Normal Lactate Research Articles

An evaluation of postmarketing reports of hyperglycaemia associated with dolutegravir for treatment of HIV in Eswatini

BackgroundDolutegravir (DTG) is an Integrase Strand Transfer Inhibitor (INSTI) indicated in combination with other antiretroviral agents for the treatment of HIV infection. It is available in a number of pharmaceutical preparations including the fixed-dose combination (TLD) containing tenofovir (300 mg) + lamivudine (300 mg) + dolutegravir (50 mg). In 2018, Eswatini adopted TLD as the preferred first-line HIV treatment regimen for adults and adolescents as per WHO recommendations. From March 2019 to March 2020, the National Pharmacovigilance Center (NPC) in Eswatini received 8 reports of hyperglycaemia associated with the use of DTG. This study was conducted to investigate if Eswatini NPC database included cases suggestive of causality between dolutegravir and hyperglycaemia.MethodA qualitative synthesis of information from the Eswatini national pharmacovigilance database from March 2019 to March 2020 was conducted to investigate a casual association between hyperglycaemia and dolutegravir.ResultsAll reports with dolutegravir containing regimen and suspected Adverse Event of hyperglycaemia in the period of March 2019 to March 2020 were included in the study. Seven of the reports were serious (resulted in hospitalization and one case concerned optic neuritis, leading to blindness). Two patients had a medical history of diabetes while the rest of the patients had never experienced hyperglycaemia before starting dolutegravir. For all the reports, the time to onset of hyperglycaemia ranges from 2–5 months after the initiation of DTG. None of the patients discontinued the use of DTG. All the patients were treated with oral hypoglycaemic medication. In severe cases, patients were treated with intravenous normal saline and ringer lactate as well as rapid-acting insulins. All patients are currently stable on oral hypoglycaemic drugs.ConclusionCases that support causality between dolutegravir containing regimen and hyperglycaemia were found. These cases were mainly serious. Based on these findings it is recommended that healthcare professionals (HCPs) actively screen all patients for risk factors of hyperglycaemia before DTG initiation. In addition, it is important that HCPs are aware of the possible association between DTG and hyperglycaemia.

Product spectrum analysis and microbial insights of medium-chain fatty acids production from waste biomass during liquor fermentation process: Effects of substrate concentrations and fermentation modes

Substrate toxicity would limit the upgrading of waste biomass to medium-chain fatty acids (MCFAs). In this work, two fermentation modes of electro-fermentation (EF) and traditional fermentation (TF) with different concentration of liquor fermentation waste (20%, 40%, 60%) were used for MCFAs production as well as mechanism investigation. The highest caproate (4.04 g/L) and butyrate (13.96 g/L) concentrations were obtained by EF at 40% substrate concentration. TF experiments showed that the substrate concentration above 40% severely inhibited ethanol oxidation and products formation. Compared with TF mode, the total substrates consumption and product yields under EF mode were significantly increased by 2.6%–43.5% and 54.0%–83.0%, respectively. Microbial analysis indicated that EF effectively alleviated substrate toxicity and enriched chain elongation bacteria, particularly Clostridium_sensu_stricto 12, thereby promoting ethanol oxidation and products formation. Caproiciproducens tolerated high-concentration substrates to ensure normal lactate metabolism. This study provides a new way to produce MCFAs from high concentration wastewater.

Low haptoglobin in pregnancy: physiological or intravascular hemolysis?

Abstract A woman in her second trimester of pregnancy (24 weeks of gestation), diagnosed with B-cell acute lymphoblastic leukemia, received induction chemotherapy. On day six of treatment, she required transfusion with two red cell (RBC) units for anemia. Less than 12 hours later, laboratory results included elevated total bilirubin, 4.3 mg/dL [reference interval <=1.2 mg/dL], direct bilirubin, 0.3 mg/dL [reference interval <=0.3 mg/dL], haptoglobin below detection limit, <10 mg/dL [reference interval: 30 - 200 mg/dL], and normal lactate dehydrogenase (LD), 186 U/L [reference interval: 122 - 241 U/L]. These tests were ordered without any clinical suspicion for intravascular hemolysis, and upon receiving the results, the primary team consulted transfusion medicine due to concern for an acute hemolytic transfusion reaction (AHTR). After finishing the corresponding workup, the patient did not meet the Center of Disease Control (CDC) criteria for AHTR. The patient was discharged and on follow-up visits her haptoglobin increased to 15 mg/dL (25 weeks 3 days of gestation). Later, during her third trimester (27 weeks 3 day of gestation), haptoglobin increased to 142 mg/dL; LD always remained normal. Hemolysis is not associated with normal LD. Instead, some literature suggest that pregnant patients may have lower haptoglobin levels than reported in the non-pregnant population, with a nadir occurring in the second trimester. It is possible that low haptoglobin in this population may be due to the combination of hemodilution and a high estrogen state. But no literature is available that provide trimester-specific reference intervals for haptoglobin, which may lead to misinterpretation. Inspired by this case, we developed a quality improvement project to determine trimester-specific reference intervals for haptoglobin in pregnancy. Haptoglobin was tested on remnant serum samples (BD Vacutainer SST) collected from routine outpatient pregnancy patients (n=401; at least 80 samples per trimester) using Roche/Hitachi cobas c systems. Derived nonparametric reference intervals were 22-188 mg/dL for first trimester, 29-177 mg/dL for second trimester, 53-185 mg/dL for third trimester, and 30-185 mg/dL for the entire sample population. While overall reference intervals were similar, consistent with previous reports, we noticed a shift in haptoglobin distribution to the low end in the second trimester [29 (CI95% 7-35) mg/dL; median 98 mg/dL] in comparison with first trimester [22 (CI95% 15-47) mg/dL; median 113 mg/dL p = 0.34] and third trimester [29 (CI95% 7-35); median 112 mg/dL p=0.34].In the case described, the first haptoglobin below limit of detection could have been due to the combination of pregnancy (second trimester), recent red cell transfusion of RBC units (28 days old) and hyperhydration with crystalloids as part of the chemotherapy plan. This case also serves as a reminder that laboratory tests should be ordered mindfully, to aid in confirming or ruling out clinically suspected syndromes/diseases that are unlikely.

EFFICACY AND SAFETY OF NIPOCALIMAB, AN FCRN BLOCKER, IN WARM AUTOIMMUNE HEMOLYTIC ANEMIA (WAIHA): ENERGY PHASE 2/3 STUDY DESIGN

Warm autoimmune hemolytic anemia (wAIHA) is characterized by the destruction of red blood cells (RBCs) by pathogenic autoantibodies which bind to RBCs and lead to their clearance in the spleen and liver. Patients with wAIHA can experience acute worsening of anemia, which can be a medical emergency, and have an increased risk of thromboembolic events and premature death. Nipocalimab is a fully human, aglycosylated, effectorless IgG1 monoclonal antibody that blocks the IgG binding site on the neonatal Fc receptor (FcRn) with high affinity. FcRn, which is expressed in endothelial cells, is responsible for recycling IgG into the circulation and for the relatively long half-life of IgG antibodies compared to other Igs. It is expected that nipocalimab, by blocking IgG binding to FcRn, will prevent IgG recycling and lower pathogenic IgG autoantibodies that cause many autoantibody diseases, including wAIHA. Nipocalimab has been studied in multiple phase 1 studies in healthy subjects and in a completed phase 2 study in subjects with Generalized Myasthenia Gravis (gMG). Treatment with nipocalimab was associated with rapid and durable total serum IgG and pathogenic IgG autoantibody reduction and meaningful clinical response. Here we share the rationale and study design for an adaptive, phase 2/3 multicenter, randomized, double-blind, placebo-controlled study in patients with wAIHA whose aim is to evaluate the efficacy, safety, tolerability, PK, and PD of nipocalimab compared with placebo (NCT04119050). Male or female subjects ≥18 years of age who have been diagnosed with primary or secondary wAIHA and have not experienced a sufficient response or have not tolerated currently available treatments will be included in the study. Subjects with cold antibody AIHA, cold agglutinin syndrome, mixed type (i.e., warm and cold) AIHA, or paroxysmal cold hemoglobinuria will be excluded. Participants will be randomized 1:1:1 to receive nipocalimab at two different dose schedules or placebo. Following completion of 24 weeks of double-blind treatment, participants may enter an open-label extension period to receive nipocalimab. The primary endpoint is percentage of participants achieving durable response of improvement in hemoglobin (Hgb). The main secondary endpoints are change from baseline in the total score from the FACIT-Fatigue Scale, number of participants who attain normal lactate dehydrogenase, normal haptoglobin, and normal indirect bilirubin levels at a minimum of 3 consecutive visits after baseline. ENERGY is a phase 2/3 study that will evaluate the efficacy and safety of nipocalimab in wAIHA. ENERGY is currently enrolling globally. IM received research support from Alexion, Annexon, Incyte, Kezar, Momenta, Rigel, and Sanofi; and served as a consultant for Apellis, Janssen, Momenta, Novartis, Rigel, and Sanofi. BF is a consultant of Alexion, Amgen, Janssen, Momenta, and Novartis. DC is an employee of Janssen Global Services, LLC, which is a wholly owned subsidiary of Johnson & Johnson, and may own stock or stock options in Johnson & Johnson; was an employee of Momenta. AMBP is an employee of Janssen Latin America, which is a wholly owned subsidiary of Johnson & Johnson, and may own stock or stock options in Johnson & Johnson. MHJ was an employee of Momenta.

Value, time and outcomes of elevated lactate levels in adult patients on extracorporeal membrane oxygenation.

Lactate levels have been recognized as a reliable tool for monitoring critically ill patients requiring venoarterial extracorporeal membrane oxygenation (VA ECMO) or venovenous extracorporeal membrane oxygenation (VV ECMO) but the reasons behind the overproduction of lactate are different and the influance for survival remains controversial. We analyzed the lactate values and lactate clearance in adult patients in these two forms of extracorporeal support. Patient demographics, ECMO duration, 30-day mortality, lactate values and lactate clearance at 24, 48 and 72h from ECMO initiation of patients supported with VV and VA ECMO at Silesian Centre for Heart Deasese, between January 2011 and April 2020 were retrospectively analyzed. The changes in lactate levels were analyzed using the non-parametric U Mann-Whitney tests and Chi-square test. The ROC curves were draw and the area under the curve was calculated. The study comprised 91 adult patients, Mortality in the first 30days from initiation of VV and VA ECMO was 39% and 66%, respectively. Lactate levels were significantly higher in non-survivors that received VV and VA ECMO (p < .001), while lactate clearance was similar (p = .256 and p = 1.000, respectively). Survival curves for patients with elevated (>2.0mmol/L) vs normal (≤2.0mmol/L) lactate levels at 72h were significantly different for VV ECMO (p = .007) and VA ECMO (p = .037) but in both groups of ECMO, lactate levels above 2.0mmol/L at 72h from ECMO initiation predicted 30 day-mortality. This results emphasized the importance of lactate levels below 2.0mmol/L at 72h from both VV and VA ECMO initiation.

TRIT1 defect leads to a recognizable phenotype of myoclonic epilepsy, speech delay, strabismus, progressive spasticity, and normal lactate levels.

TRIT1 defect is a rare, autosomal-recessive disorder of transcription, initially described as a condition with developmental delay, myoclonic seizures, and abnormal mitochondrial function. Currently, only 13 patients have been reported. We reviewed the genetic, clinical, and metabolic aspects of the disease in all known patients, including two novel, unrelated TRIT1 cases with abnormalities in oxidative phosphorylation complexes I and IV in fibroblasts. Taken together the features of all 15 patients, TRIT1 defect could be identified as a potentially recognizable syndrome including myoclonic epilepsy, speech delay, strabismus, progressive spasticity, and variable microcephaly, with normal lactate levels. Half of the patients had oxidative phosphorylation complex measurements and had multiple complex abnormalities.

Factors associated with elevated blood lactate levels in patients undergoing maintenance hemodialysis.

Factors associated with chronic elevation of the blood lactate levels in patients undergoing chronic maintenance hemodialysis (hereinafter, hemodialysis patients) have not yet been thoroughly investigated. The purpose of the present study was to clarify factors associated with elevated blood lactate levels in hemodialysis patients. We divided the hemodialysis patients into two groups according the blood lactate levels (the high blood lactate group [> 2mmol/L] and normal blood lactate group), and conducted a retrospective comparison of the following items between the two groups: (1) the creatinine generation rate (%CGR) and the geriatric nutrition risk index (GNRI) as indices of the nutritional status; (2) the left ventricular ejection fraction (LVEF) and E/A, an indicator of diastolic function; (3) the ankle-brachial index (ABI) and transcutaneous partial pressure of oxygen as indices of the adequacy of circulation in the peripheral blood vessels of the lower extremities; (4) the white blood cell count and serum level of C-reactive protein (CRP) before dialysis as markers of an inflammatory state. The mean age and serum CRP level were significantly higher in the high blood lactate group than in the normal blood lactate group. There were no significant differences in the markers of the nutritional status, cardiac function, or adequacy of circulation in the peripheral blood vessels of the lower extremities between the two groups. Advanced age and a state of chronic inflammation appear to be associated with elevated blood lactate levels in patients undergoing chronic maintenance hemodialysis.

Inborn Errors of Ketogenesis: Novel Variants, Clinical Presentation, and Follow-Up in a Series of Four Patients.

Inborn errors of ketogenesis are rare disorders that result in acute and fulminant decompensation during lipolytic stress, particularly in infants and children. These include mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase (HMGCS) deficiency and HMG-CoA lyase (HMGCL) deficiency. In this series, we describe the clinical, biochemical, and molecular profiles of four patients along with dietary interventions and their outcomes on a long-term follow-up. Two patients each of HMGCS and HMGCL deficiency were evaluated with clinical history, biochemical investigations, including tandem mass spectrometry (TMS) and urine gas chromatography-mass spectrometry (GCMS). Molecular analysis was performed by whole-exome sequencing, as well as exon array validated by long-range polymerase chain reaction. All individuals were diagnosed with acute metabolic decompensation in the early infancy period except one with HMGCL deficiency who had the first presentation at 5 years of age. Central nervous system manifestations, severe metabolic acidosis, hyperammonemia, hypoglycemia with a normal lactate, and absence of urinary ketones were observed in all the affected individuals. The disorder was life-threatening in three individuals and one succumbed to the illness. TMS was nonspecific and urine GCMS revealed dicarboxylic aciduria in HMGCS deficiency. Both the patients with HMGCL deficiency demonstrated elevated 3 hydroxyisovaleryl carnitine levels in TMS and metabolites of leucine degradation in urine GCMS. We identified five novel variants that included a large deletion involving exon 2 in HMGCL gene. There was no evidence of long-term neurological sequelae in the living individuals. Diet with moderation of fat intake was followed in two individuals with HMGCS deficiency. Low leucine and protein diet with moderation of fat intake was followed in the individual with HMGCL deficiency. All affected individuals are thriving well with no further major metabolic decompensation.

Lymphomas of palatine tonsil in patients at a tertiary care centre in coastal India: A ten-year case analysis

Introduction and Aim: Head and neck is affected in 11-33% of extra-nodal Non-Hodgkin Lymphomas with the Waldeyer’s ring comprising 50% and among which palatine tonsils are most commonly involved. Materials and Methods: A retrospective analysis was performed using medical case files to study the demographic and clinical details of 13 patients diagnosed with primary lymphoma of palatine tonsil between 2011 and 2020 at a tertiary care hospital in coastal India. Results: Mean age was 49.7 years with a male preponderance. The usual presentation was either as a unilateral palatine mass or neck swelling with dysphagia, odynophagia and otalgia. All patients had high-grade lymphoma, diffuse large B-cell lymphoma was the commonest type. B-symptoms were seen more often in B-cell lymphoma; stage I was the most frequent. Stage at diagnosis was statistically significant when compared with B-symptoms, bulky disease and International Prognostic Index (IPI) (p-values of 0.02, 0.02 and 0.035 respectively). Overall survival (OS) rate was 44.44%, being higher in females than in males. Higher OS rate was noted for IPI of 1 &amp; 2, and early stage lymphoma, unilateral tonsillar enlargement, normal lactate dehydrogenase, and European Cooperative Oncology Group score of 0. Combined chemoradiation proved to be better (50% OS) than chemotherapy (33.33% OS) alone. Conclusion: Lymphoma must be suspected in unilateral or bilateral asymmetrical tonsillar enlargement, especially in the older age group. Histopathology with immunohistochemistry plays a crucial role in diagnosis and typing of lymphoma, for proper and early institution of treatment with chemoradiation.

Relationship Between the Anion Gap and Serum Lactate in Hypovolemic Shock.

Background and objectives: Previous studies evaluating patients in the Intensive Care Unit with established lactic acidosis determined that the anion gap is an insensitive screening tool for elevated blood lactate. No prior study has examined the relationship between anion gap and serum lactate within the first hours of the development of lactic acidosis. Design, setting, participants, & measurements: Data were obtained prospectively from a convenience sample of adult trauma patients at a single level 1 trauma center. Venous samples were drawn prior to initiation of intravenous fluid resuscitation. A linear regression model was constructed to assess the relationship between serum lactate and anion gap, and 95% prediction intervals were computed. Logistic regression models were constructed to determine the sensitivity and specificity for several different anion gap and lactate cutpoints. Results: 128 patients with elevated serum lactate levels (>2.1 mmol/L) and 63 patients with normal serum lactate levels (< 2.1 mmol/L) were included. The sensitivity of an elevated anion gap (> 10) to reveal hyperlactatemia was only 43% whereas specificity was 84%. Sensitivity improved if the upper limit of normal anion gap was lowered and with increasing levels of serum lactate. The coefficient of determination between serum lactate level and AG yielded an R2 of 0.30 (p < 0.001) and the slope of this relationship was 2.185 with a 95% confidence interval of 2.011-2.359. The mean 95% prediction interval was + 8.9. Conclusions: Within the first hour of the development of lactic acidosis due to hypovolemic shock, the anion gap was not a sensitive indicator of an elevated serum lactate level, but it was fairly specific. The anion gap increased to a greater extent than the serum lactate, the 95% mean prediction interval was wide and approximately 70% of the change in anion gap could not be explained by increases in serum lactate, suggesting that other anions contribute to the anion gap in lactic acidosis.

Efficacy of ipilimumab 3mg/kg following progression on low dose ipilimumab in metastatic melanoma.

e21533 Background: Anti-cytotoxic T lymphocyte-associated antigen 4 inhibitors, such as ipilimumab (IPI), are commonly used in melanoma management. Whilst a clear dose-toxicity relationship exists, and a dose-response relationship is seen with monotherapy in people with anti PD-1 antibody-naïve melanoma, there is no data on the outcomes of patients who progress following low dose IPI and are subsequently treated with standard dose IPI. We conducted a multicentre, retrospective review to assess the efficacy of this strategy. Methods: Patients with resected stage III, unresectable stage III or IV melanoma who received low dose IPI (&lt; 3mg/kg) with an anti-PD1 antibody in the neoadjuvant, adjuvant or metastatic setting with recurrence (neo/adjuvant) or progressive disease (metastatic) as best response, who then received standard dose IPI (3mg/kg, IPI3) alone or in combination with an anti-PD1 antibody were eligible. IPI dose, frequency and best investigator-assessed RECIST response were collected. Progression free survival (PFS) and overall survival (OS) were analysed using the Kaplan Meier method. Results: 36 patients from 8 centres; 27 (75%) male, BRAF V600 mutant (18, 50%). All patients received low dose IPI with an anti-PD1 antibody, 18 (50%) in the neo/adjuvant and 18 (50%) in the metastatic setting; 15 (42%) received IPI 1mg/kg every 6 weeks, 13 (36%) IPI 1mg/kg every 3 weeks, 3 (8%) IPI 50mg every 6 weeks or 100mg every 12 weeks respectively, and 2 (6%) IPI 1mg/kg every 8 weeks. 23 (64%) received &gt;1 intervening line of systemic therapy prior to IPI3. The most common intervening therapy was BRAF/MEK inhibitors; 14/23 (61%) as 2nd line treatment, 4/8 (50%) as 3rd line treatment, and all progressed. All patients received standard dose IPI3 for unresectable stage III or stage IV melanoma; median age 60 (29-78), 18 (50%) had M1d disease, 32 (89%) ECOG 0-1, 18 (50%) normal lactate dehydrogenase. 35 (97%) received IPI3 with nivolumab and 1 received single agent IPI3. 15 (42%) received 4 cycles of IPI3. The most common reason for IPI3 cessation was progressive disease (16, 44%). The response rate to IPI3 following progression on low dose IPI was 9/36 (25%); the disease control rate was 12/36 (33%). After a median follow up of 22 months (95% CI: 15-27 months), the median PFS and OS were not reached in patients who responded;1-year PFS and OS were 73% and 100% respectively. 13/36 (36%) had grade 3-4 immune-related adverse events (irAE). In 3/36 (8%), the same irAE was observed at low dose IPI and IPI3, and 1 patient had the same irAE (rash) at a higher grade with IPI3 compared to low dose IPI. Conclusions: Standard dose IPI3 following progression on low dose IPI has clinical activity.This is a reasonable treatment strategy for patients who progress on low dose IPI and provides further evidence of a dose-response relationship for IPI. Further research is needed to manage resistance to IPI with anti-PD1.

POS-054 UTILITY OF PLASMA EXCHANGE AND RITUXIMAB IN PERIOPERATIVE PERIOD AMONG PATIENTS OF COMPLEMENT-ASSOCIATED RENAL DYSFUNCTION UNDERGOING TRANSPLANTATION: REPORT OF THREE RARE CASES

POS-054 UTILITY OF PLASMA EXCHANGE AND RITUXIMAB IN PERIOPERATIVE PERIOD AMONG PATIENTS OF COMPLEMENT-ASSOCIATED RENAL DYSFUNCTION UNDERGOING TRANSPLANTATION: REPORT OF THREE RARE CASES

AB1289 STUDY DESIGN OF A PHASE 2/3 RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY TO ASSESS THE EFFICACY AND SAFETY OF NIPOCALIMAB, AN FcRn ANTAGONIST, IN WARM AUTOIMMUNE HEMOLYTIC ANEMIA (wAIHA)

BackgroundWarm autoimmune hemolytic anemia (wAIHA) is characterized by the destruction of red blood cells (RBCs) by pathogenic autoantibodies which bind to RBCs and lead to their clearance in the spleen and liver. Patients with wAIHA can experience acute worsening of anemia, which can be a medical emergency, and have an increased risk of thromboembolic events and premature death. Nipocalimab is a fully human, aglycosylated, effectorless IgG1 monoclonal antibody that targets the IgG binding site on the neonatal Fc receptor (FcRn) with high affinity. FcRn, which is expressed in endothelial cells, is responsible for recycling IgG into the circulation and for the relatively long half-life of IgG antibodies compared to other Igs. It is expected that nipocalimab, by inhibiting IgG binding to FcRn, will prevent IgG recycling and lower pathogenic IgG autoantibodies that cause many autoimmune diseases including warm autoimmune hemolytic anemia (wAIHA).Nipocalimab has been studied in multiple phase 1 studies in healthy subjects and in a recently completed phase 2 study in subjects with Generalized Myasthenia Gravis (gMG). In the gMG phase 2 study, nipocalimab was well tolerated at doses from 5 mg/kg every 4 weeks to 60 mg/kg every 2 weeks. Treatment with nipocalimab was associated with rapid and durable total serum IgG and pathogenic IgG autoantibody reduction and meaningful clinical response. A statistically significant relationship between IgG autoantibody reduction and clinical benefit was observed. This study provided proof-of-concept evidence that lowering pathogenic IgG autoantibodies can ameliorate the autoimmune condition these antibodies cause.ObjectivesTo share the rationale and study design for an adaptive, phase 2/3 multicenter, randomized, double-blind, placebo-controlled study in patients with wAIHA whose aim is to evaluate the efficacy, safety, tolerability, PK, and PD of nipocalimab compared with placebo1.MethodsMale or female patients ≥18 years of age who have been diagnosed with primary or secondary wAIHA and have not experienced a sufficient response or have not tolerated currently available treatments will be included in the study. Patients with cold antibody AIHA, cold agglutinin syndrome, mixed type (i.e., warm and cold) AIHA, or paroxysmal cold hemoglobinuria will be excluded. Patients will be randomized 1:1:1 to receive nipocalimab at two different dose schedules or placebo. Following completion of 24 weeks of double-blind treatment, patients may enter an open-label extension period to receive nipocalimab.ResultsThe following endpoints will be analyzed:Primary endpoint:Percentage of participants achieving durable response of improvement in hemoglobin (Hgb).Main secondary endpoints:Change from baseline in the total score from the Functional Assessment of Chronic Illness Therapy-Fatigue Scale at the end of the double-blind period.Number of participants who attain normal lactate dehydrogenase, normal haptoglobin, and normal indirect bilirubin levels at a minimum of 3 consecutive visits after baseline.ConclusionA phase 2 study investigating nipocalimab in patients with gMG provided proof of concept for a phase 2/3 interventional study with nipocalimab in patients with wAIHA. This phase 2/3 study is currently enrolling in the USA and Europe.

Elevated Serum Lactate in Glioma Patients: Associated Factors.

IntroductionSerum lactate levels in brain cancer patients correlate with tumor malignancy grading, and serum lactate has been suggested as a potential biomarker and prognostic factor. The purpose of this study was to identify potential sources of elevated serum lactate in patients with brain gliomas by examining factors of importance for serum lactate production and clearance.MethodsIn this cross-sectional study, data were collected from 261 glioma patients who underwent surgery from March 2011 to June 2015. We recorded patient gender, age, blood serum measures of lactate, glucose, pH, hemoglobin and base excess, patient health status, medications, and tumor characteristics. Patients with elevated and normal serum lactate levels were compared, and we explored if there were correlations between the variables. The association of serum lactate with the measured variables was investigated by simple and multivariable linear regression models.Results and DiscussionPatients with elevated serum lactate had higher blood glucose, larger tumor volumes, and more tumor edema; more often needed pressor medication during surgery; and more often received corticosteroid treatment. The investigated variables were highly correlated. Multivariable linear regression indicated that gender, tumor volume, Charlson Comorbidity Index, hyperglycemia, and corticosteroid treatment were associated with serum lactate levels. Histopathology was not an independent factor. In conclusion, comorbidities, hyperglycemia, and presurgical corticosteroid treatment exhibited the strongest association with serum lactate in glioma patients.

Novel NARS2 variant causing leigh syndrome with normal lactate levels

Leigh syndrome is the most genetically heterogenous phenotype of mitochondrial disease. We describe a patient with Leigh syndrome whose diagnosis had not been confirmed because of normal metabolic screening results at the initial presentation. Whole-exome sequencing identified pathogenic variants in NARS2, the gene encoding a mitochondrial asparaginyl-tRNA synthetase. One of the biallelic variants was novel. This highlights the essential role of genetic testing for a definite diagnosis of Leigh syndrome.

Arterial Blood Gases and Cardiorespiratory Parameters in Etorphine-Medetomidine-Midazolam Immobilized Free-Ranging and Game-Farmed Southern White Rhinoceroses (Ceratotherium simum simum) Undergoing Electro-Ejaculation.

With the rapid loss of individuals in the wild, semen cryopreservation has gained importance to safeguard the genetic diversity of white rhinoceroses (Ceratotherium simum). For semen collection via electro-ejaculation, immobilization of free-ranging individuals requires the potent opioid etorphine, which is routinely combined with azaperone, but causes hypoxemia, hypercarbia, acidemia, muscle rigidity, tachycardia, and systemic hypertension. In this study, the suitability of two alternative immobilization protocols including etorphine, medetomidine, and midazolam at different doses (high vs. low etorphine) was evaluated in adult white rhinoceros bulls in two different management systems (free-ranging vs. game-farmed) and undergoing electro-ejaculation. Fourteen free-ranging (Group 1) and 28 game-farmed rhinoceroses (Group 2) were immobilized with ≈2.5 μg/kg etorphine (high dose), ≈2.5 μg/kg medetomidine, ≈25 μg/kg midazolam and 1,500–1,700 IU hyaluronidase and received ≈2.5 μg/kg of butorphanol intravenously at first handling. Twenty game-farmed animals (Group 3) received ≈1 μg/kg etorphine (low dose), ≈5 μg/kg medetomidine, ≈25 μg/kg midazolam and 1,700 IU hyaluronidase. Respiratory rate, heart rate and peripheral hemoglobin oxygen saturation (SpO2) were measured at 5-min intervals; non-invasive oscillometric blood pressures and arterial blood gases at first handling and before reversal of the immobilization; serum clinical chemistry analytes and hematocrit at first handling. Generalized mixed models (fixed factors: group, time, recumbency; random factor: individual rhinoceros) were applied to compare longitudinal changes between free-ranging and game-farmed rhinoceroses immobilized with the higher etorphine dose (Groups 1 and 2), and between the two protocols tested in the game-farmed rhinoceroses (Groups 2 and 3). All animals were successfully immobilized, presented with normal lactate concentrations (<5 mmol/L), experienced no muscle tremors and recovered uneventfully. Hypoxemia and hypertension persisted throughout the immobilization in all groups. Acidemia and hypercarbia were absent in Group 1, but present in the game-farmed animals. The lower etorphine dose in Group 3 resulted in significantly longer induction times, however, tachycardia was not observed. SpO2 was higher for sternal vs. lateral recumbency. Semen-rich fractions were recovered following electro-stimulation in 46 out of the 62 animals. Our findings suggest that etorphine-medetomidine-midazolam provides effective immobilization with fewer side effects compared to previous reports in white rhinoceroses and is suitable for successful electro-ejaculation.

Aging related impairment of brain microvascular bioenergetics involves oxidative phosphorylation and glycolytic pathways

Mitochondrial and glycolytic energy pathways regulate the vascular functions. Aging impairs the cerebrovascular function and increases the risk of stroke and cognitive dysfunction. The goal of our study is to characterize the impact of aging on brain microvascular energetics. We measured the oxygen consumption and extracellular acidification rates of freshly isolated brain microvessels (BMVs) from young (2–4 months) and aged (20–22 months) C57Bl/6 male mice. Cellular ATP production in BMVs was predominantly dependent on oxidative phosphorylation (OXPHOS) with glucose as the preferred energy substrate. Aged BMVs exhibit lower ATP production rate with diminished OXPHOS and glycolytic rate accompanied by increased utilization of glutamine. Impairments of glycolysis displayed by aged BMVs included reduced compensatory glycolysis whereas impairments of mitochondrial respiration involved reduction of spare respiratory capacity and proton leak. Aged BMVs showed reduced levels of key glycolysis proteins including glucose transporter 1 and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 but normal lactate dehydrogenase activity. Mitochondrial protein levels were mostly unchanged whereas citrate synthase activity was reduced, and glutamate dehydrogenase was increased in aged BMVs. Thus, for the first time, we identified the dominant role of mitochondria in bioenergetics of BMVs and the alterations of the energy pathways that make the aged BMVs vulnerable to injury.

Optimizing transfusion therapy for survivors of Haemoglobin Bart's hydrops fetalis syndrome: Defining the targets for haemoglobin-H fraction and "functional" haemoglobin level.

Owing to the unique pathophysiology of anaemia in haemoglobin Bart's hydrops fetalis (HBHF), a transfusion strategy based on beta-thalassemia guidelines is suboptimal for chronically transfused HBHF patients. A more aggressive transfusion aimed at reducing the proportion of non-functional HbH and improving the "functional" haemoglobin (f-Hb) can lead to reduced haemolysis and improved tissue oxygenation. However, the optimal transfusion targets for these parameters are not yet defined. In this retrospective, longitudinal study on four chronically transfused patients with HBHF, we used receiver operating characteristic curves to find a pre-transfusion f-Hb of 106g/l and a HbH of 16.1% to be the optimal thresholds to achieve a normal soluble transferrin receptor and lactate dehydrogenase, respectively.

Hyperlactataemia and acid–base disturbances in normotensive patients with acute heart failure

Acute heart failure (AHF) may be associated with low-tissue perfusion and/or hypoxaemia leading to increased lactate levels and acid-base perturbations. Few data are available on the clinical significance of elevated lactate levels and primary acid-base disorders in the setting of AHF. Arterial blood gas was obtained at admission in 4012 normotensive (systolic blood pressure ≥ 90 mmHg) patients with AHF. The association between lactate levels and acid-base status and in-hospital mortality was determined using multivariable logistic regression. Hyperlactataemia (>2 mmol/L) was present in 38.0% of patients and was strongly associated with markers of sympathetic activation, such as hyperglycaemia. Hyperlactataemia was present in 31.0%, 43.7%, and 42.0% of patients with normal pH, acidosis, and alkalosis, respectively. In-hospital mortality occurred in 16.4% and 11.1% of patients with and without hyperlactataemia [adjusted odds ratio (OR) 1.49; 95% confidence interval (CI) 1.22-1.82, P < 0.0001]. Compared with normal pH, the OR for in-hospital mortality was 2.48 (95% CI 1.95-3.16, P < 0.0001) in patients with acidosis and 1.77 (95% CI 1.32-2.26, P < 0.0001) in patients with alkalosis. The risk for in-hospital mortality was high with acidosis (18.1%) or alkalosis (10.4%) even with normal lactate. The most common primary acid-base disturbances included metabolic acidosis, respiratory acidosis, and metabolic alkalosis with respiratory acidosis having the highest risk for in-hospital mortality. Hyperlactataemia was common in patients without hypotension and was associated with increased risk for in-hospital mortality. Hyperlactataemia is not associated with any specific acid-base disorder. Acute heart failure patients also present with diverse acid-base disorders portending increased in-hospital mortality.

Blood lactate predicts mortality after surgical repair of type A acute aortic dissection.

Ischemia and malperfusion are strong predictors of poor postoperative outcomes in type A acute aortic dissection (TAAAD). Serum lactate is an accurate surrogate point-of-care marker of malperfusion. The aim of this study is to investigate the correlation between lactate, in-hospital outcomes, and 1-year survival following TAAAD repair. One hundred and thirty-two patients underwent operative repair of TAAAD over a 4-year period at our institution 128 patients had serum lactate measurements at three stages peri-operatively-preoperatively, at the end of cardiopulmonary bypass (post-CPB) and 6 h postintensive care unit (ICU) admission. The primary outcomes were in-hospital mortality and 1-year survival. The secondary outcomes were the incidences of in-hospital morbidities. Patients were divided into two groups: 88 (68.8%) with normal lactate and 40 (31.2%) with elevated lactate (>2.2 mmol/L). Lactate measured preoperatively (odds ratio 1.52, 95% confidence interval 1.17-2.07, p < .01), post-CPB (1.34, 1.14-1.64, p < .01) and 6 h post-ICU admission (1.29, 1.08-1.55, p < .01) was an independent predictor of in-hospital mortality. Following adjustment for the Penn Classification, lactate continued to have a significant correlation with in-hospital mortality at all three timepoints. There was a higher incidence of complications in the elevated lactate group and especially hemofiltration (20% vs. 9.1%, p = .08). 1-year survival was similar in both groups (p = .23). There is a direct correlation between elevated serum lactate and postoperative mortality after TAAAD repair, which is independent of the Penn Classification status on admission.