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During the toxicological assessment of extractables and leachables in drug products, localized hazards such as irritation or sensitization may be identified. Typically, because of the low concentration at which leachables occur in pharmaceuticals, irritation is of minimal concern; therefore, this manuscript focuses on sensitization potential. The primary objective of performing a leachable sensitization assessment is protection against Type IV induction of sensitization, rather than prevention of an elicitation response, as it is not possible to account for the immunological state of every individual. Sensitizers have a wide range of potencies and those which induce sensitization upon exposure at a low concentration (i.e. strong, or extreme sensitizers) pose the highest risk to patients and should be the focus of the risk assessment. The Extractables and Leachables Safety Information Exchange (ELSIE) consortium has reviewed the status of dermal, respiratory, and systemic risk assessment in cosmetic and pharmaceutical industries, and proposes a framework to evaluate the safety of known or potential dermal sensitizers in pharmaceuticals. Due to the lack of specific regulatory guidance on this topic, the science-driven risk-based approach proposed by ELSIE encourages consistency in the toxicological assessment of extractables and leachables to maintain high product quality and ensure patient safety.

The impact of the COVID-19 pandemic on palliative care intervention (PCIs) in patients with do-not-resuscitate (DNR) status remains uncertain.Case-control study of patients with DNR order with RT-PCR confirmed SARS-COV2 infection (cases), and those with DNR order but without SARS-COV2 infection (controls). The primary outcome measures included timing and delivery of PCIs, and secondary measures included pre-admission characteristics and in-hospital death.The ethnicity distribution was comparable between 69 cases and 138 controls, including Black/African Americans (61% vs. 44%), Latino/Hispanics (16% vs. 26%) and White (9% vs. 20%) (trend-p = .54). Cases were employed more (17% vs. 6%, adjusted-p = .012), less frail (fit 47% vs. 21%; mildly frail 22% vs. 36%; frail 31% vs. 43%, trend-p = .018) and had fewer comorbidities than controls. Cases had higher chances of intensive care unit admission (HR 1.76 [95% CI: 1.03-3.02]) and intubation (53% vs. 30%, p = .002), lower chances to be seen by palliative care team (HR .46 [.30-.70]) and a longer time to palliative care visit than controls (β per ln-day .67 [.00-1.34]). In the setting of no-visiting hospitals policy, we did not find significant increase in utilisation of video conferencing (22% vs. 13%) and religious services (12% vs. 12%) both in case and in controls.Do-not-resuscitate patients with COVID-19 had better general health and higher employment status than 'typical' DNR patients, but lower chances to be seen by the palliative care team. This study raises a question of the applicability of the current palliative care model in addressing the needs of DNR patients with COVID-19 during the pandemic.

Implantable cardioverter-defibrillator (ICD) shocks are associated with higher mortality and reduced quality of life. This study aimed to investigate the effectiveness of catheter ablation (CA) of ventricular tachycardia in patients with an ICD.An electronic literature search was conducted to retrieve randomized controlled trials comparing CA versus control. The primary outcomes were recurrence of ventricular arrhythmia (ventricular tachycardia or ventricular fibrillation [VT/VF]) and mortality. Kaplan-Meier curves for these outcomes were digitized to obtain individual patient data, which was pooled in a one-stage meta-analysis to determine hazard ratios (HRs) and 95%CIs. Secondary outcomes included cardiac hospitalization, electrical storm, syncope, appropriate ICD therapy, appropriate ICD shocks, and inappropriate shocks. For these, study-level HRs or risk ratios (RRs) were obtained and pooled under random-effects meta-analyses. Subgroup analysis was performed for trials investigating prophylactic CA (before or during ICD implantation).Nine studies and 1103 patients were retrieved. CA significantly reduced VT/VF recurrence compared to control (shared-frailty HR=0.63, 95%CI=0.49-0.81, p0.001) but not mortality (shared-frailty HR=0.84, 95%CI=0.57-1.23, p=0.361). CA was associated with significantly lower rates of cardiac hospitalization, electrical storm, appropriate ICD therapies and shocks, but not syncope or inappropriate shocks. Subgroup analysis found similar results for prophylactic CA except that no significant difference was observed for cardiac hospitalizations.CA is associated with reduced ventricular arrhythmia recurrence, appropriate ICD shocks and cardiac hospitalization, and may be effective in preventing future morbidity. Future trials are needed to support the continued benefit of these promising results, and to investigate the optimal timing of ablation.

Subcutaneous implantable cardioverter-defibrillators (S-ICD) have been shown to be noninferior to conventional transvenous ICDs with respect to device-related complications and inappropriate shocks.1 For patients who meet indications for an ICD and do not require bradycardia pacing, antitachycardia pacing, or cardiac resynchronization therapy, it is becoming an attractive option to avoid vascular complications. Complications such as lead malfunction and infection are more common with the transvenous ICD, whereas inappropriate shocks are more common with the S-ICD.1 The majority of inappropriate S-ICD therapies results from T-wave oversensing, but there are also reports of QRS double or triple counting, especially in times of electrolyte derangements. We report a case where oversensing of multiple components of a ventricular escape rhythm resulted in inappropriate shocks owing to a unique S-ICD algorithm.

Conduction system pacing has gained steady interest over recent years. While the majority of tools and delivery techniques were developed for His bundle pacing (HBP), the feasibility and reproducibility of using these similar tools for left bundle branch pacing (LBBP) has yet to be determined. We describe our technique for performing LBBP using the Abbott Agilis HisPro™ Steerable Catheter.A series of 22 patients with a mean age of 71.7 years (16 males, 72.7%), underwent LBBP procedure with this catheter between May and October 2021. Nineteen patients (86%) had successful LBBP lead implantation. There were no major complications or mortality.The Agilis HisPro™ catheter along with the stylet driven Tendril STS Model 2088TC lead is a safe and feasible delivery system for LBBP.

Autoreactive B cell-derived antibodies form immune complexes that likely play a pathogenic role in autoimmune diseases. In systemic lupus erythematosus (SLE), these antibodies bind Fc receptors on myeloid cells and induce proinflammatory cytokine production by monocytes and NETosis by neutrophils. Bruton's tyrosine kinase (BTK) is a non-receptor tyrosine kinase that signals downstream of Fc receptors and plays a transduction role in antibody expression following B cell activation. Given the roles of BTK in both the production and sensing of autoreactive antibodies, inhibitors of BTK kinase activity may provide therapeutic value to patients suffering from autoantibody-driven immune disorders. Starting from an in-house proprietary screening hit followed by structure-based rational design, we have identified a potent, reversible BTK inhibitor, BIIB068 (1), which demonstrated good kinome selectivity with good overall drug-like properties for oral dosing, was well tolerated across preclinical species at pharmacologically relevant doses with good ADME properties, and achieved >90% inhibition of BTK phosphorylation (pBTK) in humans.

Multiple Sclerosis is a chronic autoimmune neurodegenerative disorder of the central nervous system (CNS) that is characterized by inflammation, demyelination, and axonal injury leading to permeant disability. In the early stage of MS, inflammation is the primary driver of the disease progression. There remains an unmet need to develop high efficacy therapies with superior safety profiles to prevent the inflammation processes leading to disability. Herein, we describe the discovery of BIIB091, a structurally distinct orthosteric ATP competitive, reversible inhibitor that binds the BTK protein in a DFG-in confirmation designed to sequester Tyr-551, an important phosphorylation site on BTK, into an inactive conformation with excellent affinity. Preclinical studies demonstrated BIB091 to be a high potency molecule with good drug-like properties and a safety/tolerability profile suitable for clinical development as a highly selective, reversible BTKi for treating autoimmune diseases such as MS.

Introduction: We report two cases of recurrent ventricular tachycardia (VT) successfully treated by intra-coronary Gelatin sponge embolization where initial endocardial ablation was unsuccessful and epicardial approaches were unfavourable. Case Histories: (1) A 75-year-old male with Inferior STEMI who underwent PCI to oRPDA developed VT storm that required DCCV 11 times. The VT was hemodynamically unstable, hence only substrate modification was performed. He still had recurrent episodes of VT and a second ablation attempt localised VT circuit breakout to the infero-apical septum, but ablation was unsuccessful due to a deep intramural circuit. Epicardial ablation was not attempted due to a 1cm pericardial effusion after the first procedure. Unipolar signals from selective wiring of the distal rPDA with a percutaneous coronary intervention guidewire and microcatheter showed early local electrograms. 5ml of Gelatin sponge injection was injected after a 5x2mm coil failed to occlude the distal rPDA. Post occlusion, VT was not inducible with double ventricular extra-stimuli. He has been VT free for 5 months (2) A 41-year-old female with dilated cardiomyopathy, previous left ventricular assist device and revision was admitted for VT storm. The VT map identified earliest activation with far-field pre-systolic potentials at the baso-lateral LV segment. Pre-systolic far field ventricular EGMs were also seen in the adjacent coronary sinus, consistent with a likely epicardial exit site of the VT. Endocardial ablation failed, and epicardial access was not feasible due to adhesions. Coronary angiography revealed a small calibre non dominant left circumflex artery supplying the VT exit site. Cold saline injection down the mLCX terminated the VT and the vessel was occluded with 5 ml of Gelatin sponge. VT was subsequently not inducible. Discussion & Conclusion: Critical portions of VT circuits may course epicardially or intramurally 3 , limiting successful endocardial catheter ablation. Epicardial access was risky. Coronary vessel embolization using coils 4 and ethanol 5 have been performed. Use of absorbable Gelatin sponge has been described in managing coronary perforation 6 , but to the best of our knowledge these are the first cases of its use in VT ablation.

Introduction Remote monitoring of cardiac implantable electronic devices (CIED) has been shown to improve patient safety and reduce in-office visits. We report our experience with remote monitoring via the Medtronic CareLink(®) network. Methods Patients were followed up for six months with scheduled monthly remote monitoring transmissions in addition to routine in-office checks. The efficacy of remote monitoring was evaluated by recording compliance to transmissions, number of device alerts requiring intervention and time from transmission to review. Questionnaires were administered to evaluate the experiences of patients, physicians and medical technicians. Results A total of 57 patients were enrolled; 16 (28.1%) had permanent pacemakers, 34 (59.6%) had implantable cardioverter defibrillators and 7 (12.3%) had cardiac resynchronisation therapy defibrillators. Overall, of 334 remote transmissions scheduled, 73.7% were on time, 14.5% were overdue and 11.8% were missed. 84.6% of wireless transmissions were on time, compared to 53.8% of non-wireless transmissions. Among all transmissions, 4.4% contained alerts for which physicians were informed and only 1.8% required intervention. 98.6% of remote transmissions were reviewed by the second working day. 73.2% of patients preferred remote monitoring. Physicians agreed that remote transmissions provided information equivalent to in-office checks 97.1% of the time. 77.8% of medical technicians felt that remote monitoring would help the hospital improve patient management. No adverse events were reported. Conclusion Remote monitoring of CIED is safe and feasible. It has possible benefits to patient safety through earlier detection of arrhythmias or device malfunction, permitting earlier intervention. Wireless remote monitoring, in particular, may improve compliance to device monitoring. Patients may prefer remote monitoring due to possible improvements in quality of life.

Background: Targeted temperature management (TTM) is an important component of post-cardiac arrest care. Studies have suggested that cooling is associated with better outcomes. The aim of this study was to evaluate the cooling efficacy of a protocol including a novel cooling device in the Emergency Department. Methods: This was a single-center, pre-post cohort study of post-cardiac arrest patients with return of spontaneous circulation (ROSC), for whom TTM was initiated at a tertiary hospital between April 2010 and December 2017. A surface cooling device which uses a graphite cooling material in an insulating suit was introduced in July 2015. The target temperature was 34.0 °C with TTM continued in the ICUs. The primary outcome was time from ROSC to target temperature (TT). Results: Of 124 patients included, 40 were in the intervention period and 84 in the control period. Time from ROSC to TT was significantly lower in the intervention period at 119 [interquartile range (IQR), 65–250] minutes versus 482 (IQR, 356–596) minutes (P Conclusions: Use of a novel cooling device in the ED resulted in a shorter time to target temperature. As it is reusable and does not require a power source, it has potential to be an affordable solution for pre- hospital and transport cooling.

Aims The safety and feasibility of a subcutaneous implantable cardioverter-defibrillator (S-ICD) has been demonstrated in the treatment of life-threatening ventricular tachyarrhythmias (VT). Nonetheless, its safety and feasibility in an Asian population with smaller body-build is unclear. Methods and results Twenty-one Asian patients who underwent S-ICD from 1 April 2014 to 2 February 2015 in five institutions in Hong Kong and Singapore were retrospectively reviewed. Twenty-one patients with a mean age of 50.0 ± 14.1 years (range 29–77 years, 82.6% male) were included. Among them, 17 (81.0%) were Chinese, 3 (14.3%) were Malay, and 1 (4.8%) was Indian. Their mean body mass index was 23.0 ± 4.0 kg/m2. An S-ICD was implanted for primary and secondary prevention in 13 (61.9%) and 8 (38.1%) patients, respectively. The indications included Brugada syndrome ( n = 6, 28.6%), ischaemic cardiomyopathy (CMP, n = 6, 28.6%), dilated CMP ( n = 4, 19.0%), hypertrophic CMP ( n = 2, 9.5%), and idiopathic ventricular fibrillation ( n = 2, 9.5%). Three patients (14.3%) had prior infected transvenous ICD. There were no acute complications but eight wound complications (persistent wound bleeding requiring intervention = 2; delayed wound healing: upper sternal wound = 3; generator site = 1; local wound infection = 2) were observed in six (28.2%) patients. After a mean follow-up of 107.2 ± 81.3 days (range of 14–254 days), one patient underwent three successful appropriate shocks for treatment of VTs. No inappropriate therapy was documented. Conclusion Our initial experience shows that S-ICD is a feasible treatment for VT among an Asian population with smaller body-build. There was nonetheless a relatively high rate of wound complications.

Background Targeted temperature management post-cardiac arrest is currently implemented using various methods, broadly categorized as internal and external. This study aimed to evaluate survival-to-hospital discharge and neurological outcomes (Glasgow-Pittsburgh Score) of post-cardiac arrest patients undergoing internal cooling verses external cooling. Methodology A randomized controlled trial of post-resuscitation cardiac arrest patients was conducted from October 2008–September 2014. Patients were randomized to either internal or external cooling methods. Historical controls were selected matched by age and gender. Analysis using SPSS version 21.0 presented descriptive statistics and frequencies while univariate logistic regression was done using R 3.1.3. Results 23 patients were randomized to internal cooling and 22 patients to external cooling and 42 matched controls were selected. No significant difference was seen between internal and external cooling in terms of survival, neurological outcomes and complications. However in the internal cooling arm, there was lower risk of developing overcooling ( p = 0.01) and rebound hyperthermia ( p = 0.02). Compared to normothermia, internal cooling had higher survival (OR = 3.36, 95% CI = (1.130, 10.412), and lower risk of developing cardiac arrhythmias (OR = 0.18, 95% CI = (0.04, 0.63)). Subgroup analysis showed those with cardiac cause of arrest (OR = 4.29, 95% CI = (1.26, 15.80)) and sustained ROSC (OR = 5.50, 95% CI = (1.64, 20.39)) had better survival with internal cooling compared to normothermia. Cooling curves showed tighter temperature control for internal compared to external cooling. Conclusion Internal cooling showed tighter temperature control compared to external cooling. Internal cooling can potentially provide better survival-to-hospital discharge outcomes and reduce cardiac arrhythmia complications in carefully selected patients as compared to normothermia.

Co-implantation of impurities such as carbon (C) has been proven to effectively reduce Transient Enhanced Diffusion (TED) of boron during annealing, enabling the formation of high-quality ultra-shallow junctions - a requirement for advanced-node semiconductor devices. Carbon dioxide (CO2) is traditionally used as the feed gas in implant tools for carbon implantation. Recently, carbon monoxide (CO) has been widely adopted as a replacement to CO2 due to its lower oxygen content. To further improve the carbon implant performance, a mixture of CO, carbonyl fluoride (COF2), and CO2 is studied and reported in this paper. The effects of the additional fluorine and extra oxygen content from COF2 or CO2 are investigated. Our experiments show that with the right balance and mixture level of COF2 and CO2, the carbon mixture can achieve improvements in key implant tool performance parameters, such as beam current and source life. Additionally, the CO/COF2/CO2 mixture stability is studied, and a safe delivery package is described.

Sudden cardiac arrest constitutes a major public health burden in both developed and developing countries. In those successfully resuscitated from cardiac arrest, subsequent mortality is still high (∼75%) and is due to a combination of ischaemia and reperfusion injury. The purpose of this review is to describe the experimental and clinical evidence supporting therapeutic hypothermia in survivors of sudden cardiac arrest. We also discuss controversies and unresolved issues in therapeutic hypothermia, including the optimum target temperature for therapeutic hypothermia, and the role of pre-hospital induction of hypothermia. We conclude with a perspective on therapeutic hypothermia as it applies to the Singapore context.

Genome-wide association (GWA) studies have described a large number of new candidate genes that contribute to of Type 2 Diabetes (T2D). In some cases, small clusters of genes are implicated, rather than a single gene, and in all cases, the genetic contribution is not defined through the effects on a specific organ, such as the pancreas or liver. There is a significant need to develop and use human cell-based models to examine the effects these genes may have on glucose regulation. We describe the development of a primary human hepatocyte model that adjusts glucose disposition according to hormonal signals. This model was used to determine whether candidate genes identified in GWA studies regulate hepatic glucose disposition through siRNAs corresponding to the list of identified genes. We find that several genes affect the storage of glucose as glycogen (glycolytic response) and/or affect the utilization of pyruvate, the critical step in gluconeogenesis. Of the genes that affect both of these processes, CAMK1D, TSPAN8 and KIF11 affect the localization of a mediator of both gluconeogenesis and glycolysis regulation, CRTC2, to the nucleus in response to glucagon. In addition, the gene CDKAL1 was observed to affect glycogen storage, and molecular experiments using mutant forms of CDK5, a putative target of CDKAL1, in HepG2 cells show that this is mediated by coordinate regulation of CDK5 and PKA on MEK, which ultimately regulates the phosphorylation of ribosomal protein S6, a critical step in the insulin signaling pathway.

This is a case example of a patient with degenerative mitral regurgitation in Class II heart failure treated successfully with the MitraClip. This patient had declined surgery despite multiple hospital admissions and this case illustrates the step-by-step approach to such patients.

Kinases are members of a major protein family targeted for drug discovery and development. Given the ubiquitous nature of many kinases as well as the broad range of pathways controlled by these enzymes, early safety assessments of small molecule inhibitors of kinases are crucial in identifying new molecules with sufficient therapeutic window for clinical development. Failure or attrition of drug candidates in late-stage pipelines due to hepatotoxicity is a significant challenge in the drug development field. Herein we provide detailed methods for the hepatocyte imaging assay technology (HIAT) and the bile flux imaging assay technology (BIAT) to evaluate drug-induced liver injury (DILI) potentials for drug candidates. Optimized culturing methods for primary human hepatocytes, both freshly isolated and prequalified cryopreserved cells, are also presented. The applications of these high-content cellular imaging technologies in the evaluation of p38 and Her2 kinase inhibitors are highlighted to illustrate the usefulness of the research methodology in a compound screening as well as mechanistic investigative setting.