Acute antiarrhythmic effects of SGLT2 inhibitors-dapagliflozin lowers the excitability of atrial cardiomyocytes.

In recent years, SGLT2 inhibitors have become an integral part of heart failure therapy, and several mechanisms contributing to cardiorenal protection have been identified. In this study, we place special emphasis on the atria and investigate acute electrophysiological effects of dapagliflozin to assess the antiarrhythmic potential of SGLT2 inhibitors. Direct electrophysiological effects of dapagliflozin were investigated in patch clamp experiments on isolated atrial cardiomyocytes. Acute treatment with elevated-dose dapagliflozin caused a significant reduction of the action potential inducibility, the amplitude and maximum upstroke velocity. The inhibitory effects were reproduced in human induced pluripotent stem cell-derived cardiomyocytes, and were more pronounced in atrial compared to ventricular cells. Hypothesizing that dapagliflozin directly affects the depolarization phase of atrial action potentials, we examined fast inward sodium currents in human atrial cardiomyocytes and found a significant decrease of peak sodium current densities by dapagliflozin, accompanied by a moderate inhibition of the transient outward potassium current. Translating these findings into a porcine large animal model, acute elevated-dose dapagliflozin treatment caused an atrial-dominant reduction of myocardial conduction velocity in vivo. This could be utilized for both, acute cardioversion of paroxysmal atrial fibrillation episodes and rhythm control of persistent atrial fibrillation. In this study, we show that dapagliflozin alters the excitability of atrial cardiomyocytes by direct inhibition of peak sodium currents. In vivo, dapagliflozin exerts antiarrhythmic effects, revealing a potential new additional role of SGLT2 inhibitors in the treatment of atrial arrhythmias.

Combined effects of targeted blood pressure, oxygenation, and duration of device-based fever prevention after out-of-hospital cardiac arrest on 1-year survival: post hoc analysis of a randomized controlled trial.

BACKGROUND: The "Blood Pressure and Oxygenation Targets in Post Resuscitation Care" (BOX) trial investigated whether a low versus high blood pressure target, a restrictive versus liberal oxygenation target, and a shorter versus longer duration of device-based fever prevention in comatose patients could improve outcomes. No differences in rates of discharge from hospital with severe disability or 90-day mortality were found. However, long-term effects and potential interaction of the interventions are unknown. Accordingly, the objective of this study is to investigate both individual and combined effects of the interventions on 1-year mortality rates. METHODS: The BOX trial was a randomized controlled two-center trial that assigned comatose resuscitated out-of-hospital cardiac arrest patients to the following three interventions at admission: A blood pressure target of either 63 mmHg or 77 mmHg; An arterial oxygenation target of 9-10 kPa or 13-14 kPa; Device-based fever prevention administered as an initial 24 h at 36 °C and then either 12 or 48 h at 37 °C; totaling 36 or 72 h of temperature control. Randomization occurred in parallel and simultaneously to all interventions. Patients were followed for the occurrence of death from all causes for 1 year. Analyzes were performed by Cox proportional models, and assessment of interactions was performed with the interventions stated as an interaction term. RESULTS: Analysis for all three interventions included 789 patients. For the intervention of low compared to high blood pressure targets, 1-year mortality rates were 35% (138 of 396) and 36% (143 of 393), respectively, hazard ratio (HR) 0.92 (0.73-1.16) p = 0.47. For the restrictive compared to liberal oxygenation targets, 1-year mortality rates were 34% (135 of 394) and 37% (146 of 395), respectively, HR 0.92 (0.73-1.16) p = 0.46. For device-based fever prevention for a total of 36 compared to 72 h, 1-year mortality rates were 35% (139 of 393) and 36% (142 of 396), respectively, HR 0.98 (0.78-1.24) p = 0.89. There was no sign of interaction between the interventions, and accordingly, no combination of randomizations indicated differentiated treatment effects. CONCLUSIONS: There was no difference in 1-year mortality rates for a low compared to high blood pressure target, a liberal compared to restrictive oxygenation target, or a longer compared to shorter duration of device-based fever prevention after cardiac arrest. No combination of the interventions affected these findings. Trial registration ClinicalTrials.gov NCT03141099, Registered 30 April 2017.

Continued decline in the incidence of myocardial infarction beyond the COVID-19 pandemic: a nationwide study of the Swedish population aged 60 and older during 2015-2022.

The number of myocardial infarctions declined during the early COVID-19 pandemic but mechanisms behind these declines are poorly understood. COVID-19 infection is also associated with an increased risk of myocardial infarction which could lead to higher incidence rates in the population. This study aims to shed light on the seemingly paradoxical relationship between COVID-19 and myocardial infarction occurrence on the population level by exploring long-term trends in incidence rates, case fatality, and proportion of patients dying before reaching a hospital. Our work is based on a linkage of administrative registers covering the entire population aged 60 + in Sweden. Considering both long-term trends since 2015 and seasonal variability, we compared observed incidence, case fatality, and proportions of patients hospitalized to expected values during 2020-2022. Despite more than 200 laboratory-confirmed COVID-19 cases per 1000 inhabitants by the end of 2022, incidence rates of myocardial infarction continued to decline, thus following the long-term trend observed already before 2020. During the first pandemic wave there was an additional incidence decline corresponding to 13% fewer myocardial infarctions than expected. This decline was neither accompanied by increasing case fatality nor by lower shares of patients being hospitalized. We found no increase in the population-level incidence of myocardial infarction despite large-scale exposure to COVID-19, which suggests that the effect of COVID-19 on myocardial infarction risk is not substantial. Increased pressure on the Swedish health care system has not led to increased risks or poorer outcomes for patients presenting with acute myocardial infarction.

Intraoperative haemoadsorption for antithrombotic drug removal during cardiac surgery: initial report of the international safe and timely antithrombotic removal (STAR) registry.

Intraoperative antithrombotic drug removal by haemoadsorption is a novel strategy to reduce perioperative bleeding in patients on antithrombotic drugs undergoing cardiac surgery. The international STAR registry reports real-world clinical outcomes associated with this application. All patients underwent cardiac surgery before completing the recommended washout period. The haemoadsorption device was incorporated into the cardiopulmonary bypass (CPB) circuit. Patients on P2Y12 inhibitors comprised group 1, and patients on direct-acting oral anticoagulants (DOAC) group 2. Outcome measurements included bleeding events according to standardised definitions and 24-hour chest-tube-drainage (CTD). 165 patients were included from 8 institutions in Austria, Germany, Sweden, and the UK. Group 1 included 114 patients (62.9 ± 11.6years, 81% male) operated at a mean time of 33.2 h from the last P2Y12 inhibitor dose with a mean CPB duration of 117.1 ± 62.0 min. Group 2 included 51 patients (68.4 ± 9.4years, 53% male), operated at a mean time of 44.6 h after the last DOAC dose, with a CPB duration of 128.6 ± 48.4 min. In Group 1, 15 patients experienced a BARC-4 bleeding event (13%), including 3 reoperations (2.6%). The mean 24-hour CTD was 651 ± 407mL. In Group 2, 8 patients experienced a BARC-4 bleeding event (16%) including 4 reoperations (7.8%). The mean CTD was 675 ± 363mL. This initial report of the ongoing STAR registry shows that the intraoperative use of a haemoadsorption device is simple and safe, and may potentially mitigate the expected high bleeding risk of patients on antithrombotic drugs undergoing cardiac surgery before completion of the recommended washout period.Clinical registration number: ClinicalTrials.gov identifier: NCT05077124.

Recognition of psychological comorbidity and psychotherapeutic treatment status of ventricular assist device patients.

BACKGROUND: Due to its high impact on quality of life and mental health, close monitoring and often psychotherapy is recommended for patients with a ventricular assist device (VAD). This study investigates the psychological comorbidity and the corresponding psychotherapeutic treatment situation of VAD patients. Special attention is also given to the professional perspective VAD team (assistant and senior cardiologists and specialized nurses). METHODS: We conducted a cross-sectional observational study. Data from 50 VAD patients (mean age = 53.52, standard deviation = 13.82 years, 84.0% male) and their VAD team were analyzed. The presence of a psychological disorder was evaluated by structured clinical interviews for DSM-IV (SCID-I-Interviews). Patients answered a questionnaire regarding their current psychotherapeutic treatment status and their attitude towards psychotherapy. The VAD team answered a questionnaire about the patients' needs for psychotherapy and indicated whether they addressed this topic with the patient. Data were analyzed descriptively, by analysis of variance and t-test. RESULTS: A total of 58% of VAD patients suffered from at least one significant psychological disorder, 79.3% of those were not in psychotherapy. The VAD team could not identify the patients who suffered from a psychological disorder (F = 1.90; p = 0.18). They perceived more need for psychotherapy than they addressed with their patients (T = 3.39; p < 0.001). CONCLUSIONS: While there is a high psychological morbidity among VAD patients, only few receive psychotherapy. Psychological comorbidity is not easily detected by the VAD team. Standardized psychosocial care could be implemented by regular psychological assessments and further information of patients and their VAD teams.

Stroke outcomes following durable left ventricular assist device implant in patients bridged with micro-axial flow pump: Insights from a large registry.

BACKGROUND: Stroke after durable left ventricular assist device (d-LVAD) implantation portends high mortality. The incidence of ischemic and hemorrhagic stroke and the impact on stroke outcomes of temporary mechanical circulatory support (tMCS) management among patients requiring bridge to d-LVAD with micro-axial flow-pump (mAFP, Abiomed) is unsettled. METHODS: Consecutive patients, who underwent d-LVAD implantation after being bridged with mAFP at 19 institutions, were retrospectively included. The incidence of early ischemic and hemorrhagic stroke after d-LVAD implantation (<60 days) and association of pre-d-LVAD characteristics and peri-procedural management with a specific focus on tMCS strategies were studied. RESULTS: Among 341 patients, who underwent d-LVAD implantation after mAFP implantation (male gender 83.6%, age 58 [48-65] years, mAFP 5.0/5.5 72.4%), the early ischemic stroke incidence was 10.8% and early hemorrhagic stroke 2.9%. The tMCS characteristics (type of mAFP device and access, support duration, upgrade from intra-aortic balloon pump, ECMELLA, ECMELLA at d-LVAD implantation, hemolysis, and bleeding) were not associated with ischemic stroke after d-LVAD implant. Conversely, the device model (mAFP 2.5/CP vs. mAFP 5.0/5.5: HR 5.6, 95%CI 1.4-22.7, p = 0.015), hemolysis on mAFP support (HR 10.5, 95% CI 1.3-85.3, p = 0.028) and ECMELLA at d-LVAD implantation (HR 5.0, 95% CI 1.4-18.7, p = 0.016) were associated with increased risk of hemorrhagic stroke after d-LVAD implantation. Both early ischemic (HR 2.7, 95% CI 1.9-4.5, p < 0.001) and hemorrhagic (HR 3.43, 95% CI 1.49-7.88, p = 0.004) stroke were associated with increased 1-year mortality. CONCLUSIONS: Among patients undergoing d-LVAD implantation following mAFP support, tMCS characteristics do not impact ischemic stroke occurrence, while several factors are associated with hemorrhagic stroke suggesting a proactive treatment target to reduce this complication.

Profiling chronic diseases and hospitalizations in older home care recipients: a nationwide cohort study in Sweden.

BACKGROUND: Older adults with home care (HC) often have complex disease patterns and use healthcare extensively. Increased understanding is necessary to tailor their care. To our knowledge, this is the first study to describe patterns of morbidity and hospitalizations among community-dwelling older HC recipients nationwide and in subgroups defined by age, sex, and amount of HC, and to compare patterns to community-dwelling older adults without HC. METHODS: Nationwide register-based cohort study in community-dwelling adults aged 70 and older receiving publicly funded HC in Sweden on January 1st 2019 and an age-and-sex matched comparison group ("non-HC recipients"). Using register data from inpatient and specialized outpatient care, we assessed the prevalence of sixty chronic diseases, frailty, multimorbidity and hospitalizations, calculated incidence rates and explored reasons for hospitalizations during two years of follow-up. RESULTS: We identified 138,113 HC recipients (mean age 85, 66% women, 57% ≥5 chronic diseases). The most prevalent diseases were hypertension (55%) and eye conditions (48%). Compared to non-HC recipients, HC recipients had a higher prevalence of almost all diseases, with an overrepresentation of neurological (26.1 vs. 9.5%) disease and dementia (9.3 vs. 1.5%). 61% of HC recipients were hospitalized at least once during two years, which was 1.6 times as often as non-HC recipients. One third of HC recipients´ hospitalizations (37.4%) were due to injuries, infections, and heart failure. Hospitalizations for chronic obstructive pulmonary disease, confusion, infections, and breathing difficulties were 3-5 times higher among HC recipients compared to non-HC recipients. CONCLUSION: Compared to non-HC recipients, HC recipients more often live alone, have higher degrees of frailty, suffer from more chronic diseases, especially neurological disease, and are hospitalized almost twice as often. The results provide a thorough description of HC recipients, which might be useful for targeted healthcare interventions including closer collaboration between primary care, neurologists, and rehabilitation.

Adult offspring and their socioeconomic resources for development and survival of stroke: A Swedish and Danish nationwide register-based study.

AIMS: To explore the relationships between adult offspring's socioeconomic resources and the development of stroke and survival after stroke among older adults in Denmark and Sweden. METHODS: The study included 1,464,740 Swedes and 835,488 Danes who had turned 65 years old between 2000 and 2015. Multivariable Cox proportional hazard regression models were used to analyse incident stroke and survival after stroke until 2020. RESULTS: Lower level of offspring's education, occupation and income were associated with higher hazards of stroke among both men and women in Sweden and Denmark. Associations with offspring's education, occupation and income were most consistent for death after the acute phase and for educational level. From one to five years after stroke and compared with a high educational level of offspring, low and medium educational level were associated with 1.34 (95% confidence interval (CI): 1.11; 1.62) and 1.18 (95% CI: 1.10; 1.27) as well as 1.26 (95% CI: 1.06; 1.48) and 1.14 (1.07; 1.21) times higher hazard of death in Swedish women and men, respectively. The corresponding estimates in the Danish population were 1.36 (1.20; 1.53) and 1.10 (1.01; 1.20) for women and 1.23 (95% CI: 1.11; 1.32) and 1.13 (95% CI: 1.05; 1.21) for men. CONCLUSIONS: Adult offspring socioeconomic resources are, independently of how we measure them and of individual socioeconomic characteristics, associated with development of stroke in old age in both Denmark and Sweden. The relationships between offspring socioeconomic resources and death after stroke are present especially after the acute phase and most pronounced for educational level as a measure of offspring socioeconomic resources.

Fueling the success of transplantation through nutrition: recent insights into nutritional interventions, their interplay with gut microbiota and cellular mechanisms.

PURPOSE OF REVIEW: The role of nutrition in organ health including solid organ transplantation is broadly accepted, but robust data on nutritional regimens remains scarce calling for further investigation of specific dietary approaches at the different stages of organ transplantation. This review gives an update on the latest insights into nutritional interventions highlighting the potential of specific dietary regimens prior to transplantation aiming for organ protection and the interplay between dietary intake and gut microbiota. RECENT FINDINGS: Nutrition holds the potential to optimize patients' health prior to and after surgery, it may enhance patients' ability to cope with the procedure-associated stress and it may accelerate their recovery from surgery. Nutrition helps to reduce morbidity and mortality in addition to preserve graft function. In the case of living organ donation, dietary preconditioning strategies promise novel approaches to limit ischemic organ damage during transplantation and to identify the underlying molecular mechanisms of diet-induced organ protection. Functioning gut microbiota are required to limit systemic inflammation and to generate protective metabolites such as short-chain fatty acids or hydrogen sulfide. SUMMARY: Nutritional intervention is a promising therapeutic concept including the pre- and rehabilitation stage in order to improve the recipients' outcome after solid organ transplantation.

Activation of neurokinin-III receptors modulates human atrial TASK-1 currents.

RATIONALE: The neurokinin-III receptor was recently shown to regulate atrial cardiomyocyte excitability by inhibiting atrial background potassium currents. TASK-1 (hK2P3.1) two-pore-domain potassium channels, which are expressed atrial-specifically in the human heart, contribute significantly to atrial background potassium currents. As TASK-1 channels are regulated by a variety of intracellular signalling cascades, they represent a promising candidate for mediating the electrophysiological effects of the Gq-coupled neurokinin-III receptor. OBJECTIVE: To investigate whether TASK-1 channels mediate the neurokinin-III receptor activation induced effects on atrial electrophysiology. METHODS AND RESULTS: In Xenopus laevis oocytes, heterologously expressing neurokinin-III receptor and TASK-1, administration of the endogenous neurokinin-III receptor ligands substance P or neurokinin B resulted in a strong TASK-1 current inhibition. This could be reproduced by application of the high affinity neurokinin-III receptor agonist senktide. Moreover, preincubation with the neurokinin-III receptor antagonist osanetant blunted the effect of senktide. Mutagenesis studies employing TASK-1 channel constructs which lack either protein kinase C (PKC) phosphorylation sites or the domain which is regulating the diacyl glycerol (DAG) sensitivity domain of TASK-1 revealed a protein kinase C independent mechanism of TASK-1 current inhibition: upon neurokinin-III receptor activation TASK-1 channels are blocked in a DAG-dependent fashion. Finally, effects of senktide on atrial TASK-1 currents could be reproduced in patch-clamp measurements, performed on isolated human atrial cardiomyocytes. CONCLUSIONS: Heterologously expressed human TASK-1 channels are inhibited by neurokinin-III receptor activation in a DAG dependent fashion. Patch-clamp measurements, performed on human atrial cardiomyocytes suggest that the atrial-specific effects of neurokinin-III receptor activation on cardiac excitability are predominantly mediated via TASK-1 currents.

The Impact of Hip Fracture on Geriatric Care and Mortality Among Older Swedes: Mapping Care Trajectories and Their Determinants.

In this study, we examined the impact of hip fractures on trajectories of home care, nursing home residence, and mortality among individuals aged 65 years or more and explored the impacts of living arrangements, cohabitation, frailty, and socioeconomic position on these trajectories. Based on a linkage of nationwide Swedish population registers, our study included 20,573 individuals with first hip fracture in 2014-2015. Care trajectories during the 2 years following the fracture were visualized and compared with those of 2 hip-fracture-free control groups drawn from the general population: age- and sex-matched controls and health-matched controls identified through propensity score matching. Multistate modeling was employed to identify sociodemographic and health-related factors associated with care trajectories among hip fracture patients. We found that hip fracture patients already had worse health than the general population before their fracture. However, when controlling for prefracture health, hip fractures still had a considerable impact on use of elder-care services and mortality. Comparisons with the health-matched controls suggest that hip fractures have an immediate, yet short-term, impact on care trajectories. Long-term care needs are largely attributable to poorer health profiles independent of the fracture itself. This emphasizes the importance of adequate comparison groups when examining the consequences of diseases which are often accompanied by other underlying health problems.

Molecular Mechanisms of Diaphragm Myopathy in Humans With Severe Heart Failure.

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Variation in End-of-Life Trajectories in Persons Aged 70 Years and Older, Sweden, 2018‒2020.

Objectives. To analyze variation in end-of-life trajectories with regard to elder care and medical care and how they relate to age, gender, and causes of death. Methods. We analyzed all deaths of persons at age 70 years and older between the years 2018 and 2020 in Sweden, using a linkage of population registers. We applied latent class analysis to identify distinct types of end-of-life trajectories. Results. We identified 6 different types of end-of-life trajectories. The types differed substantially in the amount of utilized elder care and medical care before death. Deaths characterized by high levels of elder care and medical care utilization become more common with age. The trajectory types show distinct cause-of-death profiles. Conclusions. Most deaths today do not comply with what is often referred to as a "good" death (e.g., retaining control or requiring low levels of elder care). The results suggest that longer lifespans partly result from a prolonged dying process. Public Health Implications. The current modes of dying call for a discussion about how we want to die in an era of increasing lifespans and aging societies. (Am J Public Health. 2023;113(7):786-794. https://doi.org/10.2105/AJPH.2023.307281).

A short length of hospital stay is not associated with risk of readmission among hip fracture patients - a Swedish national register-based cohort study.

BACKGROUND: Hospital length of stay (LoS) after a hip fracture likely mirrors health status; however, a too short hospitalization might increase the risk of readmission. In this national register-based study, we investigated the association between LoS after a hip fracture and the risk of readmissions. METHODS: 73,551 patients with a first hip fracture between 2012 and 2019 were followed for 4 months after discharge. LoS was categorized by cubic splines and the association with readmissions was analyzed with Cox regression models. RESULTS: The mean LoS was 11 ± 6 days and 25% of the study population had at least one readmission. Compared to the mean LoS of 9-12 days, there was a 18% decreased risk of readmission for LoS of 2-4 days (HR 0.82 [95% CI 0.77-0.87]) and 13% decrease for 5-8 days (HR 0.87 [95% CI 0.83-0.91]), when adjusting for sex, age, walking ability, ASA score, CCI, complications during hospitalization and living arrangements. For longer LoS, risk of readmission increased (13-23 days: HR 1.09 [95% CI 1.05-1.13] and 24 + days: HR 1.19 [95% CI 1.11-1.28]). The results were robust across sex, age, and living arrangements. The most common specific reasons for readmission were trauma/injury, cardiovascular and complications, and the proportions did not differ considerably between short and long LoS-categories. CONCLUSIONS: While a long LoS can be explained by the care need of the patient, a short LoS - compared to the average stay - does not increase the risk of readmission regardless of health status and hospital complications in a Swedish setting.

Centenarians: who are they? A description of the total Swedish centenarian population in terms of living arrangements, health, and care utilization.

BACKGROUND: The global centenarian population has doubled each decade and is expected to continue growing. However, information regarding how they live, their health status, and care needs is limited. AIMS: This study aims to describe the total Swedish centenarian population in terms of health status, living arrangements, and socio-demographic characteristics. METHODS: This nationwide register-based study included all Swedish people reaching age 100 between 2013 and 2018. We analyzed their socio-demographic characteristics, living arrangements, number of prescribed drugs, and health status. Moreover, their care transitions from age 100 and two years forward were described. RESULTS: Of 5,882 centenarians (80.7% women), only 15.0% lived at home without formal care and 24.5% cohabited on their 100th birthday. Men (22.7%) were more likely than women (13.2%) to live at home without care. Approximately half of the centenarians lived in care homes, with fewer men (41.0%) than women (54.0%). Around 66.6% had a child living within the 50 km range. Most (76.5%) had an income below the median for Swedish older adults. Almost none were free from drugs, and polypharmacy was common (65.3%). Over half had at least one morbidity. Two years later, only 4.3% lived at home without care, and 63.9% died. CONCLUSION: Sweden's centenarian population is highly dependent on home care and care homes. Among the ones still living at home, the vast majority live alone and have low incomes. Strategies to manage health and social care demands of this growing population group in the coming decade are important.

The multidimensional prognostic index in hospitalized older adults: practicability with regard to time needs.

BACKGROUND: Comprehensive Geriatric Assessment (CGA) is decisive in patient-centered medicine of the aged individual, yet it is not systematically used. AIM: The aim of this study was to provide precise practice-relevant time expenditure data for the Multidimensional Prognostic Index (MPI), a questionnaire-based frailty assessment tool. METHODS: MPI was determined in ninety older multimorbid adults in three geriatric departments (cohorts 1, 2 and 3). The time needed to perform the MPI (tnpMPI) was recorded in minutes. Follow-up data were collected after 6 months. RESULTS: The median tnpMPI was 15.0 min (IQR 7.0) in the total collective. In the last visited cohort 3, the median was 10.0 min and differed significantly from cohorts 1 and 2 with medians of 15.5 and 15.0 (p < 0.001). CONCLUSION: These findings indicate, that MPI, as a highly informative frailty tool of individualized medicine, can be performed in an adequately practicable time frame.

Early peri-implant fractures after distal femur fracture locked plating?

PURPOSE: To report the peri-implant fracture rates after locked plating of distal femur fractures and examine risk factors. METHODS: Over a 7 year period, 89 AO/OTA 33A/C distal femur fractures were identified and reviewed. After excluding treatment with intramedullary nails, age under 50, those with the proximal femur protected, or those without 6 months of follow-up, 42 distal femur fractures in 41 patients, mean age 72.3 were studied. All were treated with lateral locked plating of distal femur fractures. The details of the constructs were recorded. Mean follow-up was 562 days (18.7 months). RESULTS: 3/42 were open injuries, 9/42 were type C, 16/42 were type A, and 17 were periprosthetic above a knee arthroplasty. Two patients were treated with a dynamic plating construct using all far-cortical locking (FCL) screws in the diaphysis. 40 patients were treated with a variety of non-dynamic diaphyseal constructs including locking, non-locking, and four with 1-2 FCL screws distally. There was one asymptomatic nonunion. 2/2 patients in the dynamically plated group experienced a peri-implant fracture versus 1/40 in the non-dynamically plated group (p = 0.001). 3/9 with an all-locked construct versus 0/25 patients with a most proximal non-locking screw experienced a fracture. CONCLUSIONS: The overall peri-implant fracture risk was 7.1% (3/42), 3/17 patients with a locking screw most proximal experienced a peri-implant fracture, 3/9 with an all-locking construct, and 2/2 patients with a dynamic construct experienced a fracture. These findings merit additional clinical and biomechanical study.

Treatment Effects of Interleukin-6 Receptor Antibodies for Modulating the Systemic Inflammatory Response After Out-of-Hospital Cardiac Arrest (The IMICA Trial): A Double-Blinded, Placebo-Controlled, Single-Center, Randomized, Clinical Trial.

BACKGROUND: Patients experiencing out-of-hospital cardiac arrest who remain comatose after initial resuscitation are at high risk of morbidity and mortality attributable to the ensuing post-cardiac arrest syndrome. Systemic inflammation constitutes a major component of post-cardiac arrest syndrome, and IL-6 (interleukin-6) levels are associated with post-cardiac arrest syndrome severity. The IL-6 receptor antagonist tocilizumab could potentially dampen inflammation in post-cardiac arrest syndrome. The objective of the present trial was to determine the efficacy of tocilizumab to reduce systemic inflammation after out-of-hospital cardiac arrest of a presumed cardiac cause and thereby potentially mitigate organ injury. METHODS: Eighty comatose patients with out-of-hospital cardiac arrest were randomly assigned 1:1 in a double-blinded placebo-controlled trial to a single infusion of tocilizumab or placebo in addition to standard of care including targeted temperature management. Blood samples were sequentially drawn during the initial 72 hours. The primary end point was the reduction in C-reactive protein response from baseline until 72 hours in patients treated with tocilizumab evaluated by mixed-model analysis for a treatment-by-time interaction. Secondary end points (main) were the marker of inflammation: leukocytes; the markers of myocardial injury: creatine kinase myocardial band, troponin T, and N-terminal pro B-type natriuretic peptide; and the marker of brain injury: neuron-specific enolase. These secondary end points were analyzed by mixed-model analysis. RESULTS: The primary end point of reducing the C-reactive protein response by tocilizumab was achieved since there was a significant treatment-by-time interaction, P<0.0001, and a profound effect on C-reactive protein levels. Systemic inflammation was reduced by treatment with tocilizumab because both C-reactive protein and leukocyte levels were markedly reduced, tocilizumab versus placebo at 24 hours: -84% [-90%; -76%] and -34% [-46%; -19%], respectively, both P<0.001. Myocardial injury was also reduced, documented by reductions in creatine kinase myocardial band and troponin T; tocilizumab versus placebo at 12 hours: -36% [-54%; -11%] and -38% [-53%; -19%], respectively, both P<0.01. N-terminal pro B-type natriuretic peptide was similarly reduced by active treatment; tocilizumab versus placebo at 48 hours: -65% [-80%; -41%], P<0.001. There were no differences in survival or neurological outcome. CONCLUSIONS: Treatment with tocilizumab resulted in a significant reduction in systemic inflammation and myocardial injury in comatose patients resuscitated from out-of-hospital cardiac arrest. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03863015.

Heart transplantation across preformed donor-specific antibody barriers using a perioperative desensitization protocol.

Heart transplantation across preformed donor-specific HLA-antibody barriers is associated with impaired short- and long-term survival. Therefore, in recipients with preformed anti-HLA antibodies, waiting for crossmatch-negative donors is standard practice. As an alternative strategy, recipients with preformed anti-HLA donor specific antibodies have been managed at our institutions with a perioperative desensitization regimen. A retrospective analysis was performed comparing heart transplant recipients with preformed donor-specific HLA-antibodies to recipients without donor-specific antibodies. Recipients with a positive virtual crossmatch received a perioperative desensitization protocol including tocilizumab intraoperatively, plasma exchange and rituximab followed by a six-month course of IgGAM. Among the 117 heart-transplanted patients, 19 (16%) patients underwent perioperative desensitization, and the remaining 98 (84%) patients did not. Cold ischemic time, posttransplant extracorporeal life support for primary graft dysfunction, and intensive care unit stay time did not differ between groups. At 1-year follow-up, freedom from pulsed steroid therapy for presumed rejection and biopsy-confirmed acute cellular or humoral rejection did not differ between groups. One-year survival amounted to 94.7% in the treated patients and 81.4% in the control group. Therefore, heart transplantation in sensitized recipients undergoing a perioperative desensitization appears safe with comparable postoperative outcomes as patients with a negative crossmatch.

Racial and ethnic disparities in diagnostic efficacy of comprehensive genetic testing for sensorineural hearing loss.

Understanding racial and ethnic disparities in diagnostic rates of genetic testing is critical for health equity. We sought to understand the extent and cause of racial and ethnic disparities in diagnostic efficacy of comprehensive genetic testing (CGT) for sensorineural hearing loss (SNHL). We performed a retrospective cohort study at two tertiary children's hospitals on a diverse cohort of 240 consecutive pediatric patients (76% publicly insured, 82% non-White) with SNHL of unknown etiology who underwent CGT. Definite and possible genetic diagnoses were assigned for each patient, representing the likelihood of a genetic cause of hearing loss. Associations between diagnostic rates were examined. 3.8 ± 2.1 variants were detected per patient; this frequency did not vary between White/Asian and Hispanic/Black cohorts. Overall, 82% of variants were variants of uncertain significance (VUS). Compared with White and Asian subjects, variants identified among Hispanic and Black children were less likely to be classified as pathogenic/likely pathogenic (15% vs. 24%, p < 0.001), and Hispanic and Black children were less likely to have a definite genetic diagnosis (10% vs. 37%, p < 0.001). The adjusted odds ratio for definite genetic diagnosis in Black and Hispanic children compared with White and Asian children was 0.19. Expanding genetic diagnostic criteria to include predicted deleterious VUSs reduced these disparities between White/Asian and Hispanic/Black children, with comparable molecular diagnostic rates (41% vs. 38%, p = 0.72). However, in silico predictions are insufficiently valid for clinical use. Increased inclusion of underrepresented groups in genetic hearing-loss studies to clinically validate these variants is necessary to reduce racial and ethnic disparities in diagnostic efficacy of comprehensive genetic testing.