Sudden Death Research Articles

25-Hydroxycholecalciferol Improves Cardiac Metabolic Adaption, Mitochondrial Biogenetics, and Redox Status to Ameliorate Pathological Remodeling and Functional Failure in Obese Chickens.

Broiler breeder hens allowed ad libitum (Ad) feed intake developed obesity and cardiac pathogenesis and thereby were susceptible to sudden death. A supplement of 69 µg 25-hydroxycholecalciferol (25-OH-D3)/kg feed rescued the livability of feed-restricted (R) and Ad-hens (mortality; 6.7% vs. 8.9% and 31.1% vs. 48.9%). Necropsy with the surviving counterparts along the time course confirmed alleviation of myocardial remodeling and functional failure by 25-OH-D3, as shown by BNP and MHC-β expressions, pathological hypertrophy, and cardiorespiratory responses (p < 0.05). 25-OH-D3 mitigated cardiac deficient bioenergetics in Ad-hens by rescuing PGC-1α activation, mitochondrial biogenesis, dynamics, and electron transport chain complex activities, and metabolic adaptions in glucose oxidation, pyruvate/lactate interconversion, TCA cycle, and β-oxidation, as well as in TG and ceramide accumulation to limit lipotoxic development (p < 0.05). Supplemental 25-OH-D3 also sustained Nrf2 activation and relieved MDA accumulation, protein carbonylation, and GSH depletion to potentiate cell survival in the failing heart (p < 0.05). Parts of the redox amendments were mediated via lessened blood hematocrit and heme metabolism, and improved iron status and related gene regulations (p < 0.05). In conclusion, 25-OH-D3 ameliorates cardiac pathological remodeling and functional compromise to rescue the livability of obese hens through metabolic flexibility and mitochondrial bioenergetics, and by operating at antioxidant defense, and heme and iron metabolism, to maintain redox homeostasis and sustain cell viability.

Transcatheter intervention of modified Blalock-Taussig shunts in patients with hypoplastic left heart syndrome undergoing stage 1 palliation.

While several studies have explored the outcomes of transcatheter interventions for modified Blalock-Taussig shunts (MBTSs) in a broad range of congenital heart diseases, none have specifically examined the interventions in patients with hypoplastic left heart syndrome (HLHS) who underwent Norwood palliation (NP). This retrospective study was conducted between 2020 and 2024, when 24 urgent interventions were performed on 17 patients at our center. We recorded several key outcomes, including early and late intervention-related complications, the need for reintervention, the interval between the NP and the first intervention, shunt patency following the intervention, associated morbidities, and thrombosis-related sudden events. Additionally, during follow-up, we documented the outcomes for patients who underwent the Glenn procedure and those who were palliated, including late death. The median age and weight at the time of intervention were 88 days (range: 15-300 days) and 5 kg (range: 2.6-7.6 kg), respectively. The median interval between the Norwood procedure and the transcatheter intervention was 61 days (7-160 days), with median shunt patency lasting 62 days (1-150 days). Notably, there were no intervention-related complications or deaths. In-stent thrombosis, a late complication, occurred in four patients; two of these had impaired anticoagulation, including extracorporeal membrane oxygenation (ECMO)-related causes, while the other two, who were on aspirin, had multiple stents within the shunt, one of whom experienced sudden death. Six patients required seven reinterventions: four due to shunt obstruction or restenosis and two to delay surgery or provide palliation for patients unfit for surgery, aiding in pulmonary development. The transcatheter intervention of the MBTSs in patients with HLHS undergoing NP is considered both safe and potentially life-saving in emergent situations. This approach may facilitate improved pulmonary development, postpone the need for subsequent surgeries, and provide medium-term palliative care for critically ill patients. However, managing late complications such as stent thrombosis remains a significant challenge. Our findings indicate that risk factors for shunt thrombosis include using ECMO therapy, underlying coagulation disorders, impaired lymphatic drainage, requiring multiple stents within the shunt, and a prior history of thrombosis before intervention. Dual antiplatelet therapy is recommended to alleviate the risk of thrombotic events in this population.

Sleep-Related Sudden Unexpected Infant Death Among Infants Prenatally Substance Exposed.

Maternal substance use during pregnancy heightens risk of sudden unexpected infant death (SUID), including through unsafe sleep practices. Families impacted by substance use frequently experience disproportionate social drivers of poor health and family vulnerability likely contributory to fatality risk. Characteristics of sleep-related SUID among infants born prenatally substance exposed versus nonexposed were compared to identify targeted prevention opportunities. Using the Sudden Death in the Young Registry, we examined SUID with sleep-related death between 2015 and 2020 across infants prenatally exposed versus nonexposed. Distribution of sleep environment characteristics, social drivers of poor health, and family vulnerability factors were examined using descriptive statistics and χ2. Of 2010 infants who experienced sleep-related deaths, 283 (14%) were prenatally exposed. More than half of deaths involved an adult bed (52%, n = 1045) or surface sharing with an adult (53%, n = 1074). Supervisors of prenatally exposed infants were disproportionately impaired at infant death versus nonexposed (34%, n = 97 vs 16%, n = 279). Statistically significant associations between prenatal exposure history and vulnerability factors (insurance, child welfare involvement, intimate partner violence, health care barriers) were identified (P < .05). Sleep-related SUID across infants prenatally exposed versus nonexposed differ in sleep environment characteristics and contributory social vulnerability. Disproportionate sleep environment hazards (surface sharing, supervisor impairment) are identified among prenatally exposed infants that should compel targeted prevention efforts, including safe sleep messaging, discouraging surface sharing, and engaging support persons during impairment periods. Addressing social needs and family vulnerability are also paramount to increase access to health care, safe sleep education, and material resource provision.

WONOEP appraisal: Targeted therapy development for early onset epilepsies.

The early onset epilepsies encompass a heterogeneous group of disorders, some of which result in drug-resistant seizures, developmental delay, psychiatric comorbidities, and sudden death. Advancement in the widespread use of targeted gene panels as well as genome and exome sequencing has facilitated the identification of different causative genes in a subset of these patients. The ability to recognize the genetic basis of early onset epilepsies continues to improve, with de novo coding variants accounting for most of the genetic etiologies identified. Although current disease-specific and disease-modifying therapies remain limited, novel precision medicine approaches, such as small molecules, cell therapy, and other forms of genetic therapies for early onset epilepsies, have created excitement among researchers, clinicians, and caregivers. Here, we summarize the main findings of presentations and discussions on novel therapeutic strategies for targeted treatment of early onset epilepsies that occurred during the Workshop on Neurobiology of Epilepsy (WONOEP XVI, Talloires, France, July 2022). The presentations discussed the use of chloride transporter inhibitors for neonatal seizures, targeting orexinergic signaling for childhood absence epilepsy, targeting energy metabolism in Dravet syndrome, and the role of cannabinoid receptor type 2, reversible acetylcholinesterase inhibitors, cell therapies, and RNA-based therapies in early life epilepsies.

Addressing Drivers of Sudden Unexplained Infant Death Among Prenatally Substance-Exposed Infants.

Addressing Drivers of Sudden Unexplained Infant Death Among Prenatally Substance-Exposed Infants.

SÍNDROME DE YAMAGUCHI – RELATO DE CASO

Yamaguchi Syndrome is a subtype of hypertrophic cardiomyopathy characterized by hypertrophy in the left ventricular apex. It is a rare syndrome in Brazil, being commonly found in Japan. It has a wide clinical spectrum, ranging from asymptomatic patients to sudden death. Diagnosis is elucidated through changes in the electrocardiogram and echocardiogram, with cardiac magnetic resonance imaging being the most specific exam. The initial treatment is clinical, and may be extended to surgical procedures if refractory to drug management. This study aims to present a clinical case of Yamaguchi Syndrome in a patient in the state of Ceará, emphasizing the importance of including the syndrome in the differential diagnosis of symptoms with chest pain, dyspnea and palpitations.

Mapping the intersection of sudden cardiac death and COVID-19: a comprehensive bibliometric analysis (2020-2024).

A direct causal link between Sudden Cardiac Death (SCD) and COVID-19 is unproven, although current data suggest a plausible association. This study aims to map and analyze the intersection of research on sudden cardiac death and COVID-19 through a comprehensive bibliometric analysis. This study searched the literature by applying the keywords "COVID-19" AND "Sudden Cardiac Death (SCD)". Literature retrieved using the above keywords and published were included with a time limit from 1st January 2020 to 8th Aug 2024. The bibliometric analysis of COVID-19 and Sudden Cardiac Death highlights key research trends from 2020 to 2024, revealing a rapid surge in scientific output during the pandemic. 2,915 articles were retrieved, with 70.5% being original research, reflecting a strong focus on new empirical evidence. The peak in publications occurred in 2021, driven by the urgent need to understand the cardiovascular implications of COVID-19. However, a decline in publications and citations in subsequent years suggests a shift in research priorities and a potential saturation in initial research areas. Leading institutions like Harvard Medical School, Mayo Clinic, and the University of Pennsylvania played a significant role, with the U.S., China, and the U.K. being top contributors. Despite fewer publications, China's research had a notable impact, indicated by high average citations per article. Keyword analysis identified "COVID-19" and "SARS-CoV-2" as dominant themes, with related terms like myocarditis and heart failure reflecting major cardiovascular concerns. Co-citation analysis revealed seminal works that shaped the discourse, with influential articles by Xu Z et al. and Guo T et al. frequently cited. The collaborative nature of research, especially among top institutions and countries like the U.S., Italy, and the U.K., was evident in network analyses. This study provides a comprehensive overview of the research landscape, highlighting significant contributions, emerging themes, and future research directions in understanding and mitigating the cardiovascular impacts of COVID-19.

Incidence of sudden unexplained death in childhood for children aged 1–14 years in England and Wales during 2001–2020: an observational study

ObjectiveThe objective is to determine the incidence of sudden unexplained death in childhood (SUDC) for children aged 1–14 years in England and Wales during 2001–2020.DesignObservational study using official national statistics...

Electrocardiographic Characteristics of Brugada Syndrome Type I During Exercise Stress Test.

Brugada syndrome (BS) is a genetic channelopathy characterized by an increased risk of sudden cardiac death (SCD) in the absence of structural heart disease. Prognostic stratification is necessary to determine which patients are candidates for implantable cardioverter defibrillator (ICD). The present study aims to evaluate EKG changes during exercise stress tests in patients with BS and to identify any poor prognosis variables. This was an observational, case-control study. Three comparison groups were created: patients with Type 1 BS with or without prior arrhythmic events (BE and BNoE subgroups) and age- and sex-matched healthy individuals. Patients underwent EST and electrocardiographic variables were analyzed. The study recruited 36 patients with type 1 BS, 12 with prior Event (BE) and 24 without (BNoE). Patients in the BE group, in all postexercise recordings, had lower heart rates, notably in the first minute. A significant difference was also observed in the HR drop in the recovery phase, with a greater drop in relation to maximum HR in the first minute in the group of patients who had events. BS patients with prior events had a lower capacity to increase heart rate at peak effort and a greater proportional drop in the recovery phase. No relationship was observed between the occurrence of arrhythmic events and ST-segment elevation during the exercise test.

Real-world epilepsy monitoring with ultra long-term subcutaneous EEG: a 15-month prospective study.

Novel subcutaneous electroencephalography (sqEEG) systems enable prolonged, near-continuous cerebral monitoring in real-world conditions. Nevertheless, the feasibility, acceptability and overall clinical utility of these systems remains unclear. We report on the longest observational study using ultra long-term sqEEG to date. We conducted a 15-month prospective, observational study including ten adult people with treatment-resistant epilepsy. After device implantation, patients were asked to record sqEEG, to use an electronic seizure diary and to complete acceptability and usability questionnaires. sqEEG seizures were annotated visually, aided by automated detection. Seizure clustering was assessed via Fano Factor analysis and seizure periodicity at multiple timescales was investigated through circular statistics. Over a median duration of 438 days, ten patients recorded a median 18.8 hours/day, totalling 71,984 hours of real-world sqEEG data. Adherence and acceptability remained high throughout the study. While 754 sqEEG seizures were recorded across patients, over half (52%) of these were not reported in the patient diary. Of the 140 (27%) diary reports not associated with an identifiable sqEEG seizure, the majority (68%) were reported as seizures with preserved awareness. The sqEEG to diary F1 agreement score was highly variable, ranging from 0.06 to 0.97. Patient-specific patterns of seizure clustering and seizure periodicity were observed at multiple (circadian and multidien) timescales. We demonstrate feasibility and high acceptability of ultra long-term (months-years) sqEEG monitoring. These systems help provide real-world, more objective seizure counting compared to patient diaries. It is possible to monitor individual temporal fluctuations of seizure occurrence, including seizure cycles. [I do not have a X/Twitter handle]People with epilepsy may suffer from severe injuries or sudden death due to uncontrolled seizures. Many seizures remain unnoticed by people and unreported to doctors, despite these potentially catastrophic consequences. There is an urgent need to detect seizures more objectively. Our study used a novel device placed under the skin to monitor brainwave activity continuously, at home, for many months, in people with treatment-resistant epilepsy. By monitoring epilepsy from home, we detected many seizures unreported by patients, and we also found predictable patterns (cycles) of seizure occurrence over time. In the future, this type of monitoring could revolutionize epilepsy care, by improving safety, treatment management and reducing uncertainty in patients' daily lives.

Anabolic androgen steroids cardiovascular impact. Literature review

Introduction and Purpose: The use of anabolic steroids is widespread. They can be administered either therapeutically or by individuals looking to enhance their athletic performance. This review aims to summarize the scientific understanding regarding the link between the use of AASs and the incidence of cardiovascular complications. Materials and methods The literature available in PubMed and Google Scholar databases was reviewed using the keywords. Description of the state of knowledge: A lot of studies suggest that AASs can be harmful to the cardiovascular system. It has a wide range of long-term and often irreversible consequences. AASs cause myocardial hypertrophy which results in systolic and diastolic disfunction. They disrupt lipid metabolism, act as vasoconstrictors, and promote the calcification of blood vessel walls, thereby increasing the risk of heart attack and stroke. By promoting blood clotting, they increase the incidence of pulmonary embolism, deep vein thrombosis, and cerebral venous sinus thrombosis. The effect on the occurrence of hypertension is not definitively proven. However, a very dangerous consequence of using anabolic steroids is the increased risk of life-threatening arrhythmias -especially ventricular arrhythmias- which can lead to sudden cardiac death. Conclusion: The use of anabolic steroids increases the risk of arrhythmias, heart attacks, and thromboembolic complications, ultimately leading to a higher risk of sudden cardiac death. However, the cause-and-effect relationship is not always clearly captured, and further research is necessary to draw appropriate conclusions.

The snowball effect in electrochemical degradation and safety evolution of lithium-ion batteries during long-term cycling

Lifespan and safety are the most critical issues for the application of lithium-ion batteries (LIBs). During long-term service, the degradation mechanisms and safety evolution of LIBs remain unclear, posing significant obstacles to battery design and management. This study analyzes the electrochemical degradation mechanisms of LIBs under normal temperature cycling (NTC) and high-temperature cycling (HTC) conditions, linking these mechanisms to the evolution of battery safety. The findings reveal that during NTC, there is a “snowball effect” in performance degradation and safety evolution, leading to sudden death of battery and posing serious safety risks. The degradation pattern of LIBs during NTC and HTC is consistently dominated by the increase of internal resistance and the loss of lithium inventory (LLI). In the aging process, electrolyte consumption and the growth of the solid electrolyte interface (SEI) cause localized lithium plating on the anode, resulting in accelerated capacity decay. However, in batteries subjected to NTC, rapid accumulation of localized lithium plating can trigger a snowball effect, causing electrode deformation, internal short-circuit (ISC) and separator melting. These interacting catastrophic events form a vicious cycle, ultimately leading to battery sudden death and pose significant safety hazards. Additionally, thermal safety analysis reveals the correlation between thermal safety parameters and state of health (SOH), quantifying the thermal safety degradation caused by sudden death. Sudden death directly alters the evolution pattern of battery safety, leading to a severe decline in battery safety. These findings offer new insights into potential safety hazards associated with long-term use of LIBs.

Aeromedical Fitness Considerations in Myocardial Bridging: A Case Study and Literature Review

Aims: Management of cardiac disease in aeromedical expertise can be challenging for asymptomatic crew members, especially during the first aeromedical examination, myocardial bridging is a good example. Presentation of Case: A 24-year-old student pilot candidate shows repolarization disorders at the ECG in the aeromedical examination, the exploration allowed the discovery of a myocardial bridge on The Coronary computed tomographic angiography (CCTA) of the left anterior descending (LAD) coronary artery responsible for tight stenosis. Discussion: The prevalence of MB varies according to the method of investigation, ranging from 2% in coronary angiography and 19% in coronary computed tomography to 42% in autopsy.The prevalence among active civilian aircrew (pilots and cabin crew) monitored at CEMPN is 0.4%, all revealed by electrocardiogram abnormalities. MB are usually small and of no clinical significance, the myocardial bridge proximal segment has been associated with atherosclerosis. Symptomatic patients with myocardial bridges as their only cardiac abnormality may present with myocardial ischemia, acute coronary syndromes, coronary spasm, syncope or even sudden death. The initial therapeutic strategy in the treatment of MB is medical management. Revascularization is indicated by PCI or surgery, including coronary artery bypass grafting (CABG) or myotomy in the case of symptoms recalcitrant to maximal medical treatment. The aviation environment may expose aircrew to additional physiological stressors, including hypobaria, hypoxia and sustained acceleration (+Gz). Such exposure may present a risk if associated with cardiovascular abnormalities, potentially leading to incapacity to fly due to symptoms or complications of the myocardial bridge. Conclusion: The myocardial bridge is an anatomical variant rather than a congenital anomaly with varied symptomatology (ECG abnormality, stable or unstable angina or sudden death), the aeromedical decision is made on a case-by-case basis, and makes a challenge diagnostic, particularly for asymptomatic crews.

A case of sudden natural death in custody: Medico-legal perplexity in determining the manner of death

Death arising during police custody or in prison always raises suspicion and creates public rage regarding the cause and particularly the manner of death. On the contrary, in most instances, the manner of death is natural as reported in many literature and the role of an autopsy surgeon is vital in determining the same. Among the natural causes of death during custody cardiac causes contribute the majority of fatality. Here we present a 42-year-old male prisoner who was brought dead to the casualty with history of sudden onset of breathlessness and giddiness. On autopsy, there were no signs of injuries both externally and internally. In the heart right coronary artery showed near complete occlusion 2 cm from its origin, left anterior descending, and left circumflex artery showed 60% and 80% occlusion respectively. The walls of the coronaries, and aorta showed deposition of calcified and ulcerated atheromatous plaques (Grade VI atherosclerosis). Histopathology showed evidence of atherosclerosis by deposition of calcified fibroatheromatous plaques and multiple vessels showed critical narrowing. Chemical analysis of viscera was turned negative. The final opinion to the cause of death was acute myocardial infarction (sudden natural death). This case report emphasizes the need for a complete and meticulous forensic autopsy which aids in solving the grievances of the deceased’s family on the cause and manner of death and also aids in the legal standing of the country.

Clinically suspected acute right ventricular fulminant dengue myocarditis masquerading with dual lethal arrhythmias: a case report

BackgroundAcute right ventricular myocarditis is rare, comprising only 18% of myocarditis cases. Despite being relatively infrequent at 12.4%, dengue-induced myocarditis has a high mortality risk of 26.4%. This report presents a novel case of acute fulminant right ventricular myocarditis due to severe dengue infection, complicated by dual electrical disturbances: complete heart block and ventricular tachycardia.Case reportA 49-year-old Asian male patient was referred to our hospital with a temporary pacemaker due to a complete heart block. He had a history of recurrent syncope over three days and a fever five days before admission. Initial electrocardiography showed a total atrioventricular nodal block progressing to a high-degree atrioventricular block with a left bundle branch block, indicating an infra-Hisian block. Laboratory findings included thrombocytopenia, elevated troponin, high creatinine, increased liver transaminases, and a positive dengue nonstructural protein 1 test, confirming a diagnosis of dengue infection. Echocardiography showed reduced right ventricular systolic function, normal left ventricular systolic function (ejection fraction: 50%), and dyskinetic intraventricular septum. Coronary angiography revealed normal coronary anatomy. An endomyocardial biopsy was deferred due to severe thrombocytopenia. On the third day, the patient's condition worsened, developing cardiogenic shock and left ventricular systolic dysfunction (ejection fraction: 35%). He subsequently experienced a seizure and slow ventricular tachycardia originating from the right coronary cusp, followed by cardiac arrest. The patient’s family claimed not to resuscitate the patient. Furthermore, the patient died shortly after.ConclusionThis case underscores the critical need for prompt diagnosis and aggressive management of clinically suspected acute fulminant right ventricular myocarditis because complications can rapidly progress to left ventricular systolic dysfunction, leading to cardiogenic shock and sudden cardiac death.

Optical control of cardiac electrophysiology by the photochromic ligand azobupivacaine 2.

Patients suffering from ischaemic heart disease and heart failure are at high risk of recurrent ventricular arrhythmias (VAs), eventually leading to sudden cardiac death. While high-voltage shocks delivered by an implantable defibrillator may prevent sudden cardiac death, these interventions themselves impair quality of life and raise both morbidity and mortality, which accentuates the need for developing novel defibrillation techniques. Photopharmacology allows for reversible control of biological processes by light. When relying on synthetic and externally applied chromophores, it renders genetic modification of target cells dispensable and may hence be advantageous over optogenetic approaches. Here, the photochromic ligand azobupivacaine 2 (AB2) was probed as a modulator of cardiac electrophysiology in an ex vivo intact mouse heart model. By reversibly blocking voltage-gated Na+ and K+ channels, photoswitching of AB2 modulated both the ventricular effective refractory period and the conduction velocity in native heart tissue. Moreover, photoswitching of AB2 was able to convert VA into sinus rhythm. The present study provides the first proof of concept that AB2 enables gradual control of cardiac electrophysiology by light. AB2 may hence open the door to the development of an optical defibrillator based on photopharmacology.

Radiotherapy with cetuximab or durvalumab for locoregionally advanced head and neck cancer in patients with a contraindication to cisplatin (NRG-HN004): an open-label, multicentre, parallel-group, randomised, phase 2/3 trial

Management of patients with locoregionally advanced head and neck squamous cell carcinoma (HNSCC) when cisplatin is contraindicated is controversial. We aimed to assess whether radiotherapy with concurrent and adjuvant durvalumab would improve outcomes compared with radiotherapy with cetuximab. NRG-HN004 was designed as an open-label, multicentre, parallel-group, randomised, phase 2/3 trial with safety lead-in conducted at 89 academic and community medical centres in North America. Eligible patients were aged 18 years or older with American Joint Committee on Cancer 8th edition stage III-IVB p16-negative HNSCC or unfavourable stage I-III p16-positive oropharyngeal or unknown primary carcinoma, who had a contraindication to cisplatin (Eastern Cooperative Oncology Group [ECOG] performance status 2, renal or hearing impairment, peripheral neuropathy, aged at least 70 years with moderate or severe comorbidity, or aged younger than 70 years with severe comorbidity). Patients were randomly assigned (2:1) by permuted block randomisation (multiples of 6) to intravenous durvalumab 1500 mg starting 2 weeks before radiotherapy then every 4 weeks starting week 2 of radiotherapy (seven cycles) or intravenous cetuximab 400 mg/m2 1 week before radiotherapy then 250 mg/m2 weekly beginning week 1 of radiotherapy (eight cycles), with intensity-modulated radiotherapy (70 Gy in 35 fractions over 7 weeks). Stratification factors were tumour and nodal stage, ECOG performance status and comorbidity, and primary site and p16 status. The phase 2 primary endpoint was progression-free survival in the intention-to-treat population. There was one prespecified interim futility analysis at 50% of progression-free survival information. If the observed hazard ratio was 1·0 or more, favouring cetuximab, early stopping would be considered. Extended follow-up analysis was post hoc. This trial is registered with ClinicalTrials.gov, NCT03258554, and is closed to enrolment. Following a ten-patient safety lead-in, the phase 2 trial enrolled 190 patients from March 12, 2019, to July 30, 2021, 186 of whom were randomly assigned (123 to durvalumab and 63 to cetuximab). Median age was 72 years (IQR 64-77), 30 (16%) patients were women and 156 (84%) were men. Phase 2 accrual was suspended in July 30, 2021, following an interim futility analysis, and permanently closed in Sept 1, 2022. The phase 3 part of the trial was not conducted. At a median follow-up of 2·3 years (IQR 1·9-3·1) for the extended follow-up (data cutoff July 31, 2023; post-hoc analysis), 2-year progression-free survival was 50·6% (95% CI 41·5-59·8) in the durvalumab group versus 63·7% (51·3-76·1) in the cetuximab group (hazard ratio 1·33 [95% CI 0·84-2·12]; p=0·89). Adverse events were similar in both groups. The most common grade 3-4 adverse events were dysphagia (26 [22%] of 119 patients in the durvalumab group vs 18 [30%] of 61 patients in the cetuximab group), lymphopenia (33 [28%] vs 20 [33%]), and oral mucositis (13 [11%] vs 11 [18%]). Four (3%) patients in the durvalumab group and one (2%) in the cetuximab group died from treatment-related adverse events (death not otherwise specified, laryngeal oedema, lung infection, and respiratory failure in the durvalumab group and sudden death not otherwise specified in the cetuximab group). Our findings suggest that durvalumab did not improve outcomes compared with cetuximab in patients with HNSCC with contraindications to cisplatin. Further trials are needed to define the standard of care for this population. US National Cancer Institute and AstraZeneca.

Diaphragm relaxation causes seizure-related apnoeas in chronic and acute seizure models in rats

Ictal central apnoea is a feature of focal temporal seizures. It is implicated as a risk factor for sudden unexpected death in epilepsy (SUDEP). Here we study seizure-related apnoeas in two different models of experimental seizures, one chronic and one acute, in adult genetically-unmodified rats, to determine mechanisms of seizure-related apnoeas. Under general anaesthesia rats receive sensors for nasal temperature, hippocampal and/or neocortical potentials, and ECG or EMG for subsequent tethered video-telemetry. Tetanus neurotoxin (TeNT), injected into hippocampus during surgery, induces a chronic epileptic focus. Other implanted rats receive intraperitoneal pentylenetetrazol (PTZ) to evoke acute seizures. In chronically epileptic rats, convulsive seizures cause apnoeas (9.9 ± 5.3 s; 331 of 730 convulsive seizures in 15 rats), associated with bradyarrhythmias. Absence of EEG and ECG biomarkers exclude obstructive apnoeas. All eight TeNT-rats with diaphragm EMG have apnoeas with no evidence of obstruction, and have apnoea EMGs significantly closer to expiratory relaxation than inspiratory contraction during pre-apnoeic respiration, which we term “atonic diaphragm”. Consistent with atonic diaphragm is that the pre-apnoeic nasal airflow is expiration, as it is in human ictal central apnoea. Two cases of rat sudden death occur. One, with telemetry to the end, reveals a lethal apnoea, the other only has video during the final days, which reveals cessation of breathing shortly after the last clonic epileptic movement. Telemetry following acute systemic PTZ reveals repeated seizures and seizure-related apnoeas, culminating in lethal apnoeas; ictal apnoeas are central – in 8 of 35 cases diaphragms initially contract tonically for 8.5 ± 15.0 s before relaxing, in the 27 remaining cases diaphragms are atonic throughout apnoeas. All terminal apnoeas are atonic. Differences in types of apnoea due to systemic PTZ in rats (mainly atonic) and mice (tonic) are likely species-specific. Certain genetic mouse models have apnoeas caused by tonic contraction, potentially due to expression of epileptogenic mutations throughout the brain, including in respiratory centres, in contrast with acquired focal epilepsies. We conclude that ictal apnoeas in the rat TeNT model result from atonic diaphragms. Relaxed diaphragms could be particularly helpful for therapeutic stimulation of the diaphragm to help restore respiration.

Sickle cell trait in non-firearm arrest-related deaths of Black persons.

The role of sickle cell trait (SCT) in sudden exertional death is well-recognized in sports and military training. However, it is not yet studied for non-firearm arrest-related death (NF-ARD). With extensive multi-pronged searches, a large database (n = 1389) of NF-ARDs was established. For the years 2006-2021 (inclusive) there were 50 NF-ARDs of Black persons in which postmortem evidence of SCT was found. A control cohort consisted of 414 NF-ARDs of Black persons with no reported SCT. The mean age for SCT cases was 33.1 ± 10.4 years versus 37.0 ± 10.4 years for the control group (p = 0.01). The body-mass index for SCT cases was 28.3 ± 6.6 kg/m2 versus 30.7 ± 7.6 kg/m2 for the control group (p = 0.03). The prevalence of cardiomegaly was 21% for SCT cases versus 39% in the control cohort (p = 0.008). The postmortem prevalence of SCT in NF-ARDs of Black persons (n = 50, 10.7%) was higher than the prevalence of SCT in the US Black population, which is 7.1% (p = 0.003). In this study of NF-ARDs in Black persons, the prevalence of SCT and the differences between the SCT cases and the control cohort suggest that exertional collapse associated with sickle cell trait may be a contributory factor in NF-ARDs.

Adipocyte-Mediated Electrophysiological Remodeling of PKP-2 Mutant Human Pluripotent Stem Cell-Derived Cardiomyocytes.

Arrhythmogenic cardiomyopathy (ACM) is a genetic disorder responsible for nearly a quarter of sports-related sudden cardiac deaths. ACM cases caused by mutations in desmosome proteins lead to right ventricular enlargement, the loss of cardiomyocytes, and fibrofatty tissue replacement, disrupting electrical and mechanical stability. It is currently unknown how paracrine factors secreted by infiltrating fatty tissues affect ACM cardiomyocyte electrophysiology. A normal and a PKP2 mutant (c.971_972InsT) ACM hiPSC line were cultivated and differentiated into cardiomyocytes (CMs). Adipocytes were differentiated from human adipose stem cells, and adipocyte conditioned medium (AdCM) was collected. Optical mapping and phenotypic analyses were conducted on human iPSC-cardiomyocytes (hiPSC-CMs) cultured in cardiac maintenance medium (CMM) and either with AdCM or specific cytokines. Significant differences were observed in voltage parameters such as the action potential duration (APD80, APD30), conduction velocity (CV), and CV heterogeneity. When cultured in AdCM relative to CMM, the APD80 increased and the CV decreased significantly in both groups; however, the magnitudes of changes often differed significantly between 1 and 7 days of cultivation. Cytokine exposure (IL-6, IL-8, MCP-1, CFD) affected the APD and CV in both the normal and PKP2 mutant hiPSC-CMs, with opposite effects. NF-kB signaling was also found to differ between the normal and PKP2 mutant hiPSC-CMs in response to AdCM and IL-6. Our study shows that hiPSC-CMs from normal and mPKP2 ACM lines exhibit distinct molecular and functional responses to paracrine factors, with differences in RNA expression and electrophysiology. These different responses to paracrine factors may contribute to arrhythmogenic propensity.