Clinically relevant therapeutic approaches against acetaminophen hepatotoxicity and acute liver failure.

Liver injury and acute liver failure caused by an acetaminophen (APAP) overdose is a significant clinical problem in western countries. With the introduction of the mouse model of APAP hepatotoxicity in the 1970 s, fundamental mechanisms of cell death were discovered. This included the recognition that part of the APAP dose is metabolized by cytochrome P450 generating a reactive metabolite that is detoxified by glutathione. After the partial depletion of glutathione, the reactive metabolite will covalently bind to sulfhydryl groups of proteins, which is the initiating event of the toxicity. This insight led to the introduction of N-acetyl-L-cysteine, a glutathione precursor, as antidote against APAP overdose in the clinic. Despite substantial progress in our understanding of the pathomechanisms over the last decades viable new antidotes only emerged recently. This review will discuss the background, mechanisms of action, and the clinical prospects of the existing FDA-approved antidote N-acetylcysteine, of several new drug candidates under clinical development [4-methylpyrazole (fomepizole), calmangafodipir] and examples of additional therapeutic targets (Nrf2 activators) and regeneration promoting agents (thrombopoietin mimetics, adenosine A2B receptor agonists, Wharton's Jelly mesenchymal stem cells). Although there are clear limitations of certain therapeutic approaches, there is reason to be optimistic. The substantial progress in the understanding of the pathophysiology of APAP hepatotoxicity led to the consideration of several drugs for development as clinical antidotes against APAP overdose in recent years. Based on the currently available information, it is likely that this will result in additional drugs that could be used as adjunct treatment for N-acetylcysteine.

Lack of mitochondrial Cyp2E1 drives acetaminophen-induced ER stress-mediated apoptosis in mouse and human kidneys: Inhibition by 4-methylpyrazole but not N-acetylcysteine.

Acetaminophen (APAP) overdose causes liver injury and acute liver failure, as well as acute kidney injury, which is not prevented by the clinical antidote N-acetyl-L-cysteine (NAC). The absence of therapeutics targeting APAP-induced nephrotoxicity is due to gaps in understanding the mechanisms of renal injury. APAP metabolism through Cyp2E1 drives cell death in both the liver and kidney. We demonstrate that Cyp2E1 is localized to the proximal tubular cells in mouse and human kidneys. Virtually all the Cyp2E1 in kidney cells is in the endoplasmic reticulum (ER), not in mitochondria. By contrast, hepatic Cyp2E1 is in both the ER and mitochondria of hepatocytes. Consistent with this subcellular localization, a dose of 600 mg/kg APAP in fasted C57BL/6J mice induced the formation of APAP protein adducts predominantly in mitochondria of hepatocytes, but the ER of the proximal tubular cells of the kidney. We found that reactive metabolite formation triggered ER stress-mediated activation of caspase-12 and apoptotic cell death in the kidney. While co-treatment with 4-methylpyrazole (4MP; fomepizole) or the caspase inhibitor Ac-DEVD-CHO prevented APAP-induced cleavage of procaspase-12 and apoptosis in the kidney, treatment with NAC had no effect. These mechanisms are clinically relevant because 4MP but not NAC also significantly attenuated APAP-induced apoptotic cell death in primary human kidney cells. We conclude that reactive metabolite formation by Cyp2E1 in the ER results in sustained ER stress that causes activation of procaspase-12, triggering apoptosis of proximal tubular cells, and that 4MP but not NAC may be an effective antidote against APAP-induced kidney injury.

A multi-stem cell basis for craniosynostosis and calvarial mineralization.

Craniosynostosis is a group of disorders of premature calvarial suture fusion. The identity of the calvarial stem cells (CSCs) that produce fusion-driving osteoblasts in craniosynostosis remains poorly understood. Here we show that both physiologic calvarial mineralization and pathologic calvarial fusion in craniosynostosis reflect the interaction of two separate stem cell lineages; a previously identified cathepsin K (CTSK) lineage CSC1 (CTSK+ CSC) and a separate discoidin domain-containing receptor 2 (DDR2) lineage stem cell (DDR2+ CSC) that we identified in this study. Deletion of Twist1, a gene associated with craniosynostosis in humans2,3, solely in CTSK+ CSCs is sufficient to drive craniosynostosis in mice, but the sites that are destined to fuse exhibit an unexpected depletion of CTSK+ CSCs and a corresponding expansion of DDR2+ CSCs, with DDR2+ CSC expansion being a direct maladaptive response to CTSK+ CSC depletion. DDR2+ CSCs display full stemness features, and our results establish the presence of two distinct stem cell lineages in the sutures, with both populations contributing to physiologic calvarial mineralization. DDR2+ CSCs mediate a distinct form of endochondral ossification without the typical haematopoietic marrow formation. Implantation of DDR2+ CSCs into suture sites is sufficient to induce fusion, and this phenotype was prevented by co-transplantation of CTSK+ CSCs. Finally, the human counterparts of DDR2+ CSCs and CTSK+ CSCs display conserved functional properties in xenograft assays. The interaction between these two stem cell populations provides a new biologic interface for the modulation of calvarial mineralization and suture patency.

Response to Comment on "Dying in the Sun: Direct evidence for elevated UV-B radiation at the end-Permian mass extinction".

Seddon and Zimmermann have raised questions about the evidence for increased UV-B flux across the end-Permian mass extinction (EPME) that was presented in our recent study, specifically regarding the measurement of UV-B-absorbing compound (UAC) levels in fossil pollen. We respond to these points, arguing that the comparison of FTIR spectra of >250 million-year-old Permian fossil pollen with ~700-year-old subfossil pollen is not valid and that negligible nonrandom interference derived from water vapor fluctuations during data generation cannot coincidentally produce a substantial UAC peak during the EPME. Furthermore, we refute the suggestion that the measured aromatic peak at 1600 cm-1 could have been influenced by diagenetic products from other organic constituents of pollen. The most productive route forward will be to generate sporomorph geochemical data from additional Permian-Triassic boundary sections to test the results put forward in our study.

Management of Acetaminophen Poisoning in the US and Canada: A Consensus Statement.

Importance: The US and Canada currently have no formal published nationwide guidelines for specialists in poison information or emergency departments for the management of acetaminophen poisoning, resulting in significant variability in management. Objective: To develop consensus guidelines for the management of acetaminophen poisoning in the US and Canada. Evidence Review: Four clinical toxicology societies (America's Poison Centers, American Academy of Clinical Toxicology, American College of Medical Toxicology, and Canadian Association of Poison Control Centers) selected participants (n = 21). Led by a nonvoting chairperson using a modified Delphi method, the panel created a decision framework and determined the appropriate clinical management of a patient with acetaminophen poisoning. Unique to this effort was the collection of guidelines from most poison centers in addition to systematic collection and review of the medical literature. Comments from review by external organizations were incorporated before the guideline was finalized. The project began in March 2021 and ended in March 2023. Findings: The search retrieved 84 guidelines and 278 publications. The panel developed guidelines for emergency department management of single or repeated ingestion of acetaminophen. In addition, the panel addressed extended-release formulation, high-risk ingestion, coingestion of anticholinergics or opioids, age younger than 6 years, pregnancy, weight greater than 100 kg, and intravenous acetaminophen use. Differences from current US practice include defining acute ingestion as an ingestion presentation from 4 to 24 hours after overdose was initiated. A revised form of the Rumack-Matthew nomogram was developed. The term massive ingestion was replaced with the term high-risk ingestion and denoted by a specific nomogram line. Other recommendations include specific criteria for emergency department triage, laboratory evaluation and monitoring parameters, defining the role of gastrointestinal decontamination, detailed management of acetylcysteine treatment, associated adverse effects, and stopping criteria for acetylcysteine treatment, as well as criteria for consultation with a clinical toxicologist. Finally, specific treatment considerations, including acetylcysteine dosing, fomepizole administration, and considerations for extracorporeal elimination and transplant evaluation, were addressed. Conclusions and Relevance: This qualitative study provides a consensus statement on consistent evidence-based recommendations for medical, pharmacy, and nursing education and practice to optimize care of patients with acetaminophen poisoning.

X-ray computed tomography: A novel non-invasive approach for the detection of microplastics in sediments?

As a non-invasive imaging technique, this study explores the application of Computed Tomography (CT) in microplastics research, assessing its potential to distinguish different types and sizes of microplastics (polypropylene, polyethylene terephthalate, polyethylene, and polyvinyl chloride) from homogenised river-estuarine sediment. When examined in layers within artificial cores, all microplastic types could be observed by CT imagery, with good contrast in X-ray attenuation (based on image gray level intensity) against background sediments. Large microplastics (4 mm diameter) were also detectable when distributed randomly amongst the sediment. These spiked cores had sufficient difference in attenuation to allow segmentation between type, and therefore isolate individual microplastics. Due to limitations on scan resolution, smaller microplastics (≤125 µm diameter) could not be detected in spiked cores. Scans of two sediment cores from a Thames River tributary (UK) revealed two distinctive sediment structures which could influence microplastic accumulation. This information would be lost using conventional recovery procedures.

"The Effects of Gingivoperiosteoplasty and Cleft Palate Repair on Facial Growth."

PURPOSE: Gingivoperiosteoplasty (GPP) can avoid secondary alveolar bone graft in up to 60% of patients. The effects of GPP on maxillary growth are a concern. However, palatoplasty can also negatively impact facial growth. This study quantifies the isolated effects of GPP and cleft palate repair on maxillary growth at the age of mixed dentition. METHODS: A single institution, retrospective study of all patients undergoing primary reconstruction for unilateral cleft lip and alveolus (CLA) or cleft lip and palate (CLP) was performed. Study patients had lateral cephalograms at age of mixed dentition. Patients were stratified into four groups: CLA with GPP (CLA+GPP), CLA without GPP (CLA-GPP), CLP with GPP (CLP+GPP), and CLP without GPP (CLP-GPP). Cephalometric measurements included: sella-nasion-point A (SNA), sella-nasion-point B (SNB), and A point-nasion-B point (ANB). Landmarks were compared between patient groups and to Eurocleft Center D data. RESULTS: 110 patients met inclusion criteria: 7 CLA-GPP, 16 CLA+GPP, 24 CLP-GPP, and 63 CLP+GPP patients. There were no significant differences in SNA, SNB, and ANB between CLA+GPP and CLA-GPP, or between CLP+GPP and CLP-GPP groups. In patients who did not receive GPP, SNA was significantly lower in patients with a cleft palate compared to patients with an intact palate (p < 0.05). There were no significant differences in SNA or SNB of CLP-GPP or CLP+GPP groups when compared to Eurocleft data. CONCLUSION: When controlling for the effects of cleft palate repair, GPP does not appear to negatively affect midface growth at the age of mixed dentition.

Clinical Outcomes of Bilateral Cleft Lip and Palate Repair with Nasoalveolar Molding and Gingivoperiosteoplasty to Facial Maturity.

BACKGROUND: The long-term effects of nasoalveolar molding (NAM) on patients with bilateral cleft lip and palate (BCLP) are unknown. The authors report clinical outcomes of facially mature patients with complete BCLP who underwent NAM and gingivoperiosteoplasty (GPP). METHODS: A single-institution retrospective study of nonsyndromic patients with complete BCLP who underwent NAM between 1991 and 2000 was performed. All study patients were followed to skeletal maturity, at which time a lateral cephalogram was obtained. The total number of cleft operations and cephalometric measures was compared with a previously published external cohort of patients with complete and incomplete BCLP in which a minority (16.7%) underwent presurgical orthopedics before cleft lip repair without GPP. RESULTS: Twenty-four patients with BCLP comprised the study cohort. All patients underwent GPP, 13 (54.2%) underwent alveolar bone graft, and nine (37.5%) required speech surgery. The median number of operations per patient was five (interquartile range, two), compared with eight (interquartile range, three) in the external cohort ( P < 0.001). Average age at the time of lateral cephalogram was 18.64 years (1.92). There was no significant difference between our cohort and the external cohort with respect to sella-nasion-point A angle (SNA) [73 degrees (6 degrees) versus 75 degrees (11 degrees); P = 0.186] or sella-nasion-point B angle (SNA) [78 degrees (6 degrees) versus 74 degrees (9 degrees); P = 0.574]. Median ANB (SNA - SNB) was -3 degrees (5 degrees) compared with -1 degree (7 degrees; P = 0.024). Twenty patients (83.3%) underwent orthognathic surgery. CONCLUSION: Patients with BCLP who underwent NAM and GPP had significantly fewer total cleft operations and mixed midface growth outcomes at facial maturity compared with patients who did not undergo this treatment protocol. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Dying in the Sun: Direct evidence for elevated UV-B radiation at the end-Permian mass extinction.

Land plants can adjust the concentration of protective ultraviolet B (UV-B)-absorbing compounds (UACs) in the outer wall of their reproductive propagules in response to ambient UV-B flux. To infer changes in UV-B radiation flux at Earth's surface during the end-Permian mass extinction, we analyze UAC abundances in ca. 800 pollen grains from an independently dated Permian-Triassic boundary section in Tibet. Our data reveal an excursion in UACs that coincide with a spike in mercury concentration and a negative carbon-isotope excursion in the latest Permian deposits, suggesting a close temporal link between large-scale volcanic eruptions, global carbon and mercury cycle perturbations, and ozone layer disruption. Because enhanced UV-B radiation can exacerbate the environmental deterioration induced by massive magmatism, ozone depletion is considered a compelling ecological driver for the terrestrial mass extinction.

Effect of One-Stage Bilateral Cleft Lip, Nose, and Alveolus Repair Following Nasoalveolar Molding on the Premaxilla Position at Preadolescence: An 8-Year Retrospective Study.

BACKGROUND/PURPOSE: This paper describes the changes in maxillary arch morphology in infants with bilateral cleft lip and palate (BCLP) following nasoalveolar molding (NAM) and with follow up to assess the need for secondary alveolar bone grafting (ABG) and premaxillary repositioning surgery at preadolescence. METHODS/DESCRIPTION: Treatment records of infants with BCLP treated with NAM between 2003 and 2013 were reviewed. Patients with complete BCLP who underwent NAM and had complete sets of maxillary casts at T 0 pre-NAM (mean = 27 days), T 1 post-NAM (mean = 6 months and 5 days), and T 2 before palate surgery (mean = 11 months and 15 days) were included. The sample comprised 23 infants (18 male, 5 female). Casts were digitized and analyzed using three dimensional software. The need for secondary ABG and premaxillary repositioning surgery was assessed at preadolescent follow-up (mean = 8.3 years). RESULTS: Cleft width was reduced on average by 4.73 mm (SD±3.15 mm) and 6.56 mm (SD±4.65) on the right and left sides, respectively. At T 1, 13 (56.52%) patients underwent bilateral gingivoperiosteoplasty (GPP), 8 (34.78%) patients unilateral GPP, and 2 patients (8.7%) did not undergo GPP. 34/46 clefts sites (73.91%) underwent GPP while 12 (26.08%) did not. At preadolescent follow-up of 19 patients, 7 patients (36.84%) did not need ABG on either side, 8 (42.10%) needed ABG on 1 side, and 4 (21.05%) needed ABG on both sides. None of the patients needed premaxillary repositioning surgery. CONCLUSIONS: Nasoalveolar molding treatment significantly improves the position of the premaxilla before primary repair, and there is a significant reduction in the need for secondary ABG and premaxillary repositioning surgery at preadolescence.

Psychiatric and psychosocial morbidity 1 year after epilepsy surgery.

OBJECTIVES: There is a high rate of psychiatric comorbidity in patients with epilepsy. However, the impact of surgical treatment of refractory epilepsy on psychopathology remains under investigation. We aimed to examine the impact of epilepsy surgery on psychopathology and quality of life at 1-year post-surgery in a population of patients with epilepsy refractory to medication. METHODS: This study initially assessed 48 patients with refractory epilepsy using the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I), the Hospital Anxiety and Depression Scale (HADS) and the Quality of Life in Epilepsy Inventory 89 (QOLIE-89) on admission to an Epilepsy Monitoring Unit (EMU) as part of their pre-surgical assessment. These patients were again assessed using the SCID-I, QOLIE-89 and HADS at 1-year follow-up post-surgery. RESULTS: There was a significant reduction in psychopathology, particularly psychosis, following surgery at 1-year follow-up (p < 0.021). There were no new cases of de novo psychosis and surgery was also associated with a significant improvement in the quality of life scores (p < 0.001). CONCLUSIONS: This study demonstrates the impact of epilepsy surgery on psychopathology and quality of life in a patient population with refractory surgery. The presence of a psychiatric illness should not be a barrier to access surgical treatment.

The First Hybrid International Educational Comprehensive Cleft Care Workshop.

OBJECTIVE: Describe the first hybrid global simulation-based comprehensive cleft care workshop, evaluate impact on participants, and compare experiences based on in-person versus virtual attendance. DESIGN: Cross-sectional survey-based evaluation. SETTING: International comprehensive cleft care workshop. PARTICIPANTS: Total of 489 participants. INTERVENTIONS: Three-day simulation-based hybrid comprehensive cleft care workshop. MAIN OUTCOME MEASURES: Participant demographic data, perceived barriers and interventions needed for global comprehensive cleft care delivery, participant workshop satisfaction, and perceived short-term impact on practice stratified by in-person versus virtual attendance. RESULTS: The workshop included 489 participants from 5 continents. The response rate was 39.9%. Participants perceived financial factors (30.3%) the most significant barrier and improvement in training (39.8%) as the most important intervention to overcome barriers facing cleft care delivery in low to middle-income countries. All participants reported a high level of satisfaction with the workshop and a strong positive perceived short-term impact on their practice. Importantly, while this was true for both in-person and virtual attendees, in-person attendees reported a significantly higher satisfaction with the workshop (28.63 ± 3.08 vs 27.63 ± 3.93; P = .04) and perceived impact on their clinical practice (22.37 ± 3.42 vs 21.02 ± 3.45 P = .01). CONCLUSION: Hybrid simulation-based educational comprehensive cleft care workshops are overall well received by participants and have a positive perceived impact on their clinical practices. In-person attendance is associated with significantly higher satisfaction and perceived impact on practice. Considering that financial and health constraints may limit live meeting attendance, future efforts will focus on making in-person and virtual attendance more comparable.

Simultaneous Le Fort III and Le Fort I Osteotomy: Surgical Outcomes and Clinical Parameters.

INTRODUCTION: Simultaneous Le Fort III/I (LF III/I) osteotomies are often performed when a differential advancement of the upper and lower midface is needed. This study aims to evaluate midface position preoperative and 1 week postoperative in patients with severe midface hypoplasia. In addition, this study aims to compare the planned surgical movements to the actual postoperative movements. MATERIALS AND METHODS: A retrospective review was conducted using cephalometry for patients treated with a simultaneous LF III/I osteotomy at a single institution. Osteotomies were performed during 1980-2018 on skeletally mature patients with a craniofacial syndrome, with clinical and radiographic follow-up available. RESULTS: Twelve patients met the inclusion criteria with a mean age of 20.2±6.4 years. Treatment resulted in statistically significant anterior movements related to Orbitale, anterior nasal spine, A Point, and the upper incisor tip, and inferior movements related to anterior nasal spine, A Point, upper and lower incisor tips, B point, and pogonion. Stability after 1 year showed only statistically significant changes at ANB. The predictable error for planned movements versus actual movements was greater in the vertical plane than the horizontal plane. CONCLUSIONS: A simultaneous LF III/I osteotomy significantly improved the midface position and occlusal relationship in syndromic patients with midface hypoplasia in a predictable manner. Further multicenter studies with larger sample sizes are needed to validate the conclusions.

Nutritional management of heart failure.

Nutrition in the cardiovascular field to date has focused on improving lifestyle-related diseases such as hypertension and diabetes from the viewpoint of secondary prevention. For these conditions, "nutrition for weight loss" is recommended, and nutritional guidance that restricts calories is provided. On the other hand, in symptomatic Stage C and D heart failure, it is known that underweight patients who manifest poor nutrition, sarcopenia, and cardiac cachexia have a poor prognosis. This is referred to as the "Obesity paradox". In order to "avoid weight loss" in patients with heart failure, a paradigm shift to nutritional management to prevent weight loss is needed. Rather than prescribing uniform recommendation for salt reduction of 6 g/day or less, awareness of the behavior change stage model is attracting attention. In this setting, the value of salt restriction will need to be determined to determine the priority level of intervention for undernutrition versus the need to prevent congestive signs and symptoms. In the Intensive Care Unit (ICU)/Cardiac Care Unit (CCU) for acute heart failure, nutritional intervention should be considered within 48 h of admission. Key points are selection of access route, timing of intervention, and monitoring of side effects. In nutritional management at home and in end-of-life care, food is a reflection of an individual's values, as well as a source of joy and encouragement. The importance of digestive tract should also be recognized in heart failure from oral flail to intestinal edema, constipation, and the intestinal bacteria called the heart-gut axis. Finally, we would like to propose a new term "heart nutrition" for nutritional management in patients with heart failure in this review. Compared to the evidence for exercise therapy in heart failure, studies assessing nutritional management remain scarce and there is a need for research in this area in the future.

Fifty years of paracetamol (acetaminophen) poisoning: the development of risk assessment and treatment 1973-2023 with particular focus on contributions published from Edinburgh and Denver.

INTRODUCTION: Fifty years ago, basic scientific studies and the availability of assay methods made the assessment of risk in paracetamol (acetaminophen) poisoning possible. The use of the antidote acetylcysteine linked to new methods of risk assessment transformed the treatment of this poisoning. This review will describe the way in which risk assessment and treatments have developed over the last 50 years and highlight the remaining areas of uncertainty. METHODS: A search of PubMed and its subsidiary databases revealed 1,166 references published in the period 1963-2023 using the combined terms "paracetamol", "poisoning", and "acetylcysteine". Focused searches then identified 170 papers dealing with risk assessment of paracetamol poisoning, 141 with adverse reactions to acetylcysteine and 114 describing different acetylcysteine regimens. To manage the extensive literature, we focused mainly on contributions made by the authors during their time in Edinburgh and Denver. DOSE AND CONCENTRATION RESPONSE: The key relationship between paracetamol dose and toxicity risk was established in 1971 and led to the development of the Rumack-Matthew nomogram from data collected in Edinburgh. MECHANISMS OF TOXICITY: A series of papers on the mechanisms of toxicity were published in 1973, and these showed that paracetamol hepatotoxicity was caused by the formation of a toxic intermediate epoxide metabolite normally detoxified by glutathione but which, in excess, was bound covalently to hepatic enzymes and proteins. An understanding of the relationship between the rate of paracetamol metabolism, paracetamol concentration, and toxic hazard in humans soon followed. ANTIDOTE DEVELOPMENT AND EFFICACY IN PATIENTS: These discoveries were followed by the testing of a range of sulfhydryl-donors in animals and "at risk" patients. Acetylcysteine was developed as the lead intravenous antidote in the United Kingdom. The license holder in the United States refused to make an intravenous formulation. Thus, oral acetylcysteine became the antidote trialed in the United States National Multicenter Study. Intravenous acetylcysteine regimens used initially in the United Kingdom and subsequently in the United States used loading doses of 150 mg/kg over 15 minutes or one hour, 50 mg/kg over four hours, and 100 mg/kg over 16 hours. These regimens were associated with adverse drug reactions (nausea, vomiting and anaphylactoid reactions) and hence, treatment interruption. Newer dosing regimens now give loading doses more slowly. One, the Scottish and Newcastle Anti-emetic Pretreatment protocol, using an acetylcysteine regimen of 100 mg/kg over two hours followed by 200 mg/kg over 10 hours, has been widely adopted in the United Kingdom. A cohort comparison study suggests this regimen has comparable efficacy to standard regimens and offers opportunities for selective higher acetylcysteine dosing. RISK ASSESSMENT AT PRESENTATION: No dose-ranging studies with acetylcysteine were done, and no placebo-controlled studies were performed. Thus, there is uncertainty regarding the optimal dose of acetylcysteine, particularly in patients ingesting very large overdoses of paracetamol. The choice of intervention concentration on the Rumack-Matthew nomogram has important consequences for the proportion of patients treated. The United States National Multicenter Study used a "treatment" line starting at 150 mg/L (992 µmol/L) at 4 hours post overdose, extending to 24 hours with a half-life of 4 hours, now standard there, and subsequently adopted in Australia and New Zealand. In the United Kingdom, the treatment line was initially 200 mg/L (1,323 µmol/L) at 4 hours (the Rumack-Matthew "risk" line). In 2012, the United Kingdom Medicines and Healthcare products Regulatory Agency lowered the treatment line to 100 mg/L (662 µmol/L) at 4 hours for all patients, increasing the number of patients admitted and treated at a high cost. Risk assessment is a key issue for ongoing study, particularly following the development of potential new antidotes that may act in those at greatest risk. The development of biomarkers to assess risk is ongoing but has yet to reach clinical trials. CONCLUSION: Even after 50 years, there are still areas of uncertainty. These include appropriate acetylcysteine doses in patients who ingest different paracetamol doses or multiple (staggered) ingestions, early identification of at-risk patients, and optimal treatment of late presenters.

Circulating hemopexin modulates anthracycline cardiac toxicity in patients and in mice.

Anthracyclines such as doxorubicin (Dox) are effective chemotherapies, but their use is limited by cardiac toxicity. We hypothesized that plasma proteomics in women with breast cancer could identify new mechanisms of anthracycline cardiac toxicity. We measured changes in 1317 proteins in anthracycline-treated patients (n = 30) and replicated key findings in a second cohort (n = 31). An increase in the heme-binding protein hemopexin (Hpx) 3 months after anthracycline initiation was associated with cardiac toxicity by echocardiography. To assess the functional role of Hpx, we administered Hpx to wild-type (WT) mice treated with Dox and observed improved cardiac function. Conversely, Hpx-/- mice demonstrated increased Dox cardiac toxicity compared to WT mice. Initial mechanistic studies indicate that Hpx is likely transported to the heart by circulating monocytes/macrophages and that Hpx may mitigate Dox-induced ferroptosis to confer cardioprotection. Together, these observations suggest that Hpx induction represents a compensatory response during Dox treatment.

Efficacy of Postsurgical Nostril Retainer in Patients with Unilateral Cleft Lip and Palate Treated with Presurgical Nasoalveolar Molding and Primary Cheiloplasty-Rhinoplasty.

BACKGROUND: The aim of this investigation was to determine whether the nasal form of patients with unilateral cleft lip and palate treated with presurgical nasoalveolar molding therapy, primary lip-nose surgery, and postsurgical nostril retainer was different from that of patients treated with presurgical nasoalveolar molding and primary lip and nose surgery alone. METHODS: This cross-sectional, retrospective review focused on 50 consecutive patients with nonsyndromic unilateral cleft lip and palate: 24 treated with nasoalveolar molding and primary lip and nose surgery followed by postsurgical nostril retainer (group 1) compared with 26 patients treated with nasoalveolar molding and primary lip and nose surgery without postsurgical nostril retainer (group 2). Polyvinyl siloxane nasal impressions were performed at an average age of 12 months and 6 days. Bilateral measurements of alar width at maximum convexity, total alar base width, nasal tip projection, columella length, and nostril aperture width and height were recorded. Statistical comparisons of cleft-side versus noncleft side nasal measurements were performed within group 1 and group 2, as well as comparisons of differences between the two groups. RESULTS: Cleft-side nasal dimension was statistically significantly better in group 1 than in group 2 across all measures except nasal projection ( p < 0.05). Group 1 showed less difference between the cleft side and noncleft side in all six measurements than did group 2 ( p < 0.05). CONCLUSIONS: There was a significant difference in the nasal shape of patients who used a postsurgical nostril retainer compared with those who did not. Patients who used a postsurgical nostril retainer showed better nasal shape at an average age of 12 months compared with the control group. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

TTR variants in patients with dilated cardiomyopathy: An investigation of the DCM Precision Medicine Study.

PURPOSE: The cardiac phenotype of hereditary transthyretin amyloidosis (hTTR) usually presents as a restrictive or hypertrophic cardiomyopathy, and, although rarely observed as dilated cardiomyopathy (DCM), TTR is routinely included in DCM genetic testing panels. However, the prevalence and phenotypes of TTR variants in patients with DCM have not been reported. METHODS: Exome sequences of 729 probands with idiopathic DCM were analyzed for TTR and 35 DCM genes. RESULTS: Rare TTR variants were identified in 2 (0.5%; 95% CI = 0.1%-1.8%) of 404 non-Hispanic White DCM probands; neither of them had features of hTTR. In 1 proband, a TTR His110Asn variant and a variant of uncertain significance in DSP were identified, and in the other proband, a TTR Val50Met variant known to cause hTTR and a likely pathogenic variant in FLNC were identified. The TTR Val142Ile variant was identified in 8 (3.0%) non-Hispanic Black probands, comparable with African/African American Genome Aggregation Database controls (OR = 1.01; 95% CI = 0.46-1.99). CONCLUSION: Among the 729 DCM probands, 2 had rare TTR variants identified without the features of hTTR, and both had other plausible genetic causes of DCM. Moreover, the frequency of TTR Val142Ile was comparable to a control sample. These findings suggest that hTTR variants may have a limited role in patients with DCM without TTR-specific findings.

Cardiovascular Risks with Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors and Monoclonal Antibody Therapy.

PURPOSE OF REVIEW: Tyrosine kinase inhibitors (TKI) and monoclonal antibodies (mAbs) that target the epidermal growth factor receptor (EGFR) have changed the therapeutic landscape across a range of solid malignancies. However, there is little data regarding the cardiovascular (CV) impact of these agents. The purpose of this review is to discuss reported CV effects, pathophysiology, pre-treatment screening, diagnostic workup, and treatment recommendations in this patient population. RECENT FINDINGS: It is apparent that CV events are not class dependent, and while infrequently reported in clinical trials, unique CV toxicity may occur with EGFR inhibitors, including structural, electrical, and vascular events. There remains an unmet need to fully elucidate the spectrum of CV events associated with EGFR inhibitors. Early CV screening, close clinical monitoring, coupled with a multidisciplinary approach between medical and cardio-oncology is needed to minimize the potentially detrimental impact of cardiotoxicity in this patient population.

Comparing N-acetylcysteine and 4-methylpyrazole as antidotes for acetaminophen overdose.

Acetaminophen (APAP) overdose can cause hepatotoxicity and even liver failure. N-acetylcysteine (NAC) is still the only FDA-approved antidote against APAP overdose 40 years after its introduction. The standard oral or intravenous dosing regimen of NAC is highly effective for patients with moderate overdoses who present within 8 h of APAP ingestion. However, for late-presenting patients or after ingestion of very large overdoses, the efficacy of NAC is diminished. Thus, additional antidotes with an extended therapeutic window may be needed for these patients. Fomepizole (4-methylpyrazole), a clinically approved antidote against methanol and ethylene glycol poisoning, recently emerged as a promising candidate. In animal studies, fomepizole effectively prevented APAP-induced liver injury by inhibiting Cyp2E1 when treated early, and by inhibiting c-jun N-terminal kinase (JNK) and oxidant stress when treated after the metabolism phase. In addition, fomepizole treatment, unlike NAC, prevented APAP-induced kidney damage and promoted hepatic regeneration in mice. These mechanisms of protection (inhibition of Cyp2E1 and JNK) and an extended efficacy compared to NAC could be verified in primary human hepatocytes. Furthermore, the formation of oxidative metabolites was eliminated in healthy volunteers using the established treatment protocol for fomepizole in toxic alcohol and ethylene glycol poisoning. These mechanistic findings, together with the excellent safety profile after methanol and ethylene glycol poisoning and after an APAP overdose, suggest that fomepizole may be a promising antidote against APAP overdose that could be useful as adjunct treatment to NAC. Clinical trials to support this hypothesis are warranted.