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Oxidative phosphorylation (OXPHOS) occurs through and across the inner mitochondrial membrane (IMM). Mitochondrial membranes contain a distinct lipid composition, aided by lipid biosynthetic machinery localized in the IMM and class-specific lipid transporters that limit lipid traffic in and out of mitochondria. This unique lipid composition appears to be essential for functions of mitochondria, particularly OXPHOS, by its effects on direct lipid-to-protein interactions, membrane properties, and cristae ultrastructure. This review highlights the biological significance of mitochondrial lipids, with a particular spotlight on the role of lipids in mitochondrial bioenergetics. We describe pathways for the biosynthesis of mitochondrial lipids and provide evidence for their roles in physiology, their implications in human disease, and the mechanisms by which they regulate mitochondrial bioenergetics.

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Isolated pulmonary valve (PV) infective endocarditis (IE) is a rare entity accounting for <2 % of all cases of IE. Risk of PV IE in patients with atrial septal defect (ASD) is considered negligible and there have only been a few cases reported to date. We describe a case of a 51-year-old woman with an ostium secundum ASD with associated PV endocarditis, who presented with multiple pulmonary septic emboli. Initially we tried antibiotic therapy and later she underwent successful surgery with ASD closure, vegetectomy, and PV repair. We want to draw attention to the possibility of IE of PV in a patient with ASD and report successful management with surgery and good recovery following treatment. Learning objective: In this study, we highlight the importance of keeping a strong clinical suspicion of infective endocarditis (IE) in patients presenting with fever and a pulmonary focus, especially in the setting of congenital heart disease (including even atrial septal defect). We also discuss the possible indications for surgical management in patients with pulmonary valve IE.

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OBJECTIVES: Most biomarker studies of sepsis originate from high-income countries, whereas mortality risk is higher in low- and middle-income countries. The second version of the Pediatric Sepsis Biomarker Risk Model (PERSEVERE-II) has been validated in multiple North American PICUs for prognosis. Given differences in epidemiology, we assessed the performance of PERSEVERE-II in septic children from Pakistan, a low-middle income country. Due to uncertainty regarding how well PERSEVERE-II would perform, we also assessed the utility of other select biomarkers reflecting endotheliopathy, coagulopathy, and lung injury. DESIGN: Prospective cohort study. SETTING: PICU in Aga Khan University Hospital in Karachi, Pakistan. PATIENTS: Children (< 18 yr old) meeting pediatric modifications of adult Sepsis-3 criteria between November 2020 and February 2022 were eligible. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Plasma was collected within 24 hours of admission and biomarkers quantified. The area under the receiver operating characteristic curve for PERSEVERE-II to discriminate 28-day mortality was determined. Additional biomarkers were compared between survivors and nonsurvivors and between subjects with and without acute respiratory distress syndrome. In 86 subjects (20 nonsurvivors, 23%), PERSEVERE-II discriminated mortality (area under the receiver operating characteristic curve, 0.83; 95% CI, 0.72-0.94) and stratified the cohort into low-, medium-, and high-risk of mortality. Biomarkers reflecting endotheliopathy (angiopoietin 2, intracellular adhesion molecule 1) increased across worsening risk strata. Angiopoietin 2, soluble thrombomodulin, and plasminogen activator inhibitor 1 were higher in nonsurvivors, and soluble receptor for advanced glycation end-products and surfactant protein D were higher in children meeting acute respiratory distress syndrome criteria. CONCLUSIONS: PERSEVERE-II performs well in septic children from Aga Khan University Hospital, representing the first validation of PERSEVERE-II in a low-middle income country. Patients possessed a biomarker profile comparable to that of sepsis from high-income countries, suggesting that biomarker-based enrichment strategies may be effective in this setting.

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Background@#Ultraviolet radiation has been proven to result in unwarranted effects on the skin through reactive oxygen species (ROS) and direct DNA damage. Lycopene, a naturally occurring substance, acts as an antioxidant by neutralizing ROS.@*Objective@#The objective of the study was to determine the efficacy of oral lycopene supplementation for photoprotection in adult Filipino patients seen in a tertiary hospital in Makati City.@*Design@#The study design involves single-blind, parallel, randomized controlled trial.@*Methods@#Thirty-six Filipino patients aged 18 years old and above with Fitzpatrick Skin Phototype (FSP) III–V were divided into two groups using a computer-generated randomization. Group A received lycopene 500 mg/ soft gel capsule two capsules per orem once daily for 12 weeks, while Group B received no intervention during the entire observation period. Minimal erythema dose (MED) of patients from both groups was assessed by a single treatment-blinded reader at baseline, week 6, and week 12.@*Results@#Group A showed a significant increase in MED across periods, with a 20.83% increase from baseline at week 6 and a 43.06% increase at week 12. Group B MED remained constant from baseline to week 6 and to week 12. These results show that there is a significant effect in the increase in MED as compared to the control group.@*Conclusion@#Oral lycopene is effective in increasing the MED of patients and may be used for photoprotection among patients with FSP III–V.

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Potential benefits of precision medicine in cardiovascular disease (CVD) include more accurate phenotyping of individual patients with the same condition or presentation, using multiple clinical, imaging, molecular and other variables to guide diagnosis and treatment. An approach to realising this potential is the digital twin concept, whereby a virtual representation of a patient is constructed and receives real-time updates of a range of data variables in order to predict disease and optimise treatment selection for the real-life patient. We explored the term digital twin, its defining concepts, the challenges as an emerging field, and potentially important applications in CVD. A mapping review was undertaken using a systematic search of peer-reviewed literature. Industry-based participants and patent applications were identified through web-based sources. Searches of Compendex, EMBASE, Medline, ProQuest and Scopus databases yielded 88 papers related to cardiovascular conditions (28%, n = 25), non-cardiovascular conditions (41%, n = 36), and general aspects of the health digital twin (31%, n = 27). Fifteen companies with a commercial interest in health digital twin or simulation modelling had products focused on CVD. The patent search identified 18 applications from 11 applicants, of which 73% were companies and 27% were universities. Three applicants had cardiac-related inventions. For CVD, digital twin research within industry and academia is recent, interdisciplinary, and established globally. Overall, the applications were numerical simulation models, although precursor models exist for the real-time cyber-physical system characteristic of a true digital twin. Implementation challenges include ethical constraints and clinical barriers to the adoption of decision tools derived from artificial intelligence systems.

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Coronary artery disease (CAD) remains the leading cause of death worldwide. The role of hypertension, cholesterol, diabetes mellitus, and smoking in driving disease has been well recognized at a population level and has been the target of primary prevention strategies for over 50 years with substantial impact. However, in many cases, these factors alone do not provide enough precision at the individual level to allow physicians and patients to take appropriate preventive measures and many patients continue to suffer acute coronary syndromes in the absence of these risk factors. Recent advances in user-friendly chip designs, high speed throughput, and economic efficiency of genome-wide association studies complemented by advances in statistical analytical approaches have facilitated the rapid development of polygenic risk scores (PRSs). The latest PRSs combine data regarding hundreds of thousands of single-nucleotide polymorphisms to predict chronic diseases including CAD. Novel CAD PRSs are strong predictors of risk and may have application, in a complementary manner with existing risk prediction algorithms. However, there remain substantial controversies, and ultimately, we need to move forward from observational studies to prospectively and rigorously assess the potential impact if widespread implementation is to be aspired to. Consideration needs to be made of ethnicity, sex, as well as age, and risk estimate based on existing non-genomic algorithms. We provide an overview and commentary on the important advances in deriving and validating PRSs, as well as pragmatic considerations that will be required for implementation of the new knowledge into clinical practice.

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Worldwide morbidity and mortality associated with Covid-19 are severe and ongoing. The Pfizer-BioNTech vaccine is said to be up to 95% effective against severe disease or death. We were able to demonstrate that an additional 9.8% of COVID-19 vaccine doses could theoretically be given if the residual vaccine within the reconstituted Pfizer vials after six doses are extracted were used. This could be achieved by aseptically combining this excess vaccine from multiple vials to achieve full 0.3ml doses. MethodsAn observational study was conducted in April, 2021, at a mass vaccine site run by a community volunteer organization on Bainbridge Island, Washington. We measured the amount of Pfizer-BioNTech COVID-19 vaccine that was left in 172 vials after six doses had been withdrawn per Centers for Disease Control (CDC) protocol. ResultsA total of 30.68 ml of leftover vaccine was measured and discarded as medical waste. 1,036 doses were given from these vials. An extra 102 doses theoretically could have been given using the residual vaccine in the vials. This would have resulted in 9.8% additional doses of COVID-19 vaccine without requiring new vials. ConclusionThe ability to combine solution from reconstituted Pfizer vaccine vials to minimize waste and obtain additional doses of vaccine could result in an increase in the number of individuals that could be vaccinated worldwide without additional cost. Further studies to validate our findings are warranted. Clinical trials to study the feasibility, safety and efficacy of protocols using this excess vaccine should be considered.

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Cerebral malaria (CM) is defined by WHO as coma (Blantyre Coma Score 2 or less) in a patient with Plasmodium falciparum parasitaemia and no alternative cause of coma identified. Mortality is approximately 15%-30% in African children and up to one-third of survivors have neurological sequelae. We present a patient with severe stridor and prolonged profound weakness during an intensive care admission with CM. These complications initially presented a diagnostic dilemma in our limited resourced setting. The stridor failed to improve with empiric steroids and a subsequent opportunistic ENT consult diagnosed vocal cord paresis. The weakness was so profound that the patient was unable to lift his head during the acute illness. The child received intensive physiotherapy, and at 1-month follow-up, the stridor and weakness had resolved.

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Respiratory viruses such as coronaviruses represent major ongoing global threats, causing epidemics and pandemics with huge economic burden. Rapid spread of virus through populations poses an enormous challenge for outbreak control. Like all respiratory viruses, the most recent novel human coronavirus SARS-CoV-2, initiates infection in the upper respiratory tract (URT). Infected individuals are often asymptomatic, yet highly infectious and readily transmit virus. A therapy that restricts initial replication in the URT has the potential to prevent progression of severe lower respiratory tract disease as well as limiting person-to-person transmission. We show that prophylactic intra-nasal administration of the TLR2/6 agonist INNA-051 in a SARS-CoV-2 ferret infection model effectively reduces levels of viral RNA in the nose and throat. The results of our study support clinical development of a therapy based on prophylactic TLR2/6 innate immune activation in the URT to reduce SARS-CoV-2 transmission and provide protection against COVID-19.

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A novel coronavirus, SARS-CoV-2, has been identified as the causative agent of the current COVID-19 pandemic. Animal models, and in particular non-human primates, are essential to understand the pathogenesis of emerging diseases and to the safety and efficacy of novel vaccines and therapeutics. Here, we show that SARS-CoV-2 replicates in the upper and lower respiratory tract and causes pulmonary lesions in both rhesus and cynomolgus macaques, resembling the mild clinical cases of COVID-19 in humans. Immune responses against SARS-CoV-2 were also similar in both species and equivalent to those reported in milder infections and convalescent human patients. Importantly, we have devised a new method for lung histopathology scoring that will provide a metric to enable clearer decision making for this key endpoint. In contrast to prior publications, in which rhesus are accepted to be the optimal study species, we provide convincing evidence that both macaque species authentically represent mild to moderate forms of COVID-19 observed in the majority of the human population and both species should be used to evaluate the safety and efficacy of novel and repurposed interventions against SARS-CoV-2. Accessing cynomolgus macaques will greatly alleviate the pressures on current rhesus stocks.

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In December 2019 an outbreak of coronavirus disease (COVID-19) emerged in Wuhan, China. The causative agent was subsequently identified and named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which rapidly spread worldwide causing a pandemic. Currently there are no licensed vaccines or therapeutics available against SARS-CoV-2 but numerous candidate vaccines are in development and repurposed drugs are being tested in the clinic. There is a vital need for authentic COVID-19 animal models to further our understanding of pathogenesis and viral spread in addition to pre-clinical evaluation of candidate interventions. Here we report a dose titration study of SARS-CoV-2 to determine the most suitable infectious dose to use in the ferret model. We show that a high (5x106 pfu) and medium (5x104 pfu) dose of SARS-CoV-2 induces consistent upper respiratory tract (URT) viral RNA shedding in both groups of six challenged animals, whilst a low dose (5x102 pfu) resulted in only one of six displaying signs of URT viral RNA replication. The URT shedding lasted up to 21 days in the high dose animals with intermittent positive signal from day 14. Sequential culls revealed distinct pathological signs of mild multifocal bronchopneumonia in approximately 5-15% of the lung, observed on day 3 in high and medium dosed animals, with presence of mild broncho-interstitial pneumonia on day 7 onwards. No obvious elevated temperature or signs of coughing or dyspnoea were observed although animals did present with a consistent post-viral fatigue lasting from day 9-14 in the medium and high dose groups. After virus shedding ceased, re-challenged ferrets were shown to be fully protected from acute lung pathology. The endpoints of URT viral RNA replication in addition to distinct lung pathology and post viral fatigue were observed most consistently in the high dose group. This ferret model of SARS-CoV-2 infection presents a mild clinical disease (as displayed by 80% of patients infected with SARS-CoV-2). In addition, intermittent viral shedding on days 14-21 parallel observations reported in a minority of clinical cases.

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The advent of immune checkpoint inhibitors (ICIs) for cancer therapy has heralded increasing frequency of immune-related adverse events including endocrinopathies, hepatitis, colitis and rarely myocarditis and myasthenia gravis (MG). The heterogeneity in clinical presentations regardless of organ-specific involvement can lead to delayed recognition and management of these events and adverse health outcomes. We describe a case of ICI-induced subclinical focal myocarditis that was recognised and treated in the broader context of MG. It is essential that patients with ICI-induced MG should be screened and monitored for myocarditis, a potentially fatal complication.

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Primary thyroid teratomas are rare, usually benign, and typically occur in children. We report the unusual occurrence of a malignant thyroid teratoma in a young man. Initial ultrasound and CT studies revealed an 8.5 heterogeneous mass involving the entire right thyroid lobe causing tracheal compression and deviation. Fine-needle aspiration (FNA) revealed malignant cells with possible neuroendocrine features. Similar findings have been previously reported, with an occasional interpretation as possible medullary thyroid carcinoma. In no report, as with our case, has the correct diagnosis been suggested with FNA. The surgical specimen contained abundant primitive neuroepithelium with a very minor component of mature ectodermal tissue in one area. Like this case, an abundance of immature neuroepithelium has been reported in essentially all previous reports of primary malignant thyroid teratoma, sometimes creating a challenge to find another type of germ cell tissue. Array comparative genomic hybridization studies in this case revealed a markedly complex karyotype including gain of chromosome 12 and loss of 17p. Amplification of MYCN, EWSR1 rearrangement and isochromosome 12p were not identified, providing no evidence for neuroblastoma or Ewing sarcoma/peripheral neuroectodermal tumor, both of which have also rarely been reported as primary thyroid tumors. With the use of cisplatinum-based chemotherapy combined with radiation, survival times have increased dramatically. Our patient is now disease free and back to his normal activities after relatively short follow-up. Although rare, it is important to be aware that teratomas may present as a thyroid nodule. Recognition by FNA is challenging, and requires multiple modalities for full identification.

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AIMS: Flucloxacillin dosing may be guided by measurement of its total plasma concentrations. Flucloxacillin is highly protein bound with fraction unbound in plasma (fu ) of around 0.04 in healthy individuals. The utility of measuring unbound flucloxacillin concentrations for patients outside the intensive care unit (ICU) is not established. We aimed to compare flucloxacillin fu in non-ICU hospitalised patients against healthy volunteers, and to examine the performance of a published model for predicting unbound concentrations, using total flucloxacillin and plasma albumin concentrations. METHODS: Data from 12 healthy volunteers (248 samples) and 47 hospitalized patients (61 samples) were examined. Plasma flucloxacillin concentrations were measured using a validated liquid chromatography-tandem mass spectrometry method. Flucloxacillin fu for the two groups was compared using a generalized estimating equation model to account for clustered observations. The performance of the single protein binding site prediction model in hospitalized patients was compared with measured unbound concentrations using Bland-Altman plots. RESULTS: The median (range) flucloxacillin fu for healthy (median albumin 45 g l-1 ) and hospitalized individuals (median albumin 30 g l-1 ) were 0.04 (0.02-0.07) and 0.10 (0.05-0.37), respectively (P < 0.0001). The prediction model underpredicted unbound flucloxacillin concentrations with a mean bias (95% limits of agreement) of -54% (-137%, +30%). CONCLUSIONS: The flucloxacillin fu values observed in our cohort of hospitalized patients had a wide range and were greater than those of healthy individuals. Unbound flucloxacillin plasma concentrations were predicted poorly by the model. Instead, unbound concentrations should be measured to guide dosing.

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A novel method is presented to outcouple high spatial frequency (large-k) waves from hyperbolic metamaterials (HMMs) without the use of a grating. This approach relies exclusively on dispersion engineering, and enables preferential power extraction from the top or from the side of a HMM. Multilayer (ML) HMMs are shown to be better suited for lateral outcoupling, while nanowire HMMs are the most convenient choice for top outcoupling. A 6-fold increase in laterally extracted power is predicted for a dipole-HMM system with a Ag/Si ML operating at λ = 530 nm, when metallic filling ratio is changed from an unoptimized to the optimized one. This new design concept supports the cost-effective mass production of high-speed HMM optical transmitters.