivery and synergetic effects of nanoconjugates, eradicate biofilms, and use photothermal and photodynamic therapies. Furthermore, the discovery of nanovaccines holds the potential for enhancing immune responses against multidrugresistant S. aureus. Nanoparticles show considerable promise in the battle against multidrugresistant S. aureus, but significant obstacles remain, including determining their possible toxicity, scalability, and cost-effectiveness for widespread clinical application. However, by overcoming these barriers, nanomaterial-based techniques provide a viable route for tackling multidrug resistance in S. aureus, opening the path for a future in which successful therapies are within reach.

Predictors of pacemaker requirement in patients receiving implantable loop recorders for unexplained syncope: A systematic review and meta-analysis.

BACKGROUND: Implantable loop recorders (ILRs) are increasingly used to evaluate patients with unexplained syncope. Identification of all predictors of bradycardic syncope and consequent permanent pacemaker (PPM) insertion is of substantial clinical interest as patients in the highest risk category may benefit from upfront pacemaker insertion. OBJECTIVE: We performed a systematic review and meta-analysis to identify risk predictors for PPM insertion in ILR recipients with unexplained syncope. METHODS: An electronic database search (MEDLINE, Embase, Scopus, Cochrane) was performed in June 2023. Studies evaluating ILR recipients with unexplained syncope and recording risk factors for eventual PPM insertion were included. A random effects model was used to calculate the pooled odds ratio (OR) for clinical and electrocardiographic characteristics with respect to future PPM requirement. RESULTS: Eight studies evaluating 1007 ILR recipients were included; 268 patients (26.6%) underwent PPM insertion during study follow-up. PPM recipients were older (mean age, 70.2 ± 15.4 years vs 61.6 ± 19.7 years; P < .001). PR prolongation on baseline electrocardiography was a significant predictor of PPM requirement (pooled OR, 2.91; 95% confidence interval, 1.63-5.20). The presence of distal conduction system disease, encompassing any bundle branch or fascicular block, yielded a pooled OR of 2.88 for PPM insertion (95% confidence interval, 1.53-5.41). Injurious syncope and lack of syncopal prodrome were not significant predictors of PPM insertion. Sinus node dysfunction accounted for 62% of PPM insertions, whereas atrioventricular block accounted for 26%. CONCLUSION: Approximately one-quarter of ILR recipients for unexplained syncope require eventual PPM insertion. Advancing age, PR prolongation, and distal conduction disease are the strongest predictors for PPM requirement.

HeartMate 3 implantation with an emphasis on the biventricular configuration.

OBJECTIVES: Right ventricular failure following implantation of a durable left ventricular assist device (LVAD) is a major driver of mortality. Reported survival following biventricular (BiVAD) or total artificial heart (TAH) implantation remains substantially inferior to LVAD alone. We report our outcomes with LVAD and BiVAD HeartMate 3 (HM3). METHODS: Consecutive patients undergoing implantation of an HM3 LVAD between November 2014 and December 2021, at The Alfred, Australia were included in the study. Comparison was made between the BiVAD and LVAD alone groups. RESULTS: A total of 86 patients, 65 patients with LVAD alone and 21 in a BiVAD configuration underwent implantation. The median age of the LVAD and BiVAD groups was 56 years (Interquartile range 46-62) and 49 years (Interquartile range 37-55), respectively. By 4 years after implantation, 54% of LVAD patients and 43% of BiVAD patients had undergone cardiac transplantation. The incidence of stroke in the entire experience was 3.5% and pump thrombosis 5% (all in the RVAD). There were 14 deaths in the LVAD group and 1 in the BiVAD group. The actuarial survival for LVAD patients at 1 year was 85% and BiVAD patients at 1 year was 95%. CONCLUSIONS: The application of HM 3 BiVAD support in selected patients appears to offer a satisfactory solution to patients requiring biventricular support.

Palliative Care Utilisation and Outcomes in Patients Admitted for Heart Failure in a Victorian Healthcare Service.

BACKGROUND: Heart failure (HF) has high mortality and healthcare utilisation. It has a complex and unpredictable trajectory, which is often interpreted as a barrier to guideline recommended early integration of palliative care (PC). In particular, lack of referral criteria and misconceptions around PC affect inpatient specialist PC referrals. AIMS: The main objective was to characterise the pattern and predictors of referral of HF patients to the specialist inpatient PC consultative service at our healthcare service. METHODS: A retrospective, single-centre cohort study was performed on consecutive patients admitted across the hospital with HF over a 12-month period (July 2019-June 2020). Mortality data were checked against state death registry data. RESULTS: The 502 patients admitted for HF were elderly (mean age 78±14 years), had high dependency (54% Australian-modified Karnofsky Performance Status (AKPS) 50-70, 29% AKPS 10-40), and high mortality (53% within median 32 months at death registry data linkage). Seven per cent (7%) were referred to inpatient specialist PC. AKPS 10-40 (62% of those referred vs 26% not referred, p<0.01), reliance on carers (65% vs 36%, p<0.01), and New York Heart Association (NYHA) class III-IV symptoms (86% vs 42%, p<0.01) were associated with referral, but two or more admissions in the last 12 months for HF were not (16% vs 10%, p=0.21). Many PC domains, such as symptom burden, distress, and preferred care, were not adequately assessed. CONCLUSIONS: Referral to inpatient specialist PC in hospitalised HF patients is low relative to the morbidity and mortality in these patients.

Caudal fluoroscopic guidance for the insertion of transvenous pacing leads.

BACKGROUND: Pneumothorax is a well-recognized complication of cardiac implantable electronic device (CIED) insertion. While AP fluoroscopy alone is the most commonly imaging technique for subclavian or axillary access, caudal fluoroscopy (angle 40°) is routinely used at our institution. The caudal view provides additional separation of the first rib and clavicle and may reduce the risk of pneumothorax. We assessed outcomes at our institution of AP and caudal fluoroscopic guided pacing lead insertion. METHODS: Retrospective cohort study of consecutive patients undergoing transvenous lead insertion for pacemakers, defibrillators, and cardiac resynchronization therapy devices between 2011 and 2023. Both de novo and lead replacement/upgrade procedures were included. Data were extracted from operative, radiology, and discharge reports. All patients underwent postprocedure chest radiography. RESULTS: Three thousand two hundred fifty-two patients underwent insertion of pacing leads between February 2011 and March 2023. Mean age was 71.1 years (range 16-102) and 66.7% were male. Most (n = 2536; 78.0%) procedures used caudal guidance to obtain venous access, while 716 (22.0%) procedures used AP guidance alone. Pneumothoraxes occurred in five (0.2%) patients in the caudal group and five (0.7%) patients in the AP group (p = .03). Subclavian contrast venography was performed less frequently in the caudal group (26.2% vs. 42.7%, p < .01). CONCLUSION: Caudal fluoroscopy for axillary/subclavian access is associated with a lower rate of pneumothorax and contrast venography compared with an AP approach.

Advances in synthesis and biological evaluation of CDK2 inhibitors for cancer therapy.

One of the leading causes of mortality in the world is cancer. This disease occurs when responsible genes that regulate the cell cycle become inactive due to internal or external factors. Specifically, the G1/S and S/G2 transitions in the cell cycle are controlled by a protein called cyclin-dependent kinase 2 (CDK2). CDKs, which play a crucial role in managing the cell cycle, have been a wide area of research in cancer treatment. Over the past 11 years, significant research has been made in identifying potent, targeted, and efficient inhibitors of CDK2. In this summary, we have summarized recent developments in the synthesis and biological evaluation of CDK2 inhibitors.

Transvenous versus subcutaneous implantable cardioverter defibrillators in young cardiac arrest survivors.

Secondary prevention implantable cardioverter defibrillators (ICDs) are indicated in young patients presenting with aborted sudden cardiac death (SCD) because of ventricular arrhythmias. Transvenous-ICDs (TV-ICDs) are effective, established therapies supported by evidence. The significant morbidity associated with transvenous leads led to the development of the newer subcutaneous-ICD (S-ICD). This review discusses the clinical considerations when selecting an ICD for the young patient presenting with out-of-hospital cardiac arrest. The major benefits of TV-ICDs are their ability to pace (antitachycardia pacing [ATP], bradycardia support and cardiac resynchronisation therapy [CRT]) and the robust evidence base supporting their use. Other benefits include a longer battery life. Significant complications associated with transvenous leads include pneumothorax and tamponade during insertion and infection and lead failure in the long term. Comparatively, S-ICDs, by virtue of having no intravascular leads, prevent these complications. S-ICDs have been associated with a higher incidence of inappropriate shocks. Patients with an indication for bradycardia pacing, CRT or ATP (documented ventricular tachycardia) are seen as unsuitable for a S-ICD. If venous access is unsuitable or undesirable, S-ICDs should be considered given the patient is appropriately screened. There is a need for further randomised controlled trials to directly compare the two devices. TV-ICDs are an effective therapy for preventing SCD limited by significant lead-related complications. S-ICDs are an important development hindered largely by an inability to pace. Young patients stand to gain the most from a S-ICD as the cumulative risk of lead-related complications is high. A clinical framework to aid decision-making is presented.

Alternatives to transvenous lead placement in a patient undergoing surgical tricuspid valve repair.

Tricuspid regurgitation is a widely recognised phenomenon in patients with transvenous cardiac rhythm management (CRM) devices. If tricuspid valve repair or replacement is to be considered, what to do with the existing CRM system requires scrutiny with multidisciplinary input. We present a case of multifactorial tricuspid regurgitation in a 48-year-old female with giant cell myocarditis and a transvenous implantable cardioverter-defibrillator (ICD). Key considerations in management and alternative CRM options are discussed.

When Breathing Becomes a Challenge: A Case of Congenital Myasthenia Gravis in an Indian Neonate With a DOK-7 Gene Mutation.

A rare neuromuscular condition known as congenital myasthenia gravis (CMG) affects some people from birth or very soon after. It results in fatigue and muscle weakness because of genetic abnormalities that interfere with the neuromuscular junction's ability to function, where the nerves and muscles connect. Even among those who have the same genetic mutation, the severity of CMG symptoms might differ considerably. The most typical signs of CMG include eyelid drooping, breathing issues, muscle weakness and weariness, and difficulties swallowing. Clinical examinations, neurophysiologic tests, and genetic analyses are frequently combined to make the diagnosis of CMG. Although there is no known treatment for CMG, many patients may control their symptoms and lead relatively normal lives with the right care. A newborn with CMG due to a DOK-7 gene mutation is described in this article, along with its very early onset. The DOK-7 mutation is a rare variant in the Indian population that causes CMG and usually manifests as 'limb girdle' weakness. However, due to muscle weakness, the neonate in this case developed severe respiratory distress and later died despite rigorous life-saving measures.

Chrysin based pyrimidine-piperazine hybrids: design, synthesis, in vitro antimicrobial and in silico E. coli topoisomerase II DNA gyrase efficacy.

Ten chrysin-based pyrimidine-piperazine hybrids have been evaluated in vitro for antimicrobial activity against eleven bacterial and two fungal strains. All compounds 5a-j exhibited moderate to good inhibition, with MIC values ranging from 6.25 to 250 µg/ml. At 6.25 µg/ml and 12.5 µg/ml MIC values, respectively, compounds 5b and 5h demonstrated the most promising potency against E. coli, outperforming ampicillin, chloramphenicol, and ciprofloxacin. None of the substances had the same level of action as norfloxacin. 5a, 5d, 5g, 5h, and 5i have exhibited superior antifungal efficacy than Griseofulvin against C. albicans with 250 µg/ml MIC. All the compounds were also individually docked into the E. coli DNA gyrase ATP binding site (PDB ID: 1KZN) and CYP51 inhibitor (PDB ID: 5V5Z). The most active compound, 5h and 5g displayed a Glide docking score of - 5.97 kcal/mol and - 10.99 kcal/mol against DNA gyrase and 14α-demethylase enzyme CYP51 respectively. Potent compounds 5b, 5h, and 5g may be used to design new, innovative antimicrobial agents, according to in vitro, ADMET, and in silico biological efficacy analyses.

Subcutaneous defibrillator use with unipolar pacemakers: Cautiously possible.

Implantation of subcutaneous implantable cardioverter-defibrillator in a patient with existing unipolar pacemaker is against manufacturer recommendations. We report the case of a successful subcutaneous implantable cardioverter-defibrillator implantation in a patient with Fontan circulation and concomitant active unipolar pacing and present a summary of recommendations when considering subcutaneous implantable cardioverter-defibrillator implantation with unipolar pacing. Recommendations included: pre-procedure screening, rescreening during implantation and ventricular fibrillation induction, pacemaker programming, and post-procedure investigations.

Diagnostic evaluation of unexplained ventricular tachyarrhythmias in younger adults.

BACKGROUND: The diagnostic work-up for cardiac arrest from ventricular tachyarrhythmias occurring in younger adults and structurally normal hearts is variable and often incomplete. METHODS: We reviewed records for all recipients of a secondary prevention implantable cardiac defibrillator (ICD) younger than 60 years at a single quaternary referral hospital from 2010 to 2021. Patients with unexplained ventricular arrhythmias (UVA) were identified as those with no structural heart disease on echocardiogram, no obstructive coronary disease, and no clear diagnostic features on ECG. We specifically evaluated the adoption rate of five modalities of "second-line" cardiac investigations: cardiac magnetic resonance imaging (CMR), exercise ECG, flecainide challenge, electrophysiology study (EPS), and genetic testing. We also evaluated patterns of antiarrhythmic drug therapy and device-detected arrhythmias and compared them with secondary prevention ICD recipients with a clear etiology found on initial assessment. RESULTS: One hundred and two recipients of a secondary prevention ICD under the age of 60 were analyzed. Thirty-nine patients (38.2%) were identified with UVA and were compared with the remaining 63 patients with VA of clear etiology (61.8%). UVA patients were younger (35.6 ± 13.0 vs. 46.0 ± 8.6 years, p < .001) and were more often female (48.7% vs. 28.6%, p = .04). CMR was performed in 32 patients with UVA (82.1%), whereas flecainide challenge, stress ECG, genetic testing, and EPS were only performed in a minority of patients. Overall, the use of a second-line investigation suggested an etiology in 17 patients with UVA (43.5%). Compared to patients with VA of clear etiology, UVA patients had lower rates of antiarrhythmic drug prescription (64.1% vs. 88.9%, p = .003) and had a higher rate of device-delivered tachy-therapies (30.8% vs. 14.3%, p = .045). CONCLUSION: In this real-world analysis of patients with UVA, the diagnostic work-up is often incomplete. While CMR was increasingly utilized at our institution, investigations for channelopathies and genetic causes appear to be underutilized. Implementation of a systematic protocol for work-up of these patients requires further study.

Identification of novel anti-tuberculosis agent: An in silico investigation.

BACKGROUND: Multi-drug resistance tuberculosis is chronic and highly affected to mankind. Millions of people are affected by tuberculosis and lost their lives every year. Mycobacterium tuberculosis is resistant to the most commonly used anti-TB drugs, hence new drugs need to be developed in a short time. In this direction, many chemical compounds including benzimidazole derivatives have been identified as potent anti-tb agents. METHOD: Various benzimidazole derivatives were subjected to in-silico computational screening to identify the potent anti-tubercular analogues. The ADME pharmacokinetics evaluation was performed to identify the drug-like molecules. Molecular docking investigation of selected compounds was performed against Mycobacterium Tuberculosis Enoyl Reductase (Inha) with PDB ID: 2B37, 1QG6, 4TZK, and 4TZK. The common pharmacophore hypothesis was generated using the molecular docking post-processing module. RESULT: The result of ADME pharmacokinetics of some compounds is very close to the drug-like properties and can be developed as good inhibitors. Molecular docking study suggests that the proposed benzimidazole and 4H-pyran derivative have better binding affinity than standard and triclosan derivatives. Results from the pharmacophore hypothesis development study also support and suggest our prediction regarding the minimum pharmacophore features required in ligands to behave as a Mycobacterium Tuberculosis inhibitor. CONCLUSION: Coumarin, phenylurea clubbed benzimidazole moiety and pyrano[2,3-c]pyrazole derivatives have shown greater selectivity and potency towards Mycobacterium Tuberculosis. By employing a combination of ADME, docking, and pharmacophore study calculations, novel potent hits to inhibit enoyl-acp reductase were identified with the points for consideration for designing of enoyl-acp reductase inhibitor.

Impact of Late Referral on Cardiac Transplant Outcomes.

BACKGROUND: Late referral for heart transplantation (HTx) is associated with worse patient outcomes. There are no universally accepted definitions of what constitutes a timely referral for HTx assessment. OBJECTIVES: To evaluate the impact of late referral (LR) on HTx outcomes. METHODS: This single-centre retrospective observational study included 80 patients undergoing HTx between 2016-2019. We applied a simple clinical tool, derived from markers of advanced heart failure (HF), to classify LR in HTx patients and assess the impact of LR on HTx outcomes. Outcome measures included duration of intensive care unit (ICU) stay, total hospitalisation stay, cost of transplant admission and one-year mortality. RESULTS: Based upon the clinical profile, LR was defined by the presence of four or more out of 10 criteria for more than 6 months in HTx patients. In this model, 34 patients were timely referrals and 46 were LR. Patients who were LR had: a longer median time between initial diagnosis and referral (3 vs 7 ys; p=0.03); more features of advanced HF, including inotrope requirements (p=0.004); more comorbidities (p=0.014); and hospitalisations (p<0.0001). Late referral was not associated with longer ICU (p=0.14) or hospital stay (p=0.051), however LR incurred greater total in-hospital costs (p=0.011). There was no difference in one-year mortality (6% vs 9%; p=0.64). CONCLUSION: Patients referred late for HTx are more unwell at time of referral and require greater in-hospital resource usage at the time of transplantation. Earlier referral for transplant assessment in patients with advanced HF should be encouraged.

Spontaneous Coronary Artery Dissection in an Orthotopic Heart Transplant Recipient.

We present the case of acute myocardial infarction secondary to spontaneous coronary artery dissection in a patient 2 weeks post orthotopic heart transplantation. (Level of Difficulty: Advanced.).