Autonomous vehicles will share roads with human-driven vehicles until the transition to fully autonomous transport systems is complete. The critical challenge of improving mutual understanding between both vehicle types cannot be addressed only by feeding extensive driving data into data-driven models but by enabling autonomous vehicles to understand and apply common driving behaviors analogous to human drivers. Therefore, we designed and conducted two electroencephalography experiments for comparing the cerebral activities of human linguistics and driving understanding. The results showed that driving activates hierarchical neural functions in the auditory cortex, which is analogous to abstraction in linguistic understanding. Subsequently, we proposed a neural-informed, semantics-driven framework to understand common human driving behavior in a brain-inspired manner. This study highlights the pathway of fusing neuroscience into complex human behavior understanding tasks and provides a computational neural model to understand human driving behaviors, which will enable autonomous vehicles to perceive and think like human drivers. •Reveal human auditory cortex activation during driving•Discover the hierarchical structure of human driving understanding•Propose a neural-informed semantics-driven driving understanding model•Address long-term contextual dependency of driving behaviors “Driving like humans” is the ultimate goal of autonomous driving. Hence, human-like driving understanding ability is required for autonomous vehicles to better understand the driving behaviors of surrounding human-driven vehicles. In this study, we investigated human driving neural response and subsequently built a biologically plausible model to interpret driving behaviors like humans. This study pioneers the design of bio-inspired, human-like autonomous vehicles and can ultimately benefit future research of human-machine interactions. Autonomous vehicles will share roads with human-driven vehicles and bring with them problems regarding bidirectional understanding of driving behavior. Based on cerebral neurological findings from the human process for understanding driving, a novel neural-inspired semantics-driven driving understanding model is proposed for autonomous vehicles. The model imitates the way humans understand driving and can interpret long-term driving behavior evolutions like human drivers. Every day, almost 2,700 people are killed globally in traffic crashes,,In recent years, various types of AVs were developed and tested in urban road scenarios, and they yielded promising results and applications.,,,,,Unlike the classical vehicular trajectory prediction and route planning models,,Understanding common human driving behaviors that follow the human cerebral driving thinking mechanisms of human drivers D is nece,,,,Our research is motivated by the fact that talking while driving can cause severe distractions because both behaviors or activities share the same cerebral resources,Neurological and cognitive research(1)We present biological findings that human cerebral driving understanding activates similar hierarchical linguistic neural functions in the auditory cortex as that with linguistic understanding.(2)A semantics-driven framework is proposed to understand common driving behaviors in a human-like and linguistic-inspired manner contextually. This provides AVs with the ability to perceive and think similar to human drivers.(3)A prototype is proposed to demonstrate the possible computational neural implementation of the biological findings. The evolution of human driving behavior is encoded to highly abstracted common driving units and topics in a brain-inspired manner, and it is understood using an SNN with NLP techniques to tackle the contextual reasoning limitations of state-of-the-art human-like driving behavior understanding methods and models.Our work includes the following key features.We collected EEG responses from 18 participants on three 5-min tasks—resting, driving, and listening—to investigate the relationship between human linguistics and driving-related thought processes. We compared the collected responses in the spatial and frequency domains. Counterintuitively, as reflected in the topographic maps  to understand intrinsic semantical knowledge.This finding indicates that human drivers can employ similar intrinsic hierarchical linguistic structures  in the cortex to pre-process an abstract dynamic driving scenario instead of directly utilizing raw driving information as part of the decision-making unit. In a correlative experiment, the neural responses of random driving video frames were relatively smooth, which eliminated the phrasal/sentential structure. The corresponding frequency-power visualization suggested that participants merely obtained any abstracted knowledge from these irrelevant frames; this strengthened the finding of hierarchical driving understanding abstraction in the human brain.Inspired by the hierarchical structure of driving behavior understanding, we proposed a three-level common driving semantics structure  to encode raw driving information into meaningful and comprehensible semantic units, as shown in Encoded common driving semantic units are temporally stored in the working memory and then used to understand common driving semantics, as shown in ,,,,To validate whether the proposed semantics-driven framework can effectively understand human driving evolution, we designed a prototypical implementation experiment using a semantics-driven approach to understand human driving intentions with ubiquitous traffic eye (UTE) naturalistic driving trajectory datasetsst second: 98.14%, 5th second: 95.33%, and 10th second: 95%) while retaining a low root-mean-square error  without explicitly pre-defining the potential lane-changing choice probability. This indicates the advantage of the long-term contextual prediction stability of the proposed semantics-driven understanding framework.Our experimental results indicate that the proposed method achieved high accuracy in recurrently predicting the most relevant topic  and multi-output support vector regression (MSVR) in To further validate the velocity prediction accuracy, we visualized the velocity prediction result of a typical vehicle in This article addressed the future coexistence challenge of autonomous and human-driven vehicles and proposed a brain-inspired computational neural framework to understand the evolution of common driving topics and address this challenge. We reported biological findings that driving and linguistic understanding share conspecific hierarchical neural abstractions in the auditory cortex and further proposed a semantics-driven method to understand human driving thinking. The prototypical implementation experimental results showed that the proposed framework accurately predicted driving maneuvers in the next few seconds while retaining a lower error accumulation rate benefiting from contextual driving semantics compared with other data-driven trajectory prediction baselines. Therefore, this work acts as a complementary component for current AVs, and it can provide AVs with the ability to perceive and think similar to human drivers. We lay the biological and theoretical foundations to advance the development of human-like AVs.The goal of AVs is to drive similar to human drivers. AVs and the surrounding human-driven vehicles should have a clear bidirectional understanding of each other’s driving intentions. State-of-the-art driving intention recognition models have endlessly improved the accuracy of trajectory prediction using highly stacked and complex neural networks. However, their model interpretability decreases quickly, which can create barriers to mutual human-machine understanding and result in traffic conflicts or accidents. Our work pioneers the introduction of biological and cerebral research methods for analyzing human driving understanding patterns related to driving behaviors and provides a prototypical demonstration to benefit future human-machine interaction research.There are some limitations in our study that should be addressed in future research. For example, the proposed method focuses on developing frameworks that would allow AVs to comprehend and interpret the driving behaviors of surrounding vehicles, similar to human drivers. However, the method does not address the static driving environment quantification problem. Weather, traffic signs, lane specifications, etc., strongly correlate with human driving behavior adaptation. Thus, an important future direction would be to quantify cerebral responses to various driving environment factors in a stimulus-based manner and to add them to the common driving semantics. Moreover, our work represents the first step toward developing brain-inspired, human-like AVs and addressing vehicular interactions. Therefore, future work should include a self-correcting mechanism that can actively consider the effect of contextual vehicular interactions in an attention-based manner.Autoencoders (AEs) that use machine learning algorithms, such as variational AEs, sparse AEs, and semantic AEs, can be embedded into the common semantic unit encoding process to achieve a higher-level abstracted semantic representation. Theoretically, these AEs are more biologically sound to imitate the activation of cerebral neurons and fit continuous velocity changes compared with that using the proposed discrete codebook. The employment of AEs neither improves method interpretability nor decreases computational complexity. Therefore, in this study, AEs were replaced by a more straightforward, yet effective, codebook method following the model simplicity law of Occam’s razor.chenxiqun@zju.edu.cn).Further information and requests for resources and reagents should be directed to and will be fulfilled by the lead contact, Xiqun (Michael) Chen . This study was conducted in accordance with the ethical standards of the 1964 Declaration of Helsinki. All participants provided written informed consent before the experiment, and the possible consequences of the study were explained.,Eighteen normal-hearing, right-handed adult drivers  participated in the EEG experiments. All participants were qualified drivers with driving licenses, and their average driving experience was 4.5 years. The sample size for previous linguistic experiments was between 3 and12,The EEG signals were recorded at 128 samples per second  with a 32-channel Emotiv Epoc Flex device and processed with EEGLAB software.Each participant was asked to listen to the news materials: “News 1 + 1: How to disinfect correctly in work and life?” (Mandarin),We synthesized three video clips using the Cityscapes driving video dataset,UTE naturalistic driving trajectory datasetsv stands for the uniform speed threshold, and v' denotes the mapped threshold) to balance the data distribution because vehicles tend to maintain their lane most of the time. After obtaining the bin numbers in the first and later 0.5 s, another codebook was constructed to represent the 1-Hz common driving semantic units with 900 bin numbers, which imitates the three-level abstraction process of human driving understanding.The two-dimensional vehicle velocity  was sampled every 0.25 s (4 Hz) and averaged every 0.5 s in a pairwise manner (2 Hz). Using a discrete codebook, the 2-Hz averaged velocity was divided into 30 non-overlapping cells with different thresholds. The bin interval sets of the lateral and longitudinal speeds used in this study are shown in


Introduction: Increasing survival of adult congenital heart disease (ACHD) patients comes at the price of a range of late complications—arrhythmias, heart failure, and valvular dysfunction. Transcatheter valve interventions have become a legitimate alternative to conventional surgical treatment in selected acquired heart disease patients. However, literature on technical aspects, hemodynamic effects, and clinical outcomes of percutaneous atrioventricular (AV) valve interventions in ACHD patients is scarce. Method: This is a descriptive cohort from CAHAL . ACHD patients with severe AV valve regurgitation who underwent a transcatheter intervention in the period 2020–2022 were included. Demographic, clinical, procedural, and follow-up data were collected from patient records. Results: Five ACHD patients with severe or torrential AV valve regurgitation are described. Two patients underwent a transcatheter edge-to-edge repair (TEER), one patient underwent a valve-in-valve procedure, one patient received a Cardioband system, and one patient received both a Cardioband system and TEER. No periprocedural complications occurred. Post-procedural AV valve regurgitation as well as NYHA functional class improved in all patients. The median post-procedural NYHA functional class improved from 3.0 (IQR [2.5–4.0]) to 2.0 (IQR [1.5–2.5]). One patient died 9 months after the procedure due to advanced heart failure with multiorgan dysfunction. Conclusion: Transcatheter valve repair is feasible and safe in selected complex ACHD patients. A dedicated heart team is essential for determining an individualized treatment strategy as well as pre- and periprocedural imaging to address the underlying mechanism(s) of AV regurgitation and guide the transcatheter intervention. Long-term follow-up is essential to evaluate the clinical outcomes of transcatheter AV valve repair in ACHD patients. Congenital heart disease (CHD) has an estimated prevalence of about 1% in the general population ,3. TransThis two-center observational, retrospective cohort study was performed at the departments of Cardiology of the Amsterdam University Medical Center and Leiden University Medical Center, united in the center of Congenital Heart Disease Amsterdam-Leiden (CAHAL). Consecutive ACHD patients with hemodynamically severe AV valve lesions  who underwent a catheter-based intervention to address the AV valve dysfunction between 2020 and 2022 were included in this cohort . All patDescriptive statistics were utilized to summarize data. Normally distributed continuous data are displayed as mean ± standard deviation (SD) and non-normally distributed continuous data are displayed as median and 95% and the first and third interquartiles [IQ1–IQ3]. Categorical data are presented as numbers. Statistical analyses were performed with IBM SPSS Statistics for Windows, version 28 .Five complex ACHD patients (two women), median age 52 years (44–74), with severe or torrential symptomatic AV regurgitation were included in this descriptive cohort; All procedures were performed under general anesthesia with transesophageal (TEE) and/or fluoroscopic guidance, except for one case, which was performed under local anesthesia. No periprocedural complications were reported. Post-procedural AV valve regurgitation improved significantly in all patients . The med2) and elevated levels of NT-proBNP . Despite pharmacological escalation, the patient remained in NYHA functional class III and experienced frequent recurrences of symptomatic AF. The severe functional TR due to annulus dilatation and progressive decline in systolic function of the overloaded right ventricle was deemed to be the cause. The perioperative risk of surgery involving a third thoracotomy in a septuagenarian was high, and therefore percutaneous options were evaluated. Given the malcoaptation and the dilated tricuspid valve (TV) annulus of 62 × 54 mm , presented to the emergency department with complaints of dyspnea and progressive weight gain. He was documented to have persistent AF with inadequate rate-control and signs of moderate left- and right-sided decompensation. He was treated with loop diuretics and underwent successful cardioversion to sinus rhythm after recompensation. Transthoracic echocardiography (TTE) revealed moderately reduced left and right ventricular function, normal function of the aortic bioprosthesis , trivial mitral regurgitation, and torrential tricuspid regurgitation (TR) with elevated filling pressures  A–D. Labo × 54 mm C, the heThe patient underwent a successful Cardioband annular reduction using right venous femoral access under general anesthesia with fluoroscopic (selective cannulation of the right coronary artery) and TEE guidance E–H. A toA 40-year-old female born with Ebstein’s anomaly of the TV who had previously undergone a surgical annuloplasty and a TV replacement with a bioprosthesis  and had two uncomplicated pregnancies afterwards was seen at the outpatient clinic with progressive complaints of reduced exercise tolerance, currently in NYHA functional class II. TTE revealed severe regurgitation and significant stenosis of the TVR bioprosthesis with progressively worsening right ventricular (RV) function and a giant right atrium (RA) partially compressing the left atrial compartment A–E. She This was successfully performed under local anesthesia, by means of right femoral access and fluoroscopy and TTE guidance. A temporary pacemaker wire was placed in the left ventricle and the AgilisTM steerable introducer  was used to safely access the RA, given the relatively sharp angle between the vena cava-RA and the RA-RV axis F. The Ed2) and elevated levels of NT-proBNP . TTE and TEE , mitral valve atresia, large ventricular septal defect (VSD), functionally univentricular heart with a hypoplastic left ventricle) was palliated using multiple Blalock–Taussig (BT) shunts. He had an abnormal systemic venous return with a hemiazygos continuation of the inferior caval vein (IVC) and a persistent left superior caval vein (SVC) A. The pa and TEE D showed As a result of the severely dilated annulus and tethering, the coaptation gap was large, and simultaneous grasping of both leaflets was challenging. The TriClip system has the advanced option of independent leaflet grasping. First, the anterior leaflet  was grasped and, subsequently, after minor device repositioning under TEE guidance, the septal leaflet was captured and the clip was released. The first clip was implanted near the commissure to narrow the coaptation gap so that the second clip could be implanted to treat the regurgitation C, which 2). Moderately reduced systolic and diastolic systemic ventricular function, severe atrial dilatation, and AV valve regurgitation were documented on TTE and TEE. Additional CT imaging showed a severely dilated functional mono-atrium in close proximity to the thoracic wall , pulmonary stenosis, hypoplastic left ventricle, a right-sided aortic arch, a persistent left SVC, and an interrupted IVC (azygos continuation). At the age of 30, he received a bilateral bidirectional Glenn shunt. The patient was now admitted with peripheral edema and permanent AF with adequate rate control and had preserved renal function . Furthermore, a transjugular approach was not feasible because of the bilateral Glenn connection. Therefore, it was decided that a hybrid procedure under general anesthesia with direct atrial access using a MitraClip delivery system  was the best strategy.The congenital cardiothoracic surgeon performed a right (mini) lateral thoracotomy in the fifth intercostal space to expose the giant mono-atrium. A double-purse string suture was placed and an incision was made to create an opening using a Safari wire for guidance and stability. The interventional cardiologist then placed two XTW clips under TEE guidance D, resultA 72-year-old female born with Tetralogy of Fallot (TOF) and having undergone three previous thoracotomies , numerous ablation procedures for atrial arrhythmias after which permanent AF was accepted, and a pacemaker implantation due to a high-degree AV block was evaluated at the outpatient clinic due to progressive complaints of dyspnea on exertion and a recent admission with right-sided decompensation. She was in NYHA functional class IV despite escalation in diuretic treatment.Echocardiography showed severe TR with a regurgitant jet directed towards the inflow of the inferior vena cava and a progressive dilation of the RV with preserved systolic function A,B. The Both procedures were performed in sequential order under general anesthesia, by means of right femoral access and fluoroscopy and transesophageal echocardiographic guidance C,D. A toIn this descriptive cohort, we report on the indication, methodology, and outcomes of transcatheter treatment of five consecutive ACHD patients with severe AV valve regurgitation in the setting of complex anatomical malformations: two patients underwent a TEER, one patient underwent a valve-in-valve procedure, one patient underwent a Cardioband system implantation, and one patient underwent a consecutive Cardioband implantation followed by TEER. In two out of five patients, the regurgitant AV valve was of the systemic ventricle . Post-procedural AV valve regurgitation as well as NYHA functional class improved in all patients. This cohort is illustrative of the feasibility and the wide range of applications of transcatheter techniques in addressing AV valve lesions in ACHD patients and highlights the necessity of an individualized and anatomy-tailored approach.All patients were discussed by a dedicated ACHD team and surgery was deemed to be too high risk for all patients reported. Lifetime rate of re-thoracotomies, extensive adhesions, unique anatomical challenges, hemorrhage prone collaterals, and multi-organ dysfunction are all recognized factors in this decision making favoring a transcatheter approach . Many ofHowever, despite the temptation of a less-invasive approach, it is important to recognize that data on procedural outcomes and long-term clinical results are scarce ,6,7. ThiThe Cardioband system addresses the annular dilatation pathophysiology in a minimally invasive catheter delivered approach. Nickenig et al. conducted the TRI-REPAIR study in thirty patients with moderate or greater functional TR who received a Cardioband system. The implantation of a Cardioband resulted in sustained and significant TR reduction at two years follow-up with substantial improvement in NYHA functional class . Gray etValve-in-valve transcatheter TV replacement has previously been reported to be a good alternative to surgery in patients with severe TV regurgitation and high operative risk ,13. In lFurthermore, three patients underwent a successful TEER, where one patient had a systemic left ventricle whilst the two other patients had a systemic right ventricle. In particular, one of those patients had a functional mono-ventricle with reduced systolic function in the setting of a very complex anatomy, in which the implantation of the clips was feasible and safe (patient D). Despite best efforts, the patient died 9 months after the procedure due to progressive heart failure and concomitant multi-organ dysfunction. Ott et al. previously reported that TEER in congenitally corrected TGA was feasible and safe  and SchaOf particular interest for further studies remain the patients with a failing systemic right ventricle and TR , as well as the growing group of Fontan circulation patients with functional AV-valve regurgitation (REF + REF). These groups are at specifically high surgical risk and the potential of percutaneous AV valve therapies would be a welcome development to mitigate the risk of re-operations ,16.The current series of patients illustrates the importance of a dedicated and experienced ACHD heart team in addressing AV valve dysfunction in this heterogenous patient group. Only after a thorough understanding of the mechanisms contributing to the valvular dysfunction, and careful consideration of the individual perioperative risks and the capability of a transcatheter technique in adequately addressing these mechanisms, can an individualized and weighted decision be made. Multidisciplinary expertise is essential and we advocate for all ACHD patients undergoing transcatheter AV valve repair or replacement to be discussed and treated in specialized centers by dedicated teams. As the vast majority of ACHD patients require a lifelong follow-up, the heart team can also be used as a forum to discuss treatment and follow-up strategies to ensure timely intervention .A comprehensive, multi-parametric, and multimodality approach is necessary to understand the underlying mechanism of AV valve regurgitation. This is essential to determine the optimal management strategy and timing of intervention. Given the current lack of robust data defining the optimal timing window for intervention for the vast majority of ACHD valvular lesions, and the often misleading seemingly “asymptomatic” status of the patients during long-term follow-up, serial imaging plays an essential role in timely detection of hemodynamic deterioration. Thorough review of patient records and focused imaging of the venous and arterial access and intracardiac connections is important, as many ACHD patients have concomitant vascular anatomy variants and venous return abnormalities and have undergone numerous vascular interventions, potentially compromising conventional vascular access routes. Patient C is illustrative of a transjugular venous access utilization and patient D required a hybrid procedure with surgical exposure of the functional mono-atrium and the common AV valve. Of note, several studies showed that pre-procedural planning using 3D modeling/virtual reality (VR) in pediatric cardiothoracic patients is feasible as there are some reports of the experience in ACHD patients ,18,19. VThis descriptive cohort is inherently limited by the small numbers of a heterogenous population and should therefore be interpreted in this context. It describes a two-center experience of an experienced ACHD interventional team and the techniques utilized might not be widely implemented in various settings. The follow-up period is limited and no data are available regarding the long-term  outcomes.In conclusion, novel (hybrid) transcatheter valve therapies, including transcatheter edge-to-edge repair using a TriClip or MitraClip, transcatheter annulus reduction using a Cardioband, and valve-in-valve replacement techniques are feasible and can address AV valve regurgitation in highly selected complex ACHD patients. Comprehensive multimodality imaging and a dedicated ACHD heart team are essential in successfully implementing patient-tailored transcatheter techniques and deferring high risk surgery in selected patients. Long term data on hemodynamic and clinical outcomes are essential in evaluating the efficacy and durability of transcatheter AV valve interventions in ACHD.


Duchenne muscular dystrophy (DMD) is a severe, progressive, and ultimately fatal disease of skeletal muscle wasting, respiratory insufficiency, and cardiomyopathy. The identification of the dystrophin gene as central to DMD pathogenesis has led to the understanding of the muscle membrane and the proteins involved in membrane stability as the focal point of the disease. The lessons learned from decades of research in human genetics, biochemistry, and physiology have culminated in establishing the myriad functionalities of dystrophin in striated muscle biology. Here, we review the pathophysiological basis of DMD and discuss recent progress toward the development of therapeutic strategies for DMD that are currently close to or are in human clinical trials. The first section of the review focuses on DMD and the mechanisms contributing to membrane instability, inflammation, and fibrosis. The second section discusses therapeutic strategies currently used to treat DMD. This includes a focus on outlining the strengths and limitations of approaches directed at correcting the genetic defect through dystrophin gene replacement, modification, repair, and/or a range of dystrophin-independent approaches. The final section highlights the different therapeutic strategies for DMD currently in clinical trials. Duchenne muscular dystrophy (DMD) is a severe X-linked recessive disorder caused by mutations in the dystrophin gene and consequent complete loss of dystrophin protein expression . The incde novo and the remaining caused by germline mosaicism or inheritance from a carrier mother , which protects the sarcolemma from the force associated with stretch and contraction . SecondaThe cardiac muscle must withstand significant mechanical stress to pump blood throughout the body, and the consequences of this stress are greatly exacerbated in DMD patients. Membrane instability leads to gradual cardiac myocyte death, resulting in fibrosis and secondary fatty infiltration . This prAlthough dystrophin deficiency in muscle tissues is the primary cause of the life-limiting issues associated with DMD, a lack of brain dystrophin has consequences as well . DMD patThe survival of patients with DMD has improved over time. With optimal care, patients with DMD can survive to live in their thirties and forties, mainly owing to the development of guidelines for care and management and improved treatment for cardiopulmonary dysfunction .Dystrophin is an essential cytoskeletal protein in muscle that localizes to the inner surface of the muscle cell membrane and is enriched at the costameres and sites of cell–cell contact . DystropThe dystrophin protein has four main functional domains: 1) an N-terminal region with homologies to the actin-binding domains of α-actinin that anchors the protein to the cytoskeleton; 2) a central rod domain containing 24 spectrin-like repeats separated by four hinge regions; 3) a cysteine-rich domain that anchors dystrophin to the muscle membrane via interaction with the transmembrane protein β-dystroglycan; and 4) a C-terminal domain that binds dystrobrevin and syntrophins, mediating sarcolemma localization . The N-tConnection is achieved through the dystrophin-glycoprotein complex (DGC), which consists of extracellular (α-dystroglycan), transmembrane , and cytoplasmic proteins , providing a link between the intracellular cytoskeleton and the ECM .It has been shown that α-dystroglycan resides on the extracellular surface of the sarcolemma and functions as a receptor for extracellular ligands such as laminin . Here, αIn striated muscle, force is generated through cycles of contraction and relaxation of muscle fibers as driven via the sarcomere . As discA major consequence of the increased levels of membrane instability and leakiness in DMD muscles is an increase in intracellular calcium levels and disrupted calcium homeostasis within the muscle . There iAlthough the mechanism of calcium entry is not fully resolved, it is clear that increased calcium levels in DMD muscles have a significant negative impact on function. This can be seen through the myriad of calcium-signaling pathways in the cell, including calmodulin , calpainImmune cell infiltration is a main feature of DMD and is strongly associated with disease severity . In DMD Skeletal muscle is host to a heterogeneous combination of endothelial, stem, and immune cells, including macrophages, natural killer (NK) cells, T cells, B cells, and neutrophils . Immune As detailed previously, membrane instability is a primary defect in DMD. In healthy muscles, intense exercise causes membrane damage and leakage of cytoplasmic content into the extracellular compartment . This isThe immune cell infiltration in young DMD patients is predominantly formed by macrophages and T cells . Similar+ helper T cells promote the immune response by producing inflammatory cytokines , and improved the muscle phenotype , pathogenically high levels of cytoplasmic [Ca2+] can lead to Ca2+ overload in the mitochondria and trigger the opening of the mitochondrial permeability transition pore (mPTP)  .Morphologically, mitochondria in dystrophin-deficient muscle display decreased size and sparse cristae formation, which are attributed to an increased mitochondrial fission/fusion cycle . FurtherATP synthesis capacity has also been found to be disrupted in dystrophin-deficient muscle, and this is shown by a reduction in mitochondrial density and maximal ATP synthesis rate , as well− + O2 → O2− → H2O2) at the mitochondrial matrix and cytosol  is produced, and this is required for optimal cellular function, such as contraction . Muscles cytosol . Within  cytosol .2+ sensitivity and cross-bridge kinetics causing muscle contraction dysfunction  opening, as discussed previously. Interestingly, mdx skeletal and cardiac muscle have an adaptive elevation in ROS buffering capacity that counteracts the elevated ROS production from the mitochondria  also has a considerable role in the pathology of DMD muscle as a source of ROS . NOX2 isIndeed, there have been several reports showing significant improvements in muscle function, as well as prevention of myofiber necrosis and membrane permeability from mdx skeletal muscle by N-acetylcysteine supplementation .Fibrosis is a wound-healing process wherein an excessive amount of connective tissue is formed, leading to permanent scar tissue. The fraction of ECM in normal muscle is ∼5%, which can be drastically increased in diseased or injured muscles . RepeateThe ECM functions as the major source of passive load-bearing in muscles. When comparing the normalized stiffness of a single muscle fiber, fiber bundle (ECM intact), and fiber alone (ECM non-intact), muscle fiber bundles had much higher stress, and this demonstrated that the ECM provides a large portion of the load-bearing function . In thisBecause the fibrotic process begins early in DMD, therapeutic approaches aiming to reduce fibrosis have gained increased interest as a potential strategy for DMD. Therapeutic approaches inhibiting fibrosis (collagen type 1) have been shown to increase the expression of utrophin and the number of revertant myofibers . Other tDespite major therapeutic advances over the past 30 years, there is no curative treatment for DMD . NonetheAs reviewed before, there has been great interest in developing genetic approaches to treat DMD. Herein, we highlight some of the most promising therapeutic strategies that have been used to treat DMD, including gene therapy approaches via direct replacement of dystrophin and newer approaches involving the manipulation of the cellular machinery at the level of gene transcription, mRNA processing, or translation.Viral-mediated gene therapy has long been considered a potential therapeutic strategy to treat DMD based on its capability to restore the missing dystrophin by providing a functional copy of the dystrophin gene or repairing dystrophin, thereby restoring dystrophin throughout the body. The fact that DMD patients can be candidates for replacement gene therapy regardless of the underlying dystrophin mutation makes this a very attractive approach to correct DMD defects .Implementing DMD gene therapy has turned out to be a very challenging endeavor, involving two main challenges. The first problem is the dystrophin gene’s immense size. The dystrophin gene, including its coding sequence, poses a problem for viral vector packaging . The secin vivo recombination systems have been reported to deliver full-length dystrophin, albeit at very low efficiency . ficiency . Studiesficiency . The curficiency . These vficiency  reportedficiency .Initial studies featuring direct AAV vector injection into muscle showed high-level and durable gene transfer , althougBecause AAV vectors rarely integrate into the muscle fiber genome, it follows that with muscle turnover, the microdystrophin transgenes will be diluted and lose effectiveness over time. As AAV vectors do not effectively target satellite cells, upon muscle injury, the satellite cells that are recruited to take part in the repair process will not contain the therapeutic transgene, causing the transduced cells to become diluted and eventually disappear with time .Clinical trials section).AAV administration may also induce an innate or cellular immune response to the vector, including anti-AAV capsid-neutralizing antibody production. In addition, some patients already have pre-existing AAV-neutralizing antibodies, which exclude them from receiving this treatment . StrategAs clinical trials continue to develop, other factors controlling the function and stability of the transgene are being evaluated. The Chamberlain group reported that AAV-mediated delivery of microdystrophin resulted in continued expression that was maintained for at least 27 months in both skeletal and cardiac muscles . ConversAs previously indicated, the coding sequence of the muscle isoform of the dystrophin gene is approximately 11 kb long, and this length presents a significant difficulty in developing gene transfer therapy . ObservaThe capacity to excise specific coding regions within the dystrophin gene while maximizing protein function has been made possible by the availability of the full-length sequence of dystrophin together with the knowledge of related protein domains . Some doClinical trials section.)Dystrophin structure-function studies have suggested that at least four SRs from the central rod domain are required to connect the crucial N-terminal and cysteine-rich domains. There are a variety of strategies to build such miniature dystrophins. Although it has been demonstrated that a variety of microdystrophins containing various SR combinations can alleviate the dystrophic pathophysiology, other SR arrangements have produced proteins with low or reduced functional capacity . For exaSeveral other mini-/microdystrophin designs with clinical potential have been generated and tested in animal models . Among t4cv mice and delivered using recombinant AAV6 vector. When compared to first-generation microdystrophins, two of the new microdystrophins were found to improve force generation while also localizing neuronal nitric oxide synthase to the sarcolemma, namely, μDys5 (ΔR2-R15/ΔR18-R22/ΔCT) and μDys7 (ΔH2-R15 + H3/ΔR18-R23/ΔCT)  .It is worth noting that studies are needed to fully investigate the stability, function, and proper localization of the several different micro/mini-dystrophin constructs, as it is not entirely clear if the proteins will localize correctly within the cytoskeletal network.Additional research is required to assess how functional these microdystrophins are in humans, including their therapeutic effectiveness. A functional improvement in DMD patients may also be more challenging to predict, given that the DMD animal models  frequently exhibit a milder skeletal and cardiac muscle phenotype than humans. Additionally, because microdystrophins are shorter than the typical length of truncated dystrophins in BMD patients, microdystrophin therapy in DMD patients may not fully achieve the goal of attaining a BMD-like phenotype . AccordiExon skipping has been proposed and studied as a possible treatment for DMD for more than two decades. The goal of exon skipping therapy is to restore the disrupted open reading frame (ORF) of the dystrophin gene transcripts in DMD patients, allowing them to make a Becker’s muscular dystrophy-like protein  Niks an. It is bCRISPR-Cas9 mediated gene editing strategies). U7 snRNP-mediated inhibition of splicing is another approach for exon-skipping where modified U7 snRNP genes are delivered via AAV vectors  . CRISPR  vectors . In this vectors . The thiAONs are small 20–30 nucleotides of modified DNA or RNA homologs that specifically bind to their target exon prior to pre-mRNA splicing in a Watson-Crick-like manner, hiding the target exon from the splicing machinery so that it is spliced out with its flanking introns blocking its incorporation to the mature mRNA . AntisenFor AON therapy, the majority of DMD patients would have one or more exons deleted. Overall, in DMD patients, 70% of the reading frame can be restored by single exon skipping, whereas another 8% would benefit from double exon skipping to restore the reading frame . DMD delDifferent chemical modifications have been tested to give the AONs drug-like characteristics in trying to enhance their bioavailability, improving their resistance to exonucleases and endonucleases, and increasing their affinity to the target RNA transcripts . 2ʹ-O-mein vivo intramuscular injections, and in vivo systemic delivery . Depending on the delivery technique, various oligonucleotide chemistries exhibit different degrees of myofiber delivery efficacy and exon-skipping efficiency  and prevent the splicing of the targeted exon . Three dficiency .The use of nanoparticles as a delivery vehicle has been investigated for enhancing AON uptake and reducing possible immune reactions. Polymethyl methacrylate (PMMA) nanoparticles include two subgroups: T1 and ZM2 have been tested for AON therapy in mdx mice . T1 nanoin vitro and can be absorbed via intramuscular injection. Unfortunately, their use in clinical trials has been stopped, as no detectable dystrophin production in patient muscle was observed  or via nanoparticles. Multi-exon skipping approaches, which permit the skipping of several adjacent exons at once, are under investigation in order to broaden the range of mutations eligible for treatment . CocktaiDespite the attractiveness and applicability of single or multiple exon(s) skipping techniques and the fact that four AONs have already been approved for clinical trials, it is becoming clear that their delivery efficiency is not satisfactory . This coin vitro proof of concept research of the clinical trial stage to FDA approval . The multiple exon-skipping approach is still facing hurdles   .Around 10%–15% of patients with DMD have a nonsense mutation that induces a premature termination codon (PTC) in the mRNA, causing the ribosome to terminate translation and failing to synthesize the remainder of the protein . The priOver the past decade, gene editing has moved to the forefront with the identification of mechanisms of DNA repair . The CRINumerous engineered Cas endonucleases have been generated using naturally occurring Cas enzymes as guides. Targeted modifications have improved enzyme fidelity, reduced off-target mutations, increased editing efficiency, and used a more dispensable PAM sequence . EngineeThe potential treatment of DMD using CRISPR/Cas9-mediated therapeutic techniques and the difficulties of CRISPR/Cas9-mediated therapeutic genome editing will be the main topics of this section.A single infusion of CRISPR genome-editing components can theoretically treat DMD by correcting genetic mutations at the genome level utilizing CRISPR/Cas programmable nucleases , a concein vitro and in vivo studies using CRISPR-mediated gene editing for DMD have been conducted. Therapeutic effects have been reported in human cells and mice, rats, dogs, and piglets with various DMD mutations  of DMD patients have a deletion of one or more exons. Deleting the out-of-frame exon to restore the ORF is a typical method for achieving single or multiple exon deletions. This can be accomplished by double-cut exon deletion to one exon or over the entire hotspot region. To cut out single or multiple mutant exons, two sgRNAs flanking these sites can be targeted with Cas9, and this will cause the ORF to be restored by splicing the neighboring in-frame exons together . Importain vitro following gene editing. However, this correction was not as efficient as deleting exon 51 alone, and this raised concerns about the editing efficiency for deleting a larger DNA fragment. Other groups targeted this same region in vitro and demonstrated a successful restoration of dystrophin in multiple DMD cell lines  is a gene editing method with a relatively high efficiency in postmitotic cells. HITI can accurately knock in a missing exon(s) at a specific locus using NHEJ, which bypasses the requirement of HDR. HITI has been developed to overcome the HDR-related challenges noted previously . DeliverRoughly 25%–30% of patients with DMD have point mutations . Base edin vivo distribution, prime editing provides the ability to correct a number of DMD-causing mutations. In a proof-of-concept study by More recently, a new strategy, termed prime editing, has been developed, which has been added to the CRISPR techniques to treat DMD point mutations . Prime ein vivo postnatal genome editing. Cas9 and sgRNA, the two components of the CRISPR system, can be administered to the target organs via a variety of forms. DNA/DNA, mRNA/sgRNA, and protein/sgRNA are the possible nucleotide forms for Cas9 and sgRNA, respectively. The CRISPR delivery strategies frequently employed in DMD include viral and nonviral methods  have been employed , and cliin vivo using a dual-AAV approach (Staphylococcus aureus (Sa) Cas9, a smaller Cas9 protein encoded by a 3.2-kb cDNA, has been employed for gene editing in mdx mice to avoid the requirement for a dual-vector system . Electroporation has been used to deliver negatively charged DNA or mRNA into muscle cells , featuring an infinite self-renewal capacity, can be differentiated into myogenic lineages. However, iPSCs-derived myogenic progenitors could carry the risk of unlimited growth and teratoma development in vivo (Various cell types are candidates for transplantation and are being studied for DMD therapy. Satellite cells (myoblasts) are quiescent muscle stem cells that reside beneath the basal lamina . Upon mu in vivo .One of the most challenging hurdles for cell-based clinical applications centers on delivery. Although preclinical studies show promise , most syOn another note, cardiosphere-derived stem cells offer a transplantable cell type with therapeutic potential. Preliminary results from the randomized, phase I/II HOPE-Duchenne clinical trial (NCT02485938) revealed that the intra-coronary infusion of cardiosphere-derived cells was well tolerated and suggested a positive effect on upper limb and heart function for up to 12 months . FurtherDespite the numerous trials exploring potential therapeutics, there remains a dearth of effective treatments available for DMD patients. In this context, it is worth considering additional strategic approaches that target the primary defect of DMD: severe muscle membrane fragility. As discussed previously, as the primary pathophysiological defect in DMD is the marked susceptibility to contraction-induced membrane stress, a unique therapeutic approach is the use of synthetic membrane stabilizers to prevent muscle damage by directly stabilizing the dystrophin-deficient muscle membrane ; 2017.75-PPO30-PEO75, 8400 g/mol) is a non-ionic copolymer consisting of a triblock—a hydrophobic chain of poly(propylene oxide) (PPO) in the middle flanked by two hydrophilic poly(ethylene oxide) (PEO) chains on each side , P333 (PEO20–PPO54–PEO20), and P181 (PEO2–PPO30–PEO2), insert into the liposomal membrane and eventually lyse the cell  also showed a robust protective effect at lower concentrations against the intracellular enzyme lactate dehydrogenase release induced by hypoosmotic stress (75-PPO15) with a tert-butoxy end group (-C4) showed significant protection against lengthening contraction-induced force loss in mdx mice, whereas a hydroxyl end group (-H) did not show any protection . Further research to determine the optimal structure-function of synthetic membrane-protecting copolymers will be useful in seeking a full therapeutic effect in DMD.This section focuses on the genetic strategies related to the correction of or compensation for the lack of dystrophin via meaningful alternatives to direct dystrophin reconstitution. The advantage of dystrophin complementary approaches is that they may be applied to a number of MD patients, regardless of the type of mutation. Several pharmacological strategies to slow down the disease progress, such as those reducing inflammation or fibrosis, are also in development, and these have been reviewed by different groups  and willUtrophin is a structural and functional autosomal paralog of dystrophin encoded by the UTRN gene . This laUtrophin content is increased at the sarcolemma of skeletal muscle in DMD and BMD patients compared to healthy individuals . The basUtrophin is expressed from at least two promoters, known as promoters A and B . Expressin vivo. The TAT protein transduction domain of the human immunodeficiency virus (HIV1) has been used to generate chimeric protein microutrophin (TAT-μUtr) and utrophin protein (TAT-Utr)  . PreclinTAT-Utr) . FurtherTAT-Utr) . One advTAT-Utr) . A proteUtrophin, while highly similar to dystrophin, does not share all of the dystrophin binding domains. Therefore, it may not be able to fully substitute for dystrophin. Nonetheless, utrophin upregulation has been shown as a promising therapeutic approach, applicable to all DMD and BMD patients, irrespective of their dystrophin mutation. Many pathways involved in utrophin expression are currently being investigated. However, the amount of utrophin required by dystrophic patients to achieve a relevant clinical benefit remains to be determined. Further research is required before utrophin therapies can apply to DMD and BMD patients.The α7β1 integrin protein is the predominant laminin-binding integrin in skeletal, cardiac, and vascular smooth muscle . The intmdx/utrn−/−) alleviates pathology, extends viability and mobility, and reduces kyphosis. In addition, increased expression of α7 in mdx mice significantly protected against loss of force, reversed muscle pathology, and stabilized sarcolemmal integrity . Some of these approaches have received regulatory approval in the USA, Europe, and Japan /kg) and a higher dose of 2 × 1014 vg/kg. Early data from five of six boys showed some evidence of improvement (or at least no decline) in the NorthStar Ambulatory Assessment (NSAA), compared with participants given a placebo during previous clinical trials. Side effects and serious adverse events were reported in some patients. Tragically, a death of a patient was reported, which led to the trial being put on hold due to questions about Pfizer’s potency tests. Recently, the FDA announced the removal of the clinical hold after the company had addressed the agency’s request regarding a potency assay and implementation of a protocol amendment.Clinical trial PF-06939926 is an AAV9-mediated transfer of microdystrophin currently tested in a Pfizer Phase 1b open-label clinical trial evaluating dose, safety, and tolerability of a single IV infusion of microdystrophin in ambulatory and non-ambulatory DMD patients (NCT03362502 and NCT04281485) . PF-0693SGT-001, an AAV9-mediated transfer of microdystrophin from Solid Biosciences, is also being evaluated in a phase I clinical trial, IGNITE DMD (NCT03368742) . After aOverall, to date, clinical trials have accrued preliminary results that have unfortunately demonstrated a lack of clinically meaningful success and missed milestones for efficacy . Thus faThere is a clear need for caution as several serious treatment-related adverse events have been reported. Hepatic transaminitis, classed as severe, was reported in participants in trials in DMD, following SGT001  and rAAVDMD.Consequently, other approaches aim to produce nearly full-length dystrophin by targeting only the region that encompasses the mutation in an effort to bypass the genetic defect. During the last decade, numerous approaches have been developed to directly correct genetic defects at the RNA level , as discin vivo using the mdx mouse model (https://www.ema.europa.eu/en/medicines/human/EPAR/translarna) for DMD ambulatory patients and those aged ≥2 years  is an orally bioavailable small molecule developed by PTC Therapeutics designed to enable the formation of a functioning protein in patients with genetic disorders caused by a nonsense mutation . Atalurese model . Howeverse model . Nonethese model  and in mse model , Atalure≥2 years . To date≥2 years . In both≥2 years . However≥2 years . Unfortu′-O-methyl-modified RNA, phosphorodiamidate morpholino oligomers (PMO), and tricycloDNA antisense. All of them have been used in vitro and in vivo in mouse and dog models and demonstrated efficient skipping that resulted in histology and functional improvements (A number of chemical versions of AONs exist to be applied for exon-skipping, including 2ovements , as prevovements  (Mendellovements .Regardless, the drug was approved, and efforts are underway to develop more effective oligonucleotide therapies. Tissue penetration and longevity of PMOs have remained an ongoing concern. To address these shortcomings, other delivery systems for AONs are currently being investigated to identify the modifications that can optimize cellular penetration and systemic safety, with a major focus on PPMOs . AdditioThe identification of the dystrophin gene as the cause of DMD has led to improved diagnosis while providing deep insights into the biochemistry and cellular physiology of the striated muscle cytoskeleton-membrane-ECM interface. The preceding decades have been marked by careful mechanistic studies aiming to tease apart the molecular processes disrupted by dystrophin loss in an effort to understand and correct the underlying pathology of DMD. These insights have greatly impacted DMD diagnosis and care, including the opportunity to develop novel, personalized, and effective therapeutic strategies to prolong and improve the quality of life of patients with DMD.The future of heart/skeletal muscle therapy in DMD will likely require a combination of approaches to achieve optimal outcomes, including a therapeutic approach to correct the genetic defect and target the secondary effects caused by the lack of dystrophin. Advances in technology have made many of the problems with therapeutic approaches more tractable. Despite that, two crucial and challenging issues shared by all new drugs are delivery and targeting. Finding an appropriate vehicle is critical to consistently reach the proper drug target at minimal, effective dosing. This is especially significant considering the enormous healthcare costs associated with these proposed therapies. Nonetheless, there is little doubt that although a cure remains elusive, there has been a rapid expansion in the number of treatments entering clinical trials that have the potential to provide a significant clinical impact on the quality of life for DMD patients. This turning point in the development of DMD therapies marks the beginning of a new mission for correcting monogenic muscular disorders. In turn, these approaches set an example for research progress for other related disorders.


Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome is a severe cutaneous drug reaction characterized by a skin rash, eosinophilia, atypical lymphocytosis, and involvement of multiple organs. The mortality rate of DRESS syndrome is moderate, and prompt diagnosis and treatment are essential. When DRESS syndrome is presented with significant hypereosinophilia (HE), it should be differentiated from other conditions that can cause HE through a comprehensive approach to diagnostic evaluation. Amoxicillin has been well-documented as a potential cause of DRESS syndrome. It is important to note that amoxicillin can trigger DRESS syndrome in patients who already have a known allergy to sulfasalazine, as well as when it is administered with a beta-lactamase inhibitor such as clavulanic acid. Here, we describe a case of amoxicillin alone-induced DRESS syndrome associated with significant reactive HE. A 39-year-old female presented with three days of shortness of breath, fatigue, facial swelling, and a generalized maculopapular skin rash. The patient endorsed taking amoxicillin two to three weeks prior to the presentation. Diagnostic tests revealed HE, significant generalized lymphadenopathy on computed tomography (CT) scans of the neck and abdomen, and bilateral interstitial infiltration on a CT scan of the chest suggestive of eosinophilic infiltration. Based on the European Registry of Severe Cutaneous Adverse Reactions (RegiSCAR) scoring system, the case was categorized as "probable" DRESS syndrome related to amoxicillin. High-dose steroids were initiated as the treatment of choice for suspected DRESS syndrome. Other potential causes of HE were investigated and ruled out. The patient showed significant clinical improvement, with the normalization of absolute eosinophil count (AEC) and complete resolution of lung infiltrates on a repeat CT scan of the chest. The case highlights the importance of conducting a comprehensive diagnostic evaluation to differentiate DRESS syndrome from other causes of HE when significant HE is present. Prompt treatment with high-dose steroids is essential in managing patients with severe symptoms associated with DRESS syndrome. It is crucial to consider amoxicillin as a potential trigger for DRESS syndrome, even when there is no history of sulfasalazine allergy or concurrent administration of a beta-lactamase inhibitor. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome is a delayed, potentially fatal multiorgan systemic idiosyncratic drug reaction, characterized by a maculopapular rash, fever, lymphadenopathy, and involvement of multiple organs -5. EosinThis article was previously presented as a meeting abstract at the 2023 NYACP Resident/Fellow and Medical Student Forum on May 12, 2023.A 39-year-old woman with a past medical history of migraine presented with three days of malaise, fever, shortness of breath, chest pain, and generalized maculopapular morbilliform skin lesions. Initial vital signs revealed a heart rate of 115/minute and a respiratory rate of 30/minute while the body temperature and oxygen saturation were within normal limits. The physical exam findings of bilateral crackles on lung auscultation and regular tachycardia further suggested possible underlying respiratory and cardiovascular involvement. The presence of diffuse maculopapular skin lesions on the extremities, back, and trunk was also significant. Initial laboratory studies  lung angiogram was performed to rule out pulmonary embolism, which was negative but remarkable for trace pericardial effusion and diffuse bilateral ground glass interstitial opacities indicating lung involvement. Figure . The eleThe patient was initially admitted for possible multifocal bacterial pneumonia. Ceftriaxone and azithromycin were started empirically then switched to vancomycin and piperacillin-tazobactam on admission day 4 since the patient was clinically deteriorating. CT chest and CT abdomen and pelvis were performed for further evaluation. Slight interval resolution in lung infiltrations was seen on the follow-up CT chest Figure . The sigDespite antibiotics, the patient’s WBC trended up to 28K/uL with AEC of 15,000 cells/mL on admission day 6, and she complained of neck pain and itchy skin. A physical exam showed noticeable tender cervical lymphadenopathy and faint pink erythematous scattered macules coalescing into patches mainly on the right lower leg Figure . PeripheThe decision to administer steroids was made after conducting an extensive workup to rule out other potential causes of HE. Referrals were made to the pulmonary and hematology-oncology services for further evaluation. After initiating steroid therapy, the patient's symptoms improved, and her AEC normalized within six days of starting treatment. Subsequently, the patient was discharged from the hospital on a steroid taper regimen and scheduled for follow-up appointments with multiple specialties. The above hospital courses are described in Figure During the follow-up period, the patient remained clinically stable, and a repeat CT scan of the chest showed complete resolution of bilateral lung infiltration Figure . The resDrug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a delayed, infrequent, potentially life-threatening idiosyncratic drug reaction ,2. It haThe patient also presented with HE, according to its definition Table  6], eve, eve6], DRESS syndrome associated with significant HE requires exclusive diagnosis by comprehensive investigation of other causes of HE Table  6]. Imm. Imm6]. The extensive workup came back inconclusive except for high levels of IG (immunoglobulin) E and polyclonal gammopathy on serum protein electrophoresis (SPEP). IgE levels are typically elevated in allergic reactions like type 1 hypersensitivity, lymphoid-HES (LHES), EGPA , and some immunodeficiencies associated with eosinophilia  . The patBased on the comprehensive workup results, clinical correlations, and significant improvement with steroids, it is concluded that the patient likely had amoxicillin-induced DRESS syndrome presenting as reactive hypereosinophilia (HE). Close monitoring of the patient's condition is necessary, as a single negative test result cannot completely rule out other potential differential diagnoses. It is important to note that penicillins, including amoxicillin, can elicit hypersensitivity reactions of various types, ranging from type 1 to type 4 . In thisDistinguishing DRESS syndrome presenting as reactive HE from other disorders, including other causes of reactive HE, different variants of HE, and HES, is crucial. A thorough diagnostic evaluation is necessary to determine the underlying etiology and guide appropriate treatment. Prompt empirical treatment with high doses of steroids is essential for patients with potentially life-threatening symptoms, even before the exact cause is determined. This immediate treatment can help mitigate the severe manifestations of DRESS syndrome. However, it's important to continue investigating other potential causes of HE to ensure appropriate management tailored to the specific underlying condition. Clinicians should maintain a high index of suspicion for DRESS syndrome and be aware that amoxicillin alone can induce DRESS, independent of the role of beta-lactamase in triggering the syndrome. This highlights the importance of considering amoxicillin as a potential culprit in cases of suspected DRESS syndrome. Long-term monitoring is necessary for the development of autoimmune sequelae, as patients with DRESS syndrome are at risk of developing such complications. Strict avoidance of the offending drug and any cross-reacting drugs is crucial to prevent further episodes of DRESS syndrome or exacerbation of symptoms. Education and patient awareness regarding drug allergies, avoidance of specific medications, and recognition of potential symptoms of DRESS syndrome are important aspects of long-term management.


Lung cancer is the most frequently diagnosed cancer overall and the deadliest cancer in North America. Early diagnosis through current bronchoscopy techniques is limited by poor diagnostic yield and low specificity, especially for lesions located in peripheral pulmonary locations. Even with the emergence of robotic-assisted platforms, bronchoscopy diagnostic yields remain below 80%.in situ single-point fingerprint . Biomolecular information was extracted from the fingerprint spectra to identify biomolecular features that can be used for cancer detection.Supervised machine learning models were trained using leave-one-patient-out cross-validation, showing lung cancer could be detected with a sensitivity of 94% and a specificity of 80%.This proof of concept demonstrates fingerprint Raman spectroscopy is a promising tool for the detection of lung cancer during diagnostic procedures and can capture biomolecular changes associated with the presence of cancer among a complex heterogeneous background within less than 1 s. The technique was also developed to provide fine-needle biopsies and diagnosis of early-stage cancer when standard imaging tests cannot confirm that a pulmonary nodule is benign. Endoscopic approaches have traditionally been limited to large and/or central lung nodules, often prohibiting access to smaller peripheral pulmonary lesions. In those cases, image-guided trans-thoracic needle biopsies can be used despite higher complications rates. Image-guided trans-thoracic needle biopsies use images, such as computed tomography (CT), fluoroscopy—and sometimes ultrasound or magnetic resonance imaging—to help guide the interventional radiologist’s instruments to the site of the abnormal growth. Since most lung nodules are in the lung periphery, new methods were needed to address the technical challenges related to the endoscopic navigation of small peripheral airways.Advances in bronchoscopy procedures using robotic technology improved diagnostic procedure accuracy, allowing real-time visualization of the bronchial tree deep into peripheral lungs.,–Despite impressive technological advances, current lung biopsy methods suffer from limitations, including low diagnostic yields and poor specificity.in situ use during diagnostic procedures as it is non-destructive and leaves tissue unmodified after analysis.,Thus, procedures designed to improve early diagnosis of lung cancers could greatly benefit from an adjunct tool capable of providing non-destructive, spatially precise, and real-time identification of cancerous tissue with high sensitivity and specificity. Raman spectroscopy is a molecular imaging technique that can reliably detect a range of biological indicators of cancer without the need for any labeling or contrast agents. Relying on the intrinsic inelastic light scattering properties of tissue, it is well suited to intraoperative in situ detection of high-grade dysplasia and in situ carcinoma—in 80 patients—with 90% sensitivity and 65% specificity. The intra-procedural Raman spectroscopy catheter that was used by the Zeng group relied on high wavenumber spectra  prior to each measurement. The system response was characterized using the fluorescence spectrum of a standard reference material . For each measurement, the probe was placed in contact with the specimen and a dark count measurement taken with the laser off (integration time of 50 ms). Then, a series of 10 repeat Raman measurements were acquired with an integration time of 75 ms. The laser power was manually adjusted for each measurement up to 150 mW (at the tip of the probe) to optimize the overall photon counts while ensuring no camera saturation resulted. After each measurement, a collocated biopsy sample was harvested for histopathology analysis. For each patient, the surgeon identified areas of normal/benign and cancer/necrotic tissue; up to 10 measurements were done in normal/benign and cancer/necrotic tissue, for a maximum of 20 measurements per patient. A biopsy sample was harvested co-located with the spectroscopy measurement. The samples were formalin-fixed and paraffin-embedded and hematoxylin & eosin (H&E) stained for diagnostic confirmation by a pathologist.Recruited patients were men (80%) and women (20%) with primary lung cancer undergoing thoracotomy. Each patient was monitored by the CHUM Ethics Committee. The cohort included 10 patients with different cancer types or grades and for whom surgery was the first line of treatment, with absence of neoadjuvant therapy. Demographic and clinico-pathological details relating to the patient cohort are reported, including smoking habits, age, sex, tumor localization, cancer type, and pathological stage . The RamA total of 197 spectral fingerprints  were acquired. Each spectrum was correlated with the correspondent histopathological characteristics: normal lung or benign tissue (emphysema and bronchiolitis); cancer  or necrosis . SeveralThe quality factor (QF) metric was then computed from each resulting normalized spectrum.y images . None ofSupplementary Material] or only data with ,Two machine learning models were then developed for the detection of cancer/necrosis from normal/benign tissue, either using the whole dataset [97 cancer/necrosis samples and 100 normal/benign samples  with high spectral quality. This will allow the use of many features from the fingerprint Raman spectra toward the development of generalizable models tested on independent hold-out datasets. Careful study designs will be required to ensure models can be trained from data fully capturing the heterogeneity of the normal/benign backgrounds to minimize the number of false positives. This approach could revolutionize robotic-assisted bronchoscopy, effectively providing the means to improve diagnostic yields by eliminating non-diagnostic specimens  and diminishing the vulnerability to CT-to-body divergence.Click here for additional data file.


In a recent paper published in Nature Immunology, Ding et al. provided new insights into the mechanism of how trained innate immunity could eradicate cancer. The authors demonstrated that yeast-derived whole beta-glucan particles (WGP) increased the responsiveness of lung interstitial macrophages to tumor-derived factors associated with the subsequent inhibition of tumor metastasis through enhanced cytotoxicity to cancer cells. The authors identified the metabolic sphingolipid–mitochondrial fission axis in WGP-trained macrophages as the key pathway responsible for this phenomenon and categorized it as a mechanism of trained innate immunity .Traditionally, the innate and adaptive immune systems are differentiated by their specificity and memory capacity. For a long time, it has been assumed that immunological memory is an exclusive hallmark of the adaptive immune response. On the other hand, innate immune cells have not been seen as cells that can retain a memory phenotype. In recent years, however, this paradigm has shifted: emerging evidence suggests that certain microbial stimuli and endogenous ligands induce durable changes in the function of innate immune cells that increase their responsiveness upon secondary stimulation. This process has been termed “trained innate immunity” or “trained immunity” . After tMycobacterium bovis, and fungal beta-glucans from Candida albicans, Trametes versicolor or Saccharomyces cerevisiae. Trained innate immunity has been explored in the treatment of infectious and inflammatory diseases, whereas enabling trained immunity as a therapeutic strategy for cancer has only recently emerged. For instance, BCG vaccination has been shown to have antitumor effects on bladder cancer, melanoma, lymphoma, and leukemia. Although beta-glucan has also been reported to induce an antitumor effect on primary subcutaneous tumors [Trained innate immunity has been primarily described in monocytes and macrophages  and lates tumors –7, the eLA1 mice with spontaneous development of lung cancer. Interestingly, WGP-mediated training and metastasis control were explicitly associated with the functions of lung interstitial macrophages originating from the bone marrow but not alveolar macrophages and did not depend on neutrophils or B and T cells, which has been elegantly demonstrated by using neutralizing and depletion approaches in several tumor models. However, WGP-mediated training enhanced T-cell responses in tumor-bearing mice due to a reduced proportion of regulatory T cells, decreased frequencies of PD-1-positive CD4+ and CD8+ T cells and high production of T-cell-derived TNF-α. In addition, adoptive transfer of in vitro WGP-trained bone marrow-derived macrophages (BMDMs) into naive mice that were subsequently transplanted with lung cancer cells significantly reduced the tumor burden in lungs, suggesting a potential use of trained BMDMs as adoptive cell therapy in cancer. To further test potential clinical implications, the authors used multiple metastatic disease mouse models and demonstrated that melanoma and breast cancer metastasis in lungs and the dissemination of lymphoma cells in liver were substantially reduced in WGP-treated mice, emphasizing the systemic benefit of trained immunity to effectively control lung tumorigenesis and metastasis (Fig. The group of Jun Yan from the University Louisville School of Medicine performed a comprehensive study to investigate trained immunity induced by yeast-derived WGP in macrophages and its potential therapeutic relevance for metastatic disease . The autDing et al. performed a very detailed search for the molecular mechanism underlying WGP-mediated training in macrophages. They observed that WGP increased the production of TNF-α in lung interstitial macrophages and enhanced their phagocytic capacity and cytotoxicity to tumor cells. Interestingly, previously published pathways involved in inducing trained immunity, including the mTOR/HIF-1α or Nlrp3 inflammasome and IL-1β/IL-1R pathways , did notIn summary, Ding et al. discovered a novel mechanism for trained immunity in macrophages induced by WGP with implications for the treatment of primary and metastatic tumors. This strategy might be suitable for patients who require adjuvant therapies to prevent the occurrence of lung metastasis. Currently, however, it remains unclear whether WGP-trained immunity can also be effective against the dissemination of cancer cells in other organs. Given the numerous and diverse sources and processing of beta-glucan, one of the greatest expected challenges is the standardization of the molecules suitable for clinical use. On the other hand, increased mitochondrial fission and respiratory capacity can be achieved by specific drugs . Moreove


We present an experimental study investigating the solvent-dependentdynamics of a 9,10-bis(phenylethynyl)anthracene monomer, dimer,and trimer. Using transient absorption spectroscopy, we have discoveredthat triplet excited state formation in the dimer and trimer moleculesin polar solvents is a consequence of charge recombination subsequentto symmetry-breaking charge separation rather than singlet fission.Total internal reflection emission measurements of the monomer demonstratethat excimer formation serves as the primary decay pathway at a highconcentration. In the case of highly concentrated solutions of thetrimer, we observe evidence of triplet formation without the priorformation of a charge-separated state. We postulate that this is attributedto the formation of small aggregates, suggesting that oligomers mimickingthe larger chromophore counts in crystals could potentially facilitatesinglet fission. Our experimental study sheds light on the intricatedynamics of the 9,10-bis(phenylethynyl)anthracene system, elucidatingthe role of solvent- and concentration-dependent factors for tripletformation and charge separation. These requirements includephotostability to ensure the longevity of the material under prolongedlight exposure as well as energy alignment of the resulting tripletstates with the bandgap of the photovoltaic device to enable efficientcharge separation and collection. Meeting these criteria is crucialfor harnessing the full potential of SF in practical applications.One molecule that exhibits promising characteristics to fulfill theserequirements is 9,10-bis(phenylethynyl)anthracene (BPEA). BPEAis a robust and photostable industrial dye with a triplet energy of1.2–1.3 eV,4 and it has demonstratedthe ability to undergo SF both in thin films and in nanoparticles.8 However, studies using molecular dimers mimicking the slip-stackednature of solid-state packing have suffered from low yields of SFdue to competing excimer formation.9 SFin BPEA and other materials has been shown to be highly sensitiveto the interchromophore orientation and distance.12 Because calculations suggest that the basic energeticrequirement E(S1) ≥ 2E(T1)13 for SF is fulfilled for BPEA,it is possible that there are dimer designs that can suppress theexcimer decay pathway and promote SF. Furthermore, if the calculationsare underestimating the triplet energy and SF is slightly endothermic,it might be possible to enhance the rate of SF by increasing the numberof chromophores as has been seen for other endothermic SF systems.15Singlet fission (SF) is a multipleexciton generation process in which a singlet excited state sharesits excitation energy with a neighboring ground state molecule toproduce two triplet excited states.Herein, we have synthesized and investigated a BPEA dimer(BPEAdim)and trimer (BPEAtri) connected in the meta position of the centralphenylene unit. The molecular structures are shown in Supporting Information for details). Substitution at the central benzene or peripheralphenyl moieties of BPEAdim and BPEAtri, respectively, was necessaryto provide solubility and facilitate purification. The m-phenylene-linked BPEAdim was synthesized based on a two-step procedurefrom known building blocks. The precursor to BPEAdim, acetoxy-protecteddimer BPEA-Ac  instrument . Initially,the S1 absorption, centered at 560 nm, evolves within thefirst few picoseconds, corresponding to excited state planarizationof the molecule. After planarization, the spectral features uniformlydecay across the entire spectral range with a lifetime of 3.2 ns,corroborating well the results from TCSPC (Table S3). The fsTA spectra of BPEAdim in THF have been analyzed using atwo-component sequential decay model shown in the inset of 17 we can extract the spectral components and kinetics,as illustrated in Section S4) and previous reportson BPEA dimers, we assign this new species as the CSS. Note that thespectroscopic signature of the CSS is a combination of the spectraof the radical anion and cation. For BPEAdim, however, the spectrumof the radical cation has very low molar absorptivity in the visibleregion compared to the anion . As the CSS state decays, a fourth state becomes discernible at490 nm. This state exhibits a strong resemblance to the sensitizedtriplet excited state and has not been reported in previous studieson BPEA dimers.18 It is possible that thistriplet has eluded detection due to the use of less polar solventsor, alternatively, to limitations in the length of delay stages, asthe signal becomes apparent only at longer time delays. The fsTAspectra of BPEAdim in 23 In contrast, the microsecond lifetime of the triplet excited stateobserved in our analysis , coupled with the emergenceof the signal after the decay of the CSS, suggests the formation ofone independent triplet excited state per molecule through chargerecombination via CSS. Our findings thus support the hypothesis thatthe triplet formation is not a result of SF.24 Triplet formation within organic molecules via a CSS commonly ensuesthrough one of two distinct mechanisms: spin–orbit charge transferintersystem crossing (SOCT-ISC) and radical-pair intersystem crossing(RP-ISC).27 SOCT-ISC entails direct conversion of the initial 1CSS into the T1 state, involving a reverse electrontransfer and a spin inversion process. This phenomenon is notablyamplified when the constituent subunits assume a nearly perpendicularalignment. Such an orientation facilitates compensation for changesin electron spin angular momentum during ISC through adjustments inmolecular orbital angular momentum. This intricate alignment is particularlyevident in closely spaced dyads, where steric hindrance between subunitsenforces an orthogonal arrangement, as observed in dyads linked bya single C–C bond.29 In contrast, the RP-ISCmechanism involves the emergence of an intermediate triplet charge-transferstate (3CSS) prior to charge recombination, leading toeither the triplet state or the ground state. This mechanism is moreprevalent in electron donor–acceptor dyads characterized byweak electronic coupling between their donor and acceptor subunitsdue to considerable spatial separation .This separation results in a minimal energy difference between 1CSS and 3CSS. Notably, certain studies posit thecoexistence of both mechanisms.30 Distinguishingbetween SOCT-ISC and RP-ISC through fsTA spectroscopy proves challengingbecause radical pairs are central to both processes, yielding closelyresembling optical spectral signatures. Consequently, we can onlyengage in qualitative speculation regarding the mechanism underlyingour observations. The rate of triplet excited state formation seemsto align with previous RP-ISC studies, as spin–orbit coupledmechanisms generally exhibit larger rates.31 Additionally, the interchromophore distance within BPEAdim exceeds10 Å, further reinforcing the alignment with the RP-ISC mechanism.The relatively slow charge recombination rate toward the ground state,in comparison to triplet formation, may be explicable through thesubstantial negative Gibbs free energy shift accompanying ground staterecombination. This scenario potentially gives rise to behavior consistentwith the Marcus inverted region characteristics.The emission spectra of BPEAdim and BPEAtri closelyresemble thatof BPEAmono in a dilute solution 1. Notablstrument 2b. To gastrument S4. Initistrument S4. Initistrument S4. Initistrument S4. Initistrument S4. Initistrument S4. Initi1 absorption in BPEA thin films.5 Based on this observation, it is possible thatthe triplet formation observed for BPEA thin films could originatefrom a similar charge recombination process as we have proposed inthe present study and not from SF, as previously proposed.5 The mechanism of charge recombination to formthe triplet excited state has been proposed in other thin film systems,such as in the indigo derivative cibalackrot, in which case transientintermediates with charge-transfer character are also observed priorto triplet formation.32 It is also worthnoting that the interpretation of the spectral feature as a shiftedand broadened S1 absorption in BPEA thin films could beentirely accurate, given that the excited state absorption of variouscompounds, including polyacenes, are known to differ significantlybetween solution and film states.37It is noteworthy that the CSS observed in our studyhas a spectroscopicsignature that is similar to what was previously attributed to a shiftedand broadened SSection S6. BPEAtri was not investigated in ACNdue to limited solubility.) Consequently, it seems that an additionalBPEA moiety is insufficient to drive the seemingly slightly endothermicSF of BPEA. It is possible that a larger oligomer or a linear arrangementof chromophores could enhance the entropic driving force(s), as observedin other endothermic SF systems.15 In fact, fsTAmeasurements in highly concentrated solutions (25 mM) of BPEAtri inTHF reveal a broad excited state absorption feature at 500 nm duringlater time delays that matches the sensitized triplet spectra . Although the absorption spectrumshows no evidence of significant scattering from aggregates, we positthat smaller aggregates may form, and these aggregates could facilitateSF. However, there is also evidence of excimer formation for BPEAtrias the emission lifetime depends on the probing wavelength, indicatingthe presence of at least two emissive species, similar to that observedfor BPEAmono .The photophysical behavior of BPEAtri appearsto be very similarto that of BPEAdim, and SF is not detected in dilute solution, regardlessof solvent polarity. (Further details are provided in In this study, we investigatedthe photophysical properties ofa BPEA monomer, dimer, and trimer. Our findings show that in highlyconcentrated solutions, BPEAmono exhibits excimer formation, and SFis not observed. The photophysics of BPEAdim and BPEAtri are primarilygoverned by symmetry-breaking charge separation, which outcompetesSF. Triplet excited states are, however, generated by charge recombination,where the CSS acts as an intermediate. Interestingly, there are indicationsof SF in highly concentrated solutions of the trimer as triplet excitedstate absorption is discernible without prior formation of the charge-separatedstate. This suggests that increasing the number of chromophores withlarger oligomers, mimicking the larger chromophore count in crystals,may enhance the rate of SF for BPEA and potentially for other SF systemsin solution.


On December 29, 2021, during the delta wave of the Coronavirus Disease 2019 (COVID-19) pandemic, the stock of premanufactured solutions used for continuous kidney replacement therapy (CKRT) at the University of New Mexico Hospital (UNMH) was nearly exhausted with no resupply anticipated due to supply chain disruptions. Within hours, a backup plan, devised and tested 18 months prior, to locally produce CKRT dialysate was implemented. This report describes the emergency implementation and outcomes of this on-site CKRT dialysate production system.This is a single-center retrospective case series and narrative report describing and reporting the outcomes of the implementation of an on-site CKRT dialysate production system. All adults treated with locally produced CKRT dialysate in December 2021 and January 2022 at UNMH were included. CKRT dialysate was produced locally using intermittent hemodialysis machines, hemodialysis concentrate, sterile parenteral nutrition bags, and connectors made of 3-D printed biocompatible rigid material. Outcomes analyzed included dialysate testing for composition and microbiologic contamination, CKRT prescription components, patient mortality, sequential organ failure assessment (SOFA) scores, and catheter-associated bloodstream infections (CLABSIs).Over 13 days, 22 patients were treated with 3,645 L of locally produced dialysate with a mean dose of 20.0 mL/kg/h. Fluid sample testing at 48 h revealed appropriate electrolyte composition and endotoxin levels and bacterial colony counts at or below the lower limit of detection. No CLABSIs occurred within 7 days of exposure to locally produced dialysate. In-hospital mortality was 81.8% and 28-day mortality was 68.2%, though illness severity was high, with a mean SOFA score of 14.5.Though producing CKRT fluid with IHD machines is not novel, this report represents the first description of the rapid and successful implementation of a backup plan for local CKRT dialysate production at a large academic medical center in the U.S. during the COVID-19 pandemic. Though conclusions are limited by the retrospective design and limited sample size of our analysis, our experience could serve as a guide for other centers navigating similar severe supply constraints in the future.The online version contains supplementary material available at 10.1186/s12882-023-03260-9. The Coronavirus Disease 2019 (COVID-19) pandemic has profoundly impacted healthcare delivery worldwide. The combination of the immense strain of extreme patient volumes and repeated pandemic-related disruptions in vital supply chains has posed major challenges to healthcare systems, including challenges in the ability to provide kidney replacement therapy (KRT) . At the At the University of New Mexico Hospital (UNMH), these challenges culminated in late December 2021, as the delta wave of the COVID-19 pandemic was transitioning to the omicron wave in New Mexico . On the This is a single-center retrospective case series and narrative report describing and reporting the outcomes of the implementation of an on-site CKRT dialysate production system. UNMH is a publicly funded, tertiary care center serving as the primary safety net hospital for the state of New Mexico, providing care to a largely medically underserved population . It has All adults treated with locally produced CKRT dialysate were identified using fluid inventory records generated during the period of program operation, December 30, 2021, to January 11, 2022.Outcomes include results of testing of dialysate samples at 24 and 48 h after fluid production, rates of catheter-associated bloodstream infection (CLABSI) within 7 and 28 days of exposure to locally produced dialysate, and in-hospital mortality and mortality within 28 days of exposure.Testing of CKRT dialysate samples for composition and microbiologic contamination was performed using the same procedures used for surveillance of our acute dialysis program, including shipping specimens at room temperature to a reference laboratory  where testing occurs approximately 24 h after collection. Endotoxin units (EUs) were measured using a kinetic quantitative chromogenic test and 48-h colony forming units (CFUs) were measured on trypticase soy agar using the heterotrophic plate count method, with lower limits of detection of 0.010 EU/mL and 2 CFUs/mL, respectively.CLABSI cases were independently identified by our institutional healthcare-associated infection surveillance program and corroborated with the electronic health record (EHR). All other data were obtained from the EHR and fluid inventory records, with follow-up performed through the end of each index admission.Given the high mortality associated with AKI requiring KRT in the ICU –13, espeContinuous variables were tested for normality by histogram visualization and the Shapiro–Wilk test. Continuous variables with normal distribution are presented as mean ± standard deviation whereas those that are not normally distributed are presented as median [interquartile range]. Categorical variables are presented as frequencies and proportions. Data compilation and statistical analyses were performed using Excel  and R version 4.2.2 .In July 2020, the nephrology division at UNM developed a backup plan for CKRT provision using locally generated fluid based largely on protocols previously published in the medical literature , 18 and After being informed on the morning of December 29, 2021, that UNMH had less than a 24-h supply of premanufactured CKRT solutions, the on-service medical ICU and nephrology consult attendings, acute dialysis program medical and nursing directors, nephrology division leadership, UNMH ICU nursing leadership, and UNMH pharmacy leadership had a series of impromptu phone and text discussions about options for managing the shortage. After considering alternatives, such as converting entirely from CKRT to sustained low-efficiency dialysis (SLED) and the use of lactated Ringer’s solution as CKRT solution [Additional dialysis unit staff were called into service. Three IHD machines in the pediatric inpatient hemodialysis unit, which is closer to the adult ICUs and typically runs at lower capacity than the adult hemodialysis unit, were commandeered. The first batch of dialysate was prepared and, after obtaining permission from hospital leadership and the UNMH COVID-19 Emergency Operations Committee, the first patient was transitioned from premanufactured CKRT solutions to locally produced CKRT dialysate later that afternoon. After observing the first patient for approximately an hour, the remaining six patients on CKRT were transitioned over to the new solutions. Given that our default CKRT prescription is usually continuous venovenous hemodiafiltration (CVVHDF) using approximately equal amounts of dialysate and replacement fluid, all patients were converted to prescriptions of equal total effluent dose using the locally produced fluid as dialysate only. As we follow the CKRT device manufacturer’s recommendation to infuse a minimum of 200 mL/h of fluid into the post-filter deaeration chamber to prevent clot formation in the chamber, we continued to run our machines in CVVHDF mode but with the bulk of therapy fluid run as dialysate and replacement fluid limited to 200 mL/h of post-filter saline or isotonic sodium bicarbonate. We opted, rather than adjusting the potassium concentration, to use our available supply of 3K hemodialysis concentrate and generate all CKRT dialysate with 3 mEq/L of potassium, unlike our default premanufactured solutions which have 4 mEq/L.A logistical system was rapidly devised and implemented which included nightly fluid inventory, coordinated by the nephrology division and performed at approximately 8–10 pm by the nightshift charge nurses in the three adult ICUs, using usage sheets transmitted by secure email and spreadsheets maintained by the nephrology division and acute dialysis staff  is technically not sterile, is not regulated by the FDA as a medication, and therefore may not be directly infused into patients . HoweverFinally, the use of IHD machines to generate CKRT dialysate is not an FDA approved procedure. Ultimately, we agree with the recommendation that centers that normally utilize premanufactured CKRT solutions should continue whenever possible to use such solutions during pandemic-related surges in patient volumes to minimize risk of errors .However, despite these notable caveats, this system allowed us to sustain our CKRT program for nearly two weeks despite the unexpected disruption in our supply of premanufactured CKRT solutions during a period in the pandemic when transferring these 22 extremely ill patients would have likely not proven feasible. Though this report has many inherent limitations and the specifics of our program may not be fully generalizable to other centers, this detailed description of our experience could prove useful to other institutions navigating similar disruptions to their CKRT fluid supply in the future.Additional file 1. Inventory.xlsx: CKRT dialysate inventory example.Additional file 2. Usage_sheet.docx: Daily MICU CRRT usage sheet.