Elevated Lactate Levels Research Articles

Synthesis of organic photothermal agents for combined photothermal/enzymatic dynamic therapy of breast cancer

Nanoparticle-based photothermal therapy is an effective treatment for superficial tumors. However, due to the highly heterogeneous nature of breast cancer, photothermal therapy (PTT) used alone was unable to achieve satisfactory therapeutic results. Therefore, combining PTT with other therapies is a promising strategy for tumor treatment. Inspired by the significant elevation of lactate levels at the tumor site, we prepared a novel nanocomposite therapeutic platform (PPy-LOX) for combined PTT and enzyme dynamic treatment (EDT) of breast cancer. In detail, Polypyrrole (PPy) nanoparticles were synthesized using a simple chemical oxygenation method and polyvinylpyrrolidone (PVP) was used as a surface linker to enhance its colloidal stability. Further, the loading of lactate oxidase (LOX) is accomplished by simple physical mixing. The in vivo and in vitro results demonstrated the excellent biocompatibility of the synthesized PPy-LOX NPs. More importantly, PPy-LOX NPs has excellent photothermal conversion (η = 29.9%) and lactic acid catalytic ability. On the one hand, the temperature increase induced by near-infrared light irradiation can cause apoptosis of tumor cells; on the other hand, LOX can catalyze the generation of hydrogen peroxide from excess lactate in the tumor microenvironment to induce oxidative stress to kill tumor cells. In conclusion, the combination of PTT and EDT can effectively kill tumor cells. This work provides new ideas on how to design rational nanotherapeutic systems by exploiting the tumor microenvironment.

Warburg-Effect Driven Lactic Acidosis Is Associated with Early Death in Patients with Lymphoma

Introduction: Lactic acidosis is a medical emergency and in most cases results from an imbalance between tissue oxygenation and oxygen demand (Type A). However, Type B lactic acidosis occurs in the absence of a recognizable impairment in systemic oxygen delivery, and is most commonly associated with drug or toxin ingestion, sepsis, severe nutritional deficits such as thiamine, and less commonly, malignancy. The capacity of shifting glucose metabolism to anaerobic pathway despite the presence of adequate oxygen, enhancing the rate of glucose uptake, accelerated glycolysis and hence producing more lactate, is a well-defined phenomenon in malignant cell metabolism, and is called the Warburg Effect (WE) or aerobic glycolysis. A systemic rise in lactate and lactic acidosis has been reported in hematologic malignancies and less commonly in solid tumors, and is thought to occur as a consequence of both increased production of lactate- reflecting high malignancy burden, and impaired lactate turnover or elimination by liver or kidney. Few case reports or series have demonstrated a possible correlation between early death and elevated lactate in patients with hematologic malignancy (Table 1). We aimed to characterize the incidence and clinical impact of Warburg-driven lactic acidosis on outcome including early death. Methods: A retrospective study of patients admitted to the haemato-oncology department in a large tertiary medical center between the years 2013- 2022, that presented with elevated lactate levels during the first week of admission. Patients with hematologic diseases other than lymphoma were excluded. Of 40 patients reviewed, 21 patients were excluded because of underlying hematological malignancy other than lymphoma. Medical records were retrieved and reviewed for a recognizable cause for elevated lactate, or non (assigned as the WE group). Early-death was defined as death of any cause within 4 weeks of admission. Results: Nineteen patients had lymphoma and elevated lactate levels within the first week of admission. Of these, 12 patients fulfilled the criteria for WE and 7 patients had their high lactate attributed to other causes such as hemorrhagic shock (n=1), sepsis (n=5) and concomitant metformin use (n=1). Median age among patients with WE was 72.5 years (range 66-86) with 41.6% (n=5) males. All but one had aggressive lymphoma. Diffuse Large B cell Lymphoma was the most frequent type (n=9) followed by T cell Lymphoma (n=2) and follicular lymphoma (n=1). Most patients had advanced disease (Stage III-IV in 75%) and the median International Prognostic Index (IPI) of the patients was 4 (range 3-5). The median lactate level was 31.5 mg/dL (range 25-64; with upper limit of normal value-20 mg/dL). Two patients received thiamin therapy once WE was recognized. Early-death rate was 75% (9 patients) among patients with WE. The established cause of death in this population was: sepsis (n=3), DIC (n=1), uremia and multi organ failure (n=2) and respiratory failure due to lung infiltration by lymphoma (n=3). Both steroid and chemotherapy were initiated earlier in surviving patients as compared to those who died early (within 4 weeks of admission); in surviving patients, chemotherapy was initiated at a median of 3 days before first elevated lactate was detected (range (-)7-1), and steroids at median of 3 days before first elevated lactate was detected, while in those who died early, chemotherapy was initiated at median of 5 days after first elevated lactate was detected (range (-)2-18) and steroids at median 1 day after first elevated lactate (p=0.29 and 0.05 for steroids and chemo, respectively). (Table 2). Conclusion: Warburg driven lactic acidosis is a marker of ‘acute cancer’ in lymphoma patients and is associated with a very high mortality rate. Early recognition of this very high-risk clinical scenario is of utmost importance and should prompt immediate anti-lymphoma therapy that may improve outcome.

Optimization of the flip angles of narrow-band editing pulses in J-difference edited MRS of lactate at 3T.

Application of highly selective editing RF pulses provides a means of minimizing co-editing of contaminants in J-difference MRS (MEGA), but it causes reduction in editing yield. We examined the flip angles (FAs) of narrow-band editing pulses to maximize the lactate edited signal with minimal co-editing of threonine. The effect of editing-pulse FA on the editing performance was examined, with numerical and phantom analyses, for bandwidths of 17.6-300 Hz in MEGA-PRESS editing of lactate at 3T. The FA and envelope of 46 ms Gaussian editing pulses were tailored to maximize the lactate edited signal at 1.3 ppm and minimize co-editing of threonine. The optimized editing-pulse FA MEGA scheme was tested in brain tumor patients. Simulation and phantom data indicated that the optimum FA of MEGA editing pulses is progressively larger than 180° as the editing-pulse bandwidth decreases. For 46 ms long 17.6 Hz bandwidth Gaussian pulses and other given sequence parameters, the lactate edited signal was maximum at the first and second editing-pulse FAs of 241° and 249°, respectively. The edit-on and difference-edited lactate peak areas of the optimized FA MEGA were greater by 43% and 25% compared to the 180°-FA MEGA, respectively. In-vivo data confirmed the simulation and phantom results. The lesions of the brain tumor patients showed elevated lactate and physiological levels of threonine. The lactate MEGA editing yield is significantly increased with editing-pulse FA much larger than 180° when the editing-pulse bandwidth is comparable to the lactate quartet frequency width.

Hyperlactatemia in patients undergoing pulmonary endarterectomy with deep hypothermic circulatory arrest: Risk factors and its effects on the outcome.

To determine the risk factors of hyperlactatemia in pulmonary endarterectomy (PEA) surgery and assess whether elevated blood lactate levels are associated with adverse outcomes. In this retrospective observational study, a total of 111 consecutive patients who underwent PEA for chronic thromboembolic pulmonary hypertension at the XXX Hospital between December 2016 and January 2022 were included. We retrospectively evaluated arterial blood samples analyzed intraoperatively. The pre- and intraoperative risk factors for hyperlactatemia and the postoperative outcomes were recorded. Lactate levels gradually increased during surgery. The optimal cut-off lactate level for major postoperative complications, calculated using receiver operating characteristic analysis, was 7.0mmol/L. Deep hypothermic circulatory arrest (DHCA) duration, nadir hematocrit, and preoperative pulmonary vascular resistance were risk factors for lactate levels >7mmol/L. Moreover, the intraoperative peak lactate level during PEA under DHCA was found to be a statistically significant predictor of major complications being associated with longer mechanical ventilation time (r = 0.294; p = .003) and intensive care unit length of stay (r = 0.327; p = .001). Deep hypothermic circulatory arrest duration, nadir hematocrit, and preoperative pulmonary vascular resistance were associated with hyperlactatemia. Increased lactate levels were independent predictors of longer mechanical ventilation time, intensive care unit length of stay, and major complications.

A preclinical model of TB meningitis to determine drug penetration and activity at the sites of disease.

Tuberculosis meningitis (TBM) is essentially treated with the first-line regimen used against pulmonary tuberculosis, with a prolonged continuation phase. However, clinical outcomes are poor in comparison, for reasons that are only partially understood, highlighting the need for improved preclinical tools to measure drug distribution and activity at the site of disease. A predictive animal model of TBM would also be of great value to prioritize promising drug regimens to be tested in clinical trials, given the healthy state of the development pipeline for the first time in decades. Here, we report the optimization of a rabbit model of TBM disease induced via inoculation of Mycobacterium tuberculosis into the cisterna magna, recapitulating features typical of clinical TBM: neurological deterioration within months post-infection, acid-fast bacilli in necrotic lesions in the brain and spinal cord, and elevated lactate levels in cerebrospinal fluid (CSF). None of the infected rabbits recovered or controlled the disease. We used young adult rabbits, the size of which allows for spatial drug quantitation in critical compartments of the central nervous system that cannot be collected in clinical studies. To illustrate the translational value of the model, we report the penetration of linezolid from plasma into the CSF, meninges, anatomically distinct brain areas, cervical spine, and lumbar spine. Across animals, we measured the bacterial burden concomitant with neurological deterioration, offering a useful readout for drug efficacy studies. The model thus forms the basis for building a preclinical platform to identify improved regimens and inform clinical trial design.

Unlocking the role of lactate: metabolic pathways, signaling, and gene regulation in postmitotic retinal cells.

The Warburg effect, which was first described a century ago, asserts that mitotic tumor cells generate higher quantities of lactate. Intriguingly, even in typical physiological circumstances, postmitotic retinal photoreceptor cells also produce elevated levels of lactate. Initially classified as metabolic waste, lactate has since gained recognition as a significant intracellular signaling mediator and extracellular ligand. This current review endeavors to provide a concise overview and discourse on the following topics: the localization of lactate-producing enzymes, the functional significance of these enzymes, the signaling functions of lactate, and its impact on the gene expression of photoreceptors in retinal cells.

Abstract 18707: Concomitant Occurrence of Takotsubo Cardiomyopathy and Posterior Reversible Encephalopathy Syndrome: An Uncommon Encounter With Shared Pathophysiology

CASE PRESENTATION: A 61-year-old African American woman presented in an unconscious state after a seizure. She was febrile, tachycardic, tachypneic alongside elevated lactate, leukocyte counts, and procalcitonin levels. Initial high-sensitivity troponin I was notably raised at 4,217 ng/l, with ekg revealing a new onset left bundle branch block (LBBB). Patient was intubated and needed pressor support. Echocardiogram revealed hypokinesis in the basal-mid left ventricle, with a significantly decreased ejection fraction (EF) of 40%. Chest imaging showed a consolidation in the left lower lobe, and Hemophilus influenzae was identified in the sputum culture. A subsequent lumbar puncture yielded elevated leukocytes and proteins, suggesting a secondary meningitic process. DISCUSSION: She was started on antibiotic therapy for pneumonia and meningitis. LV hypokinesis was thought to be due to Takotsubo cardiomyopathy (TTC) or myocardial infarction. Although uncommon LBBB can be seen in TTC. Her clinical presentation, echocardiogram findings further points her LBBB and troponinemia towards TTC than Myocardial infarction. Patient was managed conservatively. Neuroimaging later on revealed restricted diffusion in bilateral occipital and parietal lobes, consistent with Posterior Reversible Encephalopathy Syndrome (PRES). A delayed coronary angiogram after clinical stabilization ruled out obstructive atherosclerotic disease. Weakness and ataxia improved over the course. EF at discharge was 80%.This case illustrates the possibility of concomitant TTS and PRES, conditions hypothesized to arise following intense physical or emotional stress, in this case, likely triggered by pneumonia and meningitis. This clinical scenario underscores the importance of awareness and understanding of these two entities and their potential for simultaneous presentation, providing valuable insights for clinical decision-making in such complex cases.

Dynamic changes in lactate levels within the first 24 hours in septic patients as a prognostic indicator: A retrospective cohort study utilizing latent class growth analysis.

Elevated lactate levels are common in sepsis patients. This study aimed to assess the effect of dynamic changes in lactate levels within the first 24 hours following admission on patient prognosis. We extracted data from the Medical Information Mart for Intensive Care (MIMIC)-IV database and classified patients using latent class growth analysis (LCGA). This analysis classified sepsis patients into different groups based on dynamic changes in lactate levels during the initial 24 hours post-admission, dividing this time frame into four periods (0-3 h, 3-6 h, 6-12 h, and 12-24 h). The highest lactate level recorded in each period was then used for patient classification. We subsequently compared the baseline characteristics and outcomes between these different groups. Our study encompassed 7,830 patients, whom LCGA successfully divided into two classes: class 1 (steady lactate class) and class 2 (increasing lactate class). Class 2 demonstrated a worse clinical status at baseline, as indicated by vital signs, disease severity scores, and laboratory results. Importantly, class 2 also had a significantly higher 28-day mortality rate than class 1 (55.6% vs 13.5%, P < 0.001). In conclusion, LCGA effectively categorized sepsis patients into two distinct groups based on their dynamic changes in lactate levels during the first 24 hours post-admission. This methodology has potential utility in clinical practice for managing sepsis patients.

Secondary Hemophagocytic Lymphohistiocytosis in Adults: A Single Institution Case Series

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome caused by the abnormal activation of macrophages and T cells. The primary form, resulting from lymphocyte-related mutations, is more common in children, while the secondary (acquired) form known as sHLH prevails in adults. sHLH is often triggered by infections or malignancies (Mal-HLH) but can also be induced by autoinflammatory disorders called macrophage activation syndrome (MAS; or MAS-HLH). We present a retrospective case series of adults treated for sHLH at a single institution from 2012 to 2023. Methods: Retrospective data was collected using the EDW database, and 36 patients were identified using ICD 9/10 codes 288.4 and D76.1 for HLH. Subsequently, a manual review of electronic medical records was conducted; criteria for inclusion were age &amp;gt;18 years at the time of diagnosis and meeting HLH-2004 criteria ( Panel-1). Results: Out of the 36 patients reviewed, 11 met the criteria and were included in the analysis. These cases occurred between 2015 and 2023. The median age at diagnosis was 52 (range 18 to 81). The female-to-male ratio in our study was 4:7. Most patients (73%) were white. Additionally, 45% of the patients were immunocompromised. 91% of the patients presented with fever, while only 45% had splenomegaly. Trilineage cytopenias were observed in all patients. In our study, 5/11 had hypofibrinogenemia, and 6/11 had hypertriglyceridemia. Hemophagocytosis was evident in 91% of the patients. Natural Killer (NK) cell activity was measured in 4 patients, and all exhibited low or no NK cell activity. In 10 out of 10 patients, soluble IL-2 receptors were elevated. None of the patients in the study had hepatomegaly, but all had transaminitis and hyperbilirubinemia, and 82% had elevated alkaline phosphatase levels. Elevated lactate levels were observed in 78% of patients, and 27% had a rash. Neurological features were observed in 6 out of 10 patients. Lactate dehydrogenase was elevated in all patients with a median value of 1551 U/L (range 354 - 3689) Presumed etiologies for sHLH included malignancy (4), infection (3), autoimmune disease (3), and unknown cause (1). Treatment was highly individualized based on the underlying trigger and was guided by the HLH-94 protocol ( Panel-2). All patients received high-dose steroids, 6/11 received etoposide, and 2 received intrathecal therapy for neurological involvement. Conclusion: At a median follow-up period of 16 days, five patients had died. The survival rates at 30 days and 1 year were 45% and 27%, respectively. The overall mortality rate was 55%. While mortality rates were 75% in the Mal-HLH arm and 67% in the infectious arm, all patients with MAS-HLH survived while performing the study indicating a better prognosis for patients with this type of HLH.

Clinical Spectrum of Biopsy Proven Mitochondrial Myopathy.

Clinical spectrum of mitochondrial myopathy extends beyond chronic progressive external ophthalmoplegia (CPEO). While information on encephalomyopathies is abundant, clinical data on predominant myopathic presentation of mitochondrial disorders are lacking. Clinical, electrophysiological, biochemical, and follow-up data of patients with predominant myopathic presentation and muscle biopsy confirmed primary mitochondrial myopathy was obtained. We excluded known syndromes of mitochondrial cytopathies and encephalomyopathies. Among 16 patients, 7 had CPEO, 4 had CPEO with limb-girdle muscle weakness (LGMW), and 5 had isolated LGMW. Systemic features included seizures with photosensitivity (n = 3), diabetes (n = 1), cardiomyopathy (n = 1), and sensorineural hearing loss (n = 1) and were more common in isolated LGMW. Elevated serum creatine kinase (CK) and lactate levels and electromyography (EMG) myopathic potentials were more frequent with LGMW. During follow-up, LGMW had more severe progression of weakness. We identified three subsets of mitochondrial myopathy with distinct clinical features and evolutionary patterns. Isolated LGMW was seen in 30% of patients and would represent severe end of the spectrum.

Mechanical Thrombectomy for High-Risk Pulmonary Embolism: Insights From the US Cohort of the FLASH Registry

BackgroundAcute mortality for high-risk, or massive, pulmonary embolism (PE) is almost 30% even when treated using advanced therapies. This analysis assessed the safety and effectiveness of mechanical thrombectomy (MT) for high-risk PE. MethodsThe prospective, multicenter FlowTriever All-comer Registry for Patient Safety and Hemodynamics (FLASH) study is designed to evaluate real-world PE patient outcomes after MT with the FlowTriever System (Inari Medical). In this study, acute outcomes through 30 days were evaluated for the subset of patients with high-risk PE as determined by the sites and following European Society of Cardiology guidelines. An independent medical monitor adjudicated adverse events (AEs), including major AEs: device-related mortality, major bleeding, or intraprocedural device-related or procedure-related AEs. ResultsOf the 799 patients in the US cohort, 63 (7.9%) were diagnosed with high-risk PE; 30 (47.6%) patients showed a systolic blood pressure <90 mm Hg, 29 (46.0%) required vasopressors, and 4 (6.3%) experienced cardiac arrest. The mean age of patients with high-risk PE was 59.4 ± 15.6 years, and 34 (54.0%) were women. At baseline, 45 (72.6%) patients were tachycardic, 18 (54.5%) showed elevated lactate levels of ≥2.5 mM, and 21 (42.9%) demonstrated depressed cardiac index of <2 L/min/m2. Immediately after MT, heart rate improved to 93.5 ± 17.9 bpm. Twenty-five (42.4%) patients did not require an overnight stay in the intensive care unit, and no mortalities or major AEs occurred through 48 hours. Moreover, no mortalities occurred in 61 (96.8%) patients followed up through the 30-day visit. ConclusionsIn this cohort of 63 patients with high-risk PE, MT was safe and effective, with no acute mortalities reported. Further prospective data are needed in this population.

Clinical Warburg effect in lymphoma patients admitted to intensive care unit

BackgroundThe Warburg effect, characterized by elevated lactate levels without tissue hypoxia or shock, has been described in patients with aggressive lymphoproliferative malignancies. However, the clinical characteristics and long-term outcomes in this population remain poorly understood.MethodsWe retrospectively analyzed 135 patients with aggressive lymphoproliferative malignancies admitted to the ICU between January 2017 and December 2022. Patients were classified into three groups: Clinical Warburg Effect (CWE), No Warburg with High Lactate level (NW-HL), and No Warburg with Normal Lactate level (NW-NL). Clinical characteristics and outcomes were compared between the groups and factors associated with 1-year mortality and CWE were identified using multivariable analyses.ResultsOf the 135 patients, 46 (34%) had a CWE. This group had a higher proportion of Burkitt and T cell lymphomas, greater tumor burden, and more frequent bone and cerebral involvement than the other groups. At 1 year, 72 patients (53%) died, with significantly higher mortality in the CWE and NW-HL groups (70% each) than in the NW-NL group (38%). Factors independently associated with 1-year mortality were age [HR = 1.02 CI 95% (1.00–1.04)], total SOFA score at admission [HR = 1.19 CI 95% (1.12–1.25)], and CWE [HR = 3.87 CI 95% (2.13–7.02)]. The main factors associated with the CWE were tumor lysis syndrome [OR = 2.84 CI 95% (1.14–7.42)], bone involvement of the underlying malignancy [OR = 3.58 CI 95% (1.02–12.91)], the total SOFA score at admission [OR = 0.81 CI 95% (0.69–0.91)] and hypoglycemia at admission [OR = 14.90 CI 95% (5.42–47.18)].ConclusionCWE is associated with a higher tumor burden and increased 1-year mortality compared to patients without this condition. Our findings underscore the importance of recognizing patients with CWE as a high-risk cohort, as their outcomes closely resemble those of individuals with lymphoma and shock, despite not requiring advanced organ support. Clinicians should recognize the urgency of managing these patients and consider early intervention to improve their prognosis.

ОСТРЫЕ ИШЕМИЧЕСКИЕ ПОРАЖЕНИЯ КИШЕЧНИКА НА ФОНЕ НОВОЙ КОРОНАВИРУСНОЙ ИНФЕКЦИИ

Purpose of the study. Acute ischemic intestinal (AII) lesions developed against the background of a new coronavirus infection. Materials and methods. The study included 23 patients with AII. The mean age of the patients was 59.9±15.0 with male predominance (17 males, 73.91% versus 6 females, 26.09%). The diagnosis of all patients: a new coronavirus infection caused by SARS-CoV-2 was confirmed by the results of PCR tests (polymerase chain reaction). All patients underwent computed tomography of the abdominal organs (CT of the abdominal cavity). The diagnostic algorithm was contrast-enhanced computed tomography, which is considered a valuable instrumental method of investigation in patients with COVID-19 with suspected AII. Statistical processing of the results of the study was carried out using the program STATISTICA. Results. It was confirmed that ischemia of the small intestine is the most common case in surgical examination, resection of the necrotic part of the small intestine with the formation of anastomosis was the most common surgical procedure in 14 (60.85%) patients, resections of the large intestine were performed in 7 (30.45%) patients, and only 2 (8.7%) patients underwent open thrombectomy. Histopathological examination was performed in 21 patients (91.30%) and revealed general features including necrosis, ulcer, hemorrhage in 11 patients (47.82%), neutrophilic infiltration in 7 patients (30.4%) or abscess in 3 patients (13.04%). Following the dynamics of changes in blood biomarkers in patients included in this study, we can conclude that there were such changes in biomarkers as a persistent increase in blood biomarkers evaluated in this study, such as D-dimer, LDH, ferritin and IL-6. Conclusion. Because of the high mortality rate in GI ischemia, clinicians should always be alert for ischemia to prevent its progression and promptly treat any complications. If patients have clinical signs of peritonitis, regardless of the presence of concomitant pathology, an immediate operation should be performed to eliminate the source of infection in the abdominal cavity. Changes in biomarkers and elevated levels of CRP (C-reactive protein), lactate, and D-dimer may be of low predictive value as possible prognostic factors because they may be found in severe COVID-19 infection.

Lactate – from villain to guardian

Elevated plasma lactate level is a useful warning sign in patients presenting with a variety of critical illnesses. Our understanding of hyperlactatemia, however, has improved and we can no longer associate lactate itself with any harmful effects. Lactate is a crucial intracellular buffer, and a central molecule in the interorgan exchange of carbon and redox potential. While lactate levels correlate with severity of acidaemia in shock there is little evidence to support the commonly held view that its origin is mainly secondary to anaerobic metabolism because of reduced tissue oxygen delivery.

Use of Electronic Clinical Data to Track Incidence and Mortality for SARS-CoV-2–Associated Sepsis

Efforts to quantify the burden of SARS-CoV-2-associated sepsis have been limited by inconsistent definitions and underrecognition of viral sepsis. To describe the incidence and outcomes of SARS-CoV-2-associated sepsis vs presumed bacterial sepsis using objective electronic clinical criteria. This retrospective cohort study included adults hospitalized at 5 Massachusetts hospitals between March 2020 and November 2022. SARS-CoV-2-associated sepsis was defined as a positive SARS-CoV-2 polymerase chain reaction test and concurrent organ dysfunction (ie, oxygen support above simple nasal cannula, vasopressors, elevated lactate level, rise in creatine or bilirubin level, and/or decline in platelets). Presumed bacterial sepsis was defined by modified US Centers for Disease Control and Prevention adult sepsis event criteria (ie, blood culture order, sustained treatment with antibiotics, and organ dysfunction using identical thresholds as for SARS-CoV-2-associated sepsis). Trends in the quarterly incidence (ie, proportion of hospitalizations) and in-hospital mortality for SARS-CoV-2-associated and presumed bacterial sepsis were assessed using negative binomial and logistic regression models. This study included 431 017 hospital encounters from 261 595 individuals (mean [SD] age 57.9 [19.8] years, 241 131 (55.9%) females, 286 397 [66.5%] from academic hospital site). Of these encounters, 23 276 (5.4%) were from SARS-CoV-2, 6558 (1.5%) had SARS-CoV-2-associated sepsis, and 30 604 patients (7.1%) had presumed bacterial sepsis without SARS-CoV-2 infection. Crude in-hospital mortality for SARS-CoV-2-associated sepsis declined from 490 of 1469 (33.4%) in the first quarter to 67 of 450 (14.9%) in the last (adjusted odds ratio [aOR], 0.88 [95% CI, 0.85-0.90] per quarter). Crude mortality for presumed bacterial sepsis was 4451 of 30 604 patients (14.5%) and stable across quarters (aOR, 1.00 [95% CI, 0.99-1.01]). Medical record reviews of 200 SARS-CoV-2-positive hospitalizations confirmed electronic health record (EHR)-based SARS-CoV-2-associated sepsis criteria performed well relative to sepsis-3 criteria (90.6% [95% CI, 80.7%-96.5%] sensitivity; 91.2% [95% CI, 85.1%-95.4%] specificity). In this retrospective cohort study of hospitalized adults, SARS-CoV-2 accounted for approximately 1 in 6 cases of sepsis during the first 33 months of the COVID-19 pandemic. In-hospital mortality rates for SARS-CoV-2-associated sepsis were high but declined over time and ultimately were similar to presumed bacterial sepsis. These findings highlight the high burden of SARS-CoV-2-associated sepsis and demonstrate the utility of EHR-based algorithms to conduct surveillance for viral and bacterial sepsis.

In-ear integrated sensor array for the continuous monitoring of brain activity and of lactate in sweat

Owing to the proximity of the ear canal to the central nervous system, in-ear electrophysiological systems can be used to unobtrusively monitor brain states. Here, by taking advantage of the ear’s exocrine sweat glands, we describe an in-ear integrated array of electrochemical and electrophysiological sensors placed on a flexible substrate surrounding a user-generic earphone for the simultaneous monitoring of lactate concentration and brain states via electroencephalography, electrooculography and electrodermal activity. In volunteers performing an acute bout of exercise, the device detected elevated lactate levels in sweat concurrently with the modulation of brain activity across all electroencephalography frequency bands. Simultaneous and continuous unobtrusive in-ear monitoring of metabolic biomarkers and brain electrophysiology may allow for the discovery of dynamic and synergetic interactions between brain and body biomarkers in real-world settings for long-term health monitoring or for the detection or monitoring of neurodegenerative diseases.

Case 321.

A 9-month-old preterm male infant born at 33 weeks gestation presented with a 2-month history of developmental decline. The parents reported that over the past several months, they noted regression of milestones, where the infant stopped smiling, crying, expressing himself, or making eye contact. The parents also reported that the infant had multiple seizures during which he would wake up stiff and stare into space for 10-20 seconds while his lips would become blue. The parents were referred to a neurologist, where physical examination was notable for hypotonia. Electroencephalography (EEG) revealed frequent bilateral parietal epileptiform discharges. The patient was subsequently started on lacosamide. The patient's medical history was notable for abnormally low citrulline levels at birth, with negative results of urea cycle disorder testing at the time, along with left inguinal hernia repair performed 3 months ago. More recent laboratory analysis had shown persistently elevated serum lactate and alanine levels. There was no history of travel, recent infection, or vaccine administration. MRI of the brain with spectroscopy was performed for further evaluation (Figs 1-6).

Mitochondrial DNA mutations in Medulloblastoma

To date, several studies on genomic events underlying medulloblastoma (MB) biology have expanded our understanding of this tumour entity and led to its division into four groups—WNT, SHH, group 3 (G3) and group 4 (G4). However, there is little information about the relevance of pathogenic mitochondrial DNA (mtDNA) mutations and their consequences across these. In this report, we describe the case of a female patient with MB and a mitochondriopathy, followed by a study of mtDNA variants in MB groups. After being diagnosed with G4 MB, the index patient was treated in line with the HIT 2000 protocol with no indications of relapse after five years. Long-term side effects of treatment were complemented by additional neurological symptoms and elevated lactate levels ten years later, resulting in suspected mitochondrial disease. This was confirmed by identifying a mutation in the MT-TS1 gene which appeared homoplasmic in patient tissue and heteroplasmic in the patient’s mother. Motivated by this case, we explored mtDNA mutations across 444 patients from ICGC and HIT cohorts. While there was no statistically significant enrichment of mutations in one MB group, both cohorts encompassed a small group of patients harbouring potentially deleterious mtDNA variants. The case presented here highlights the possible similarities between sequelae caused by MB treatment and neurological symptoms of mitochondrial dysfunction, which may apply to patients across all MB groups. In the context of the current advances in characterising and interpreting mtDNA aberrations, recognising affected patients could enhance our future knowledge regarding the mutations’ impact on carcinogenesis and cancer treatment.

Study of predictors of low cardiac output syndrome after cardiac valve surgery

Objective: Low cardiac output syndrome (LCOS) is defined as a decrease in cardiac index (CI) &lt;2.0L/min/m2 and systolic blood pressure &lt;90mmHg, accompanied by signs of a tissue hypoperfusion (cool peripheries, clammy skin, altered mental status, reduced urine output, elevated serum lactate levels) and the need for medication or mechanical circulatory support to improve hemodynamics [4,7]. LCOS is one of the serious complications after open cardiac surgery with a rate of 2-14% depending on the patient and the risk of death increases 12-25 times [3]. Besides modern equipment, early detection and timely treatment reduce mortality as well as increase myocardial recovery. LCOS prognostic factors play an important role. The aim of this study is to identify the prognostic signs of LCOS after valvular surgery.&#x0D; Subjects and methods: A cross-sectional descriptive study on patients undergoing valvular heart surgery at the Cardiovascular Anesthesiology Department - Cardiovascular Center - Hue Central Hospital from February 2022 to July 2022. LCOS is the dependent variable and the independent variable was divided into three groups before surgery, during surgery and after surgery. The data were processed by software R4.2.2. Using univariate logistic regression to identify independent prognostic factors. &#x0D; Results: A study on 60 patients after heart valve surgery showed that: LCOS after heart valve surgery has a rate of 28.3% with an average time of 5.88 hours after surgery. Through univariate logistic regression analysis, the results found independent prognostic factors including: EF &lt;=40% at preoperative time points (OR=12.9, 95%CI 1.73 – 26.5), EF 0h (OR) =2.3, 95%CI 2.4-8.9), EF 4h (OR=2.9, 95%CI 1.9-6.7), EF 24h (OR=1.9, 95%CI 1.5-9.5), lactate at 0h postoperative time (OR=1.81, 95%CI 1.25-2.8), 4h (OR=1.41, 95%CI 1.13-1.85), 8h (OR=1.38, 95%CI 1.14-1.73), 12h (OR=1.35, 95%CI 1.11-1.72), creatinine at 24 h after surgery (OR=1.02, 95%CI 1.01-1.04), time to extracorporeal circulation (OR=1.02, 95%CI 1.02-1.04), time to clamp aorta (OR=1.2, 95%CI 1.1-1.2).[1]&#x0D; Conclusion: Low cardiac output syndrome is one of the serious complications after heart valve surgery, early detection and timely treatment reduce the risk of death for patients. The study showed that many factors before, during and after surgery are independent prognostic factors for LCOS after surgery.

Interdisciplinary perspectives on computed tomography in sepsis: survey among medical doctors at a large university medical center

ObjectivesThis study aims to describe physicians’ perspectives on the use of computed tomography (CT) in patients with sepsis.MethodsIn January 2022, physicians of a large European university medical center were surveyed using a web-based questionnaire asking about their views on the role of CT in sepsis. A total of 371 questionnaires met the inclusion criteria and were analyzed using work experience, workplace, and medical specialty of physicians as variables. Chi-square tests were performed.ResultsPhysicians considered the ability to detect an unknown focus as the greatest benefit of CT scans in sepsis (70.9%, n = 263/371). Two clinical criteria — “signs of decreased vigilance” (89.2%, n = 331/371) and “increased catecholamine demand” (84.7%, n = 314/371) — were considered highly relevant for a CT request. Elevated procalcitonin (82.7%, n = 307/371) and lactate levels (83.6%, n = 310/371) were consistently found to be critical laboratory values to request a CT. As long as there is evidence of infection in one organ region, most physicians (42.6%, n = 158/371) would order a CT scan based on clinical assessment. Combined examination of the chest, abdomen, and pelvis was favored (34.8%, n = 129/371) in cases without clinical clues of an infection source. A time window of ≥ 1–6 h was preferred for both CT examinations (53.9%, n = 200/371) and CT-guided interventions (59.3%, n = 220/371) in patients with sepsis.ConclusionDespite much consensus, there are significant differences in attitudes towards the use of CT in septic patients among physicians from different workplaces and medical specialties. Knowledge of these perspectives may improve patient management and interprofessional communication.Key PointsDespite interdisciplinary consensus on the use of CT in sepsis, statistically significant differences in the responses are apparent among physicians from different workplaces and medical specialties.The detection of a previously unknown source of infection and the ability to plan interventions and/or surgery based on CT findings are considered key advantages of CT in septic patients.Timing of CT reflects the requirements of specific disciplines.