A Leaky False Pouch: Left Ventricle Pseudoaneurysm with Active Hemopericardium Detected on Cardiac Computed Tomography Angiography.

Pseudoaneurysm is a rare but fatal complication of myocardial infarction (MI). With the advances in cardiovascular disease detection and treatments, fatal structural complications post-MI are now rare. When they occur, advanced diagnostic modalities can be used for early diagnosis, aiding surgical planning, and improving prognosis. In our case, post-MI left ventricle pseudoaneurysm complicated by hemopericardium was diagnosed using cardiac computed tomography angiography (CCTA). Use of attenuation measurement on CCTA helped diagnose active extravasation into the hemopericardium. This case highlights the high index of suspicion needed for rare but fatal complications post-MI and the utility of CCTA in their management.

Risk assessment of failure during transitioning from in-centre to home haemodialysis.

BACKGROUND: Introducing a de-novo home haemodialysis (HHD) program often raises safety concerns as errors could potentially lead to serious adverse events. Despite the complexity of performing haemodialysis at home without the supervision of healthcare staff, HHD has a good safety record. We aim to pre-emptively identify and reduce the risks to our new HHD program by risk assessment and using failure mode and effects analysis (FMEA) to identify potential defects in the design and planning of HHD. METHODS: We performed a general risk assessment of failure during transitioning from in-centre to HHD with a failure mode and effects analysis focused on the highest areas of failure. We collaborated with key team members from a well-established HHD program and one HHD patient. Risk assessment was conducted separately and then through video conference meetings for joint deliberation. We listed all key processes, sub-processes, step and then identified failure mode by scoring based on risk priority numbers. Solutions were then designed to eliminate and mitigate risk. RESULTS: Transitioning to HHD was found to have the highest risk of failure with 3 main processes and 34 steps. We identified a total of 59 areas with potential failures. The median and mean risk priority number (RPN) scores from failure mode effect analysis were 5 and 38, with the highest RPN related to vascular access at 256. As many failure modes with high RPN scores were related to vascular access, we focussed on FMEA by identifying the risk mitigation strategies and possible solutions in all 9 areas in access-related medical emergencies in a bundled- approach. We discussed, the risk reduction areas of setting up HHD and how to address incidents that occurred and those not preventable. CONCLUSIONS: We developed a safety framework for a de-novo HHD program by performing FMEA in high-risk areas. The involvement of two teams with different clinical experience for HHD allowed us to successfully pre-emptively identify risks and develop solutions.

Role of Occupational Health Services in Planning and Implementing of Staff COVID-19 Vaccination Clinic: A Tertiary Hospital Experience in Singapore.

CONTEXT: Healthcare workers all over the world were prioritized for vaccination against COVID-19 in view of the high-risk nature of their job scopes when vaccines were first available in late 2020. Vaccine hesitancy was an important problem to tackle in order to achieve a high vaccination rate, especially for vaccines that were developed using mRNA technology. We aimed to use the '3Cs' model to address vaccine hesitancy to ensure maximal uptake of the Pfizer-BioNTech vaccine among healthcare workers in a tertiary hospital in Singapore. METHODS: Various measures were used to reduce the confidence, complacency, and convenience barriers. The staff vaccination clinic was on-site and centralized, with appointments given in advance to ensure vaccine availability and to reduce wait time, providing convenience to staff. Direct and repeated communications with the staff via multiple channels were used to address vaccine safety and efficacy so as to promote confidence in the vaccines and overcome complacency barriers. To further encourage staff to get vaccinated, staff were allowed time off for vaccination when at work. Staff with a high risk of exposure to COVID-19 or those caring for immunocompromised patients were prioritized to take the vaccines first. The collection of data on adverse events was via on-site monitoring and consultation at Occupational Health Clinic (OHC). RESULTS: Nearly 80% of staff had completed vaccination when the vaccination exercise ended at the end of March 2021. With the loosening of the contraindications to vaccination over time, staff vaccination rates reached 89.3% in early July and nearly 99.9% by the end of the year. No major or serious vaccine-related medication or administration errors were reported. No staff had anaphylaxis. CONCLUSIONS: By using the '3Cs' model to plan out the vaccination exercise, it is possible to achieve a high vaccination rate coupled with effective and customized communications. This multi-disciplinary team approach can be adapted to guide vaccination efforts in various settings in future pandemics.

How platinum-induced nephrotoxicity occurs? Machine learning prediction in non-small cell lung cancer patients.

BACKGROUND AND OBJECTIVE: Platinum-induced nephrotoxicity is a severe and unexpected adverse drug reaction that could lead to treatment failure in non-small cell lung cancer patients. Better prediction and management of this nephrotoxicity can increase patient survival. Our study aimed to build up and compare the best machine learning models with clinical and genomic features to predict platinum-induced nephrotoxicity in non-small cell lung cancer patients. METHODS: Clinical and genomic data of patients undergoing platinum chemotherapy at Wan Fang Hospital were collected after they were recruited. Twelve models were established by artificial neural network, logistic regression, random forest, and support vector machine with integrated, clinical, and genomic modes. Grid search and genetic algorithm were applied to construct the fine-tuned model with the best combination of predictive hyperparameters and features. Accuracy, precision, recall, F1 score, and area under the receiver operating characteristic curve were calculated to compare the performance of the 12 models. RESULTS: In total, 118 patients were recruited for this study, among which 28 (23.73%) were experiencing nephrotoxicity. Machine learning models with clinical and genomic features achieved better prediction performances than clinical or genomic features alone. Artificial neural network with clinical and genomic features demonstrated the best predictive outcomes among all 12 models. The average accuracy, precision, recall, F1 score and area under the receiver operating characteristic curve of the artificial neural network with integrated mode were 0.923, 0.950, 0.713, 0.808 and 0.900, respectively. CONCLUSIONS: Machine learning models with clinical and genomic features can be a preliminary tool for oncologists to predict platinum-induced nephrotoxicity and provide preventive strategies in advance.

Tape Splint Tarsorrhaphy for Persistent Corneal Epithelial Defects.

PURPOSE: To report outcomes of tape splint tarsorrhaphy (TST) for persistent corneal epithelial defects (PCED). DESIGN: Retrospective, interventional case series. METHODS: The study population was consecutive patients with a PCED (14 days or longer) treated at a tertiary cornea clinic with TST. Patients with a corneal epithelial defect that did not respond to treatment with a bandage contact lens were included. Patients with a follow-up time of less than 3 months were excluded. Time to PCED resolution was the main outcome measure. RESULTS: Thirty-four eyes of 33 patients (mean age 62.9 ± 17.8 years; range, 27-90 years) were included in this study. The main etiologies of the PCED were post keratoplasty (n = 15), herpes simplex virus (n = 4), superficial keratectomy (n = 3), neurotrophic cornea (n = 4), fungal keratitis (n = 2), exposure keratopathy (n = 2), failed graft (n = 1), peripheral ulcerative keratitis (n = 1), rosacea (n = 1), and stitch abscess (n = 1). Mean ± SD time from PCED presentation to TST was 58.9 ± 106.3 days (range, 14-390 days). The mean ± SD area of the PCED was 25.1 ± 15.7 mm2 (range, 0.50-42.0 mm2). After TST, resolution of the PCED was achieved in 29/34 eyes (85.3%) without the need for additional interventions within 22.5 ± 24.3 days (range, 2-105 days). The mean ± SD logMAR best-corrected visual acuity improved significantly from 1.11 ± 0.41 to 0.83 ± 0.70 (P = .02). There were no complications attributed to TST and 2 patients elected to discontinue due to discomfort. CONCLUSIONS: TST achieved resolution of PCEDs secondary to various etiologies in 85.3% of eyes, with significant improvement in vision demonstrated. This simple, inexpensive, noninvasive technique may be considered for patients with PCEDs.

Identification of a PCSK9-LDLR disruptor peptide with in vivo function.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates plasma low-density lipoprotein cholesterol (LDL-C) levels by promoting hepatic LDL receptor (LDLR) degradation. Therapeutic antibodies that disrupt PCSK9-LDLR binding reduce LDL-C concentrations and cardiovascular disease risk. The epidermal growth factor precursor homology domain A (EGF-A) of the LDLR serves as a primary contact with PCSK9 via a flat interface, presenting a challenge for identifying small molecule PCSK9-LDLR disruptors. We employ an affinity-based screen of 1013in vitro-translated macrocyclic peptides to identify high-affinity PCSK9 ligands that utilize a unique, induced-fit pocket and partially disrupt the PCSK9-LDLR interaction. Structure-based design led to molecules with enhanced function and pharmacokinetic properties (e.g., 13PCSK9i). In mice, 13PCSK9i reduces plasma cholesterol levels and increases hepatic LDLR density in a dose-dependent manner. 13PCSK9i functions by a unique, allosteric mechanism and is the smallest molecule identified to date with in vivo PCSK9-LDLR disruptor function.

Structural basis of HLX10 PD-1 receptor recognition, a promising anti-PD-1 antibody clinical candidate for cancer immunotherapy.

Cancer immunotherapies, such as checkpoint blockade of programmed cell death protein-1 (PD-1), represents a breakthrough in cancer treatment, resulting in unprecedented results in terms of overall and progression-free survival. Discovery and development of novel anti PD-1 inhibitors remains a field of intense investigation, where novel monoclonal antibodies (mAbs) and novel antibody formats (e.g., novel isotype, bispecific mAb and low-molecular-weight compounds) are major source of future therapeutic candidates. HLX10, a fully humanized IgG4 monoclonal antibody against PD-1 receptor, increased functional activities of human T-cells and showed in vitro, and anti-tumor activity in several tumor models. The combined inhibition of PD-1/PDL-1 and angiogenesis pathways using anti-VEGF antibody may enhance a sustained suppression of cancer-related angiogenesis and tumor elimination. To elucidate HLX10's mode of action, we solved the structure of HLX10 in complex with PD-1 receptor. Detailed epitope analysis showed that HLX10 has a unique mode of recognition compared to the clinically approved PD1 antibodies Pembrolizumab and Nivolumab. Notably, HLX10's epitope was closer to Pembrolizumab's epitope than Nivolumab's epitope. However, HLX10 and Pembrolizumab showed an opposite heavy chain (HC) and light chain (LC) usage, which recognizes several overlapping amino acid residues on PD-1. We compared HLX10 to Nivolumab and Pembrolizumab and it showed similar or better bioactivity in vitro and in vivo, providing a rationale for clinical evaluation in cancer immunotherapy.

Safety and side effect profile of Pfizer-BioNTech COVID-19 vaccination among healthcare workers: A tertiary hospital experience in Singapore.

INTRODUCTION: Vaccination remains a key strategy to living endemically with COVID-19. The Pfizer-BioNTech COVID-19 vaccine was first granted interim authorisation for use in Singapore in December 2020. With overseas studies published about the safety and side effect profiles of mRNA COVID-19 vaccines focusing mainly on non-Asian populations, we described the side effects of Pfizer-BioNTech COVID-19 vaccination experienced by the healthcare workers (HCWs) in a tertiary hospital in Singapore. METHODS: Data were obtained from the Occupational Health Clinic (OHC) at the National University Hospital in Singapore, which monitored staff for any adverse effects within 30 minutes post vaccination on-site and any adverse effects after that. A cross-sectional study among the vaccinated HCWs was conducted using an online survey, which established basic demographics, histories of allergies or atopic disorders, and adverse events encountered after dose 1 and dose 2 of vaccination. RESULTS: No anaphylaxis was reported. Most common symptom was giddiness (32.7%) experienced by HCWs within 30 minutes. Adverse events attended post-vaccination by OHC were generally mild and self-limiting. From the survey, odds of experiencing an adverse event after dose 2 was significantly higher than after the first dose, especially for fever/chills (odds ratio [OR] 22.5). Fever/chills, injection site reactions, headache, aches and pains, and feeling unwell were significantly more common in HCWs below 60 years compared to those ≥60 years. An allergy to food (adjusted OR 2.7) and a history of eczema/sensitive skin (adjusted OR 2.6) were associated with a skin reaction not at injection site. CONCLUSION: The side effects experienced after Pfizer-BioNTech COVID-19 vaccines are generally self-limiting and mild, with no anaphylaxis reported.

Distinguishing features of a novel humanized anti-EGFR monoclonal antibody based on cetuximab with superior antitumor efficacy.

BACKGROUND: Cetuximab, the first approved EGFR targeting therapeutic antibody, is currently used to treat colorectal cancer and head and neck cancer. While effective, cetuximab is associated with a higher rate of skin rash, infusion reactions, and gastrointestinal toxicity, which was suggested to be linked to the presence of heterogeneous glycan contents on the Fab of the SP2/0-produced cetuximab. OBJECTIVE AND METHODS: To improve efficacy and minimize toxicity of EGFR inhibition treatment, we re-engineered cetuximab by humanizing its Fab regions and minimizing its glycan contents to generate HLX07. RESULTS: HLX07 binds to EGFR with similar affinity as cetuximab and shows better bioactivity compared to cetuximab in vitro. In vivo studies demonstrated that HLX07 significantly inhibited the growth of A431, FaDu, NCI-H292, and WiDr tumor cells and synergized them with chemotherapeutics and immune simulator agents such as anti-PD-1. In cynomolgus monkeys, 13-week repeat-dose GLP toxicokinetic studies showed minimal-to-mild toxicities in the dose range of up to 60 mg/kg/wk. In the preliminary phase 1 dose-escalation study, HLX07 had showed lower incidence of skin rashes with grade >2 severities. CONCLUSION: HLX07 is currently under phase 1/2 clinical development. We believe HLX07 would potentially be an alternative for patients who have been suffering from cetuximab-mediated toxicity.

Cutaneous Leishmaniasis Caused by an Unknown Leishmania Strain, Arizona, USA.

We investigated an autochthonous case of cutaneous leishmaniasis caused by a genetically different Leishmania sp. in a patient in Arizona, USA. This parasite was classified into the subgenus Leishmania on the basis of multilocus DNA sequence and phylogenetic analyses of the rRNA locus and 11 reference genes.

Design of Thioether Cyclic Peptide Scaffolds with Passive Permeability and Oral Exposure.

Advances in the design of permeable peptides and in the synthesis of large arrays of macrocyclic peptides with diverse amino acids have evolved on parallel but independent tracks. Less precedent combines their respective attributes, thereby limiting the potential to identify permeable peptide ligands for key targets. Herein, we present novel 6-, 7-, and 8-mer cyclic peptides (MW 774-1076 g·mol-1) with passive permeability and oral exposure that feature the amino acids and thioether ring-closing common to large array formats, including DNA- and RNA-templated synthesis. Each oral peptide herein, selected from virtual libraries of partially N-methylated peptides using in silico methods, reflects the subset consistent with low energy conformations, low desolvation penalties, and passive permeability. We envision that, by retaining the backbone N-methylation pattern and consequent bias toward permeability, one can generate large peptide arrays with sufficient side chain diversity to identify permeability-biased ligands to a variety of protein targets.

Clinical and demographic features associated with infections with extended-spectrum beta-lactamase-producing Escherichia coli in a health system in Maine, 2017.

In this case-case control study, we identified receipt of ß-lactam antibiotics and older age as independently associated with increased infection risk with ESBL-producing Escherichia coli among residents aged 20-88 years in a rural Maine hospital system where the infection prevalence of antibiotic-resistant E. coli is low.

Establishing a New Normal for Hospital Care: A Whole of Hospital Approach to Coronavirus Disease 2019 (COVID-19).

Singapore's hospitals had prepared to receive patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), planning various scenarios and levels of surge with a policy of isolating all confirmed cases as inpatients. The National University Hospital adopted a whole of hospital approach to coronavirus disease 2019 (COVID-19) with 3 primary goals: zero hospital-acquired COVID-19, all patients receive timely necessary care, and maintenance of staff morale. These goals to date have been met. A large influx of COVID-19 cases required significant transformation of clinical and operational processes. Isolation room numbers almost tripled and dedicated COVID-19 cohort wards were established, elective care was postponed, and intensive care units were augmented with equipment and manpower. In the wake of the surge, establishing a new normal for hospital care requires maintaining vigilance to detect endemic COVID-19, establishing contingency plans to ramp up in case of another surge, while returning to business as usual.

Investigation of Dracunculiasis Transmission among Humans, Chad, 2013-2017.

Dracunculiasis, slated for global eradication, typically is acquired by drinking stagnant water containing microscopic crustaceans (copepods) infected with Dracunculus medinensis larvae, causing clusters of case persons with worms emerging from the skin. Following a 10-year absence of reported cases, 9-26 sporadic human cases with few epidemiologic links have been reported annually in Chad since 2010; dog infections have also been reported since 2012. We conducted an investigation of human cases in Chad to identify risk factors. We conducted a case-control study using a standardized questionnaire to assess water and aquatic animal consumption, and links to dog infections. Case persons had laboratory-confirmed D. medinensis during 2013-2017. Each case person was matched to one to three controls without history of disease by age, gender, and residency in the village where the case person was likely infected. We estimated odds ratios (ORs) using simple conditional logistic regression. We enrolled 25 case persons with 63 matched controls. Dracunculiasis was associated with consumption of untreated water from hand-dug wells (OR: 13.4; 95% CI: 1.7-108.6), but neither with consumption of aquatic animals nor presence of infected dogs in villages. Unsafe water consumption remains associated with dracunculiasis. Education of populations about consuming safe water and using copepod filters to strain unsafe water should continue and expand, as should efforts to develop and maintain safe drinking water sources. Nevertheless, the peculiar epidemiology in Chad remains incompletely explained. Future studies of dogs might identify other risk factors.

Responding to COVID-19: how an academic infectious diseases division mobilized in Singapore.

BACKGROUND: On January 30, COVID-19 was declared a Public Health Emergency of International Concern-a week after Singapore's first imported case and 5 days before local transmission. The National University Hospital (NUH) is Singapore's third largest hospital with 1200 beds, heavy clinical workloads, and major roles in research and teaching. MAIN BODY: With memories of SARS still vivid, there was an urgent requirement for the NUH Division of Infectious Diseases to adapt-undergoing major reorganization to face rapidly changing priorities while ensuring usual essential services and standards. Leveraging on individual strengths, our division mobilized to meet the demands of COVID-19 while engaging in high-level coordination, strategy, and advocacy. We present our experience of the 60 days since the nation's first case. During this time, our hospital has managed 3030 suspect cases, including 1300 inpatients, 37 confirmed cases, and overseen 4384 samples tested for COVID-19. CONCLUSION: Complex hospital adaptations were supported by an unprecedented number of workflows and coordination channels essential to safe and effective operations. The actions we describe, aligned with international recommendations and emerging evidence-based best practices, may serve as a framework for other divisions and institutions facing the spread of COVID-19 globally.

A phase 3 study of rituximab biosimilar HLX01 in patients with diffuse large B-cell lymphoma.

Rituximab in combination with chemotherapy has shown efficacy in patients with diffuse large B-cell lymphoma (DLBCL) for more than 15 years. HLX01 was developed as the rituximab biosimilar following a stepwise approach to demonstrate biosimilarity in analytical, pre-clinical, and clinical investigations to reference rituximab. With demonstrated pharmacokinetic similarity, a phase 3 multi-center, randomized, parallel, double-blind study (HLX01-NHL03) was subsequently conducted to compare efficacy and safety between HLX01 plus cyclophosphamide, doxorubicin, vincristine, and prednisone (H-CHOP) and reference rituximab plus CHOP (R-CHOP) in a total of 407 treatment-naïve, CD20-positive DLBCL patients aged 18-80 years. The primary efficacy endpoint was best overall response rate (ORR) within six cycles of treatment in the per-protocol set (PPS). Secondary endpoints included 1-year efficacy outcomes, safety, and immunogenicity profile. The results showed difference in ORRs [H-CHOP 94.1%; R-CHOP 92.8%] between two treatment groups was 1.4% (95% confidence interval [CI], - 3.59 to 6.32, p = 0.608) which falls within the pre-defined equivalence margin of ± 12%. The safety profile was comparable between the treatment groups, with a similar overall incidence of treatment-emergent adverse events (H-CHOP 99.5%, R-CHOP 99.0%, p = 1.000) and serious adverse events (H-CHOP 34.0%, R-CHOP 32.5%, p = 0.752). This study established bioequivalence in efficacy and safety between HLX01 and reference rituximab. The trial was registered at http://www.chinadrugtrials.org.cn on 26 August 2015 [#CTR20150583].