Individual Titration Research Articles

Brain Network Interconnectivity Dynamics Explain Metacognitive Differences in Listening Behavior.

Complex auditory scenes pose a challenge to attentive listening, rendering listeners slower and more uncertain in their perceptual decisions. How can we explain such behaviors from the dynamics of cortical networks that pertain to the control of listening behavior? We here follow up on the hypothesis that human adaptive perception in challenging listening situations is supported by modular reconfiguration of auditory-control networks in a sample of N = 40 participants (13 males) who underwent resting-state and task functional magnetic resonance imaging (fMRI). Individual titration of a spatial selective auditory attention task maintained an average accuracy of ∼70% but yielded considerable interindividual differences in listeners' response speed and reported confidence in their own perceptual decisions. Whole-brain network modularity increased from rest to task by reconfiguring auditory, cinguloopercular, and dorsal attention networks. Specifically, interconnectivity between the auditory network and cinguloopercular network decreased during the task relative to the resting state. Additionally, interconnectivity between the dorsal attention network and cinguloopercular network increased. These interconnectivity dynamics were predictive of individual differences in response confidence, the degree of which was more pronounced after incorrect judgments. Our findings uncover the behavioral relevance of functional cross talk between auditory and attentional-control networks during metacognitive assessment of one's own perception in challenging listening situations and suggest two functionally dissociable cortical networked systems that shape the considerable metacognitive differences between individuals in adaptive listening behavior.

The futility of post-haemodialysis blood glucose levels: A retrospective cohort study.

Frequent blood glucose tests are performed for people with diabetes receiving haemodialysis. To determine the rate of out-of-range post-haemodialysis blood glucose levels that are clinically acted upon, the intervention and outcome of each intervention, and the associations between post-haemodialysis blood glucose levels and relevant clinical predictors. 12-month retrospective cohort medical record review in one Australian haemodialysis centre. Post-haemodialysis blood glucose levels, prehaemodialysis blood glucose levels, time of treatment, diabetes medications, intradialytic fluid removal, dialysate dextrose concentration, clinical actions, interventions, and outcomes on out-of-range blood glucose levels were retrieved. 22 participants with a median time receiving dialysis 3.1 years (interquartile range 2.3-4.7). The proportion of out-of-range post-haemodialysis blood glucose levels was 87.3% (95% confidence interval, 86.1%-88.5%). No out-of-range post-haemodialysis blood glucose levels were clinically acted upon. Out-of-range post-haemodialysis blood glucose levels were 4.6 times more likely if a higher dextrose bath was used (95% confidence interval: 3.3; 6.3. p < 0.001). The odds of the post-haemodialysis blood glucose levels increased by each 1 mmol/L. Intradialytic fluid removal, dialysate dextrose concentration, sex, dialysis time, anti-hyperglycaemic agents were also associated with out-of-range post-haemodialysis blood glucose levels. Routine post-haemodialysis blood glucose levels testing has limited clinical utility in care for people with diabetes receiving maintenance haemodialysis. Higher dextrose dialysate may require individual titration depending on prehaemodialysis blood glucose levels.

Validation of a Model for Predicting Magnesium Concentration in Women with Preeclampsia: A Retrospective Cohort Study.

To validate a model for predicting magnesium concentration in magnesium sulfate treatment in preeclampsia. Retrospective cohort study. Setting. Three secondary care hospitals, one accepting neonates from gestational week 28 + 0. Population. Women with preeclampsia undergoing magnesium sulfate treatment. Subjects initially received Zuspan treatment (4 g bolus and 1 g/h maintenance dose), commonly increased by individual titration. Main Outcome Measures. Difference in mean between measured and predicted magnesium concentration. Proportion of women reaching target concentration (>2 mM) in 25 h. 56 women were included, with 356 magnesium measurements available. Mean magnesium concentration was 1.82 mM. The prediction model overestimated magnesium concentration by 0.10 mM (CI 0.04-0.16) but exhibited no bias for weight, creatinine, or treatment duration. Weighted mean infusion rate was 1.22 g/h during 30 hours. Overall success rate in reaching target concentration was 54%, decreasing to 40% in women > 95 kg. Overall success rate at 8 hours was 11%. No toxic concentrations were found. Zuspan regimen is very safe, but slow to reach therapeutic concentrations-despite efforts of individual titration. Success rate is lower in heavy women, which is of particular importance considering their predisposition to develop preeclampsia. The validated pharmacokinetic model performs well and may be used to individually tailor treatment from the outset.

Combinatorial antibody titrations for high-parameter flow cytometry.

The objective of titrating fluorochrome-labeled antibodies is to identify the optimal concentration for a given marker-fluorochrome pair that results in the best possible separation between the positive and negative cell populations, while minimizing the background within the negative population. Best practices in flow cytometry dictate that each new lot of antibody should be titrated on the sample of interest. However, many researchers routinely use large (30+) color panels due to recent technical advancements in fluorescence-based cytometry instrumentation which quickly leads to an unmanageable number of individual titrations. In this technical note, we provide evidence that antibodies can be effectively titrated in groups rather than individually, resulting in considerable time and cost savings. This approach streamlines the process, without compromising data quality, thereby enhancing the efficiency of setting up high-parameter cytometry experiments.

Subthreshold Micropulse Laser (577 nm) Therapy with an Individual Approach for Power Titration in Patients with Chronic Central Serous Chorioretinopathy (Pilot Study)

Purpose. To study the safety and effectiveness of subthreshold micropulse (SML) 577 nm laser therapy with an individual power titration in treating patients with chronic central serous chorioretinopathy (CSC). Methods. The study was a prospective, single‐centre observation of 30 patients (30 eyes) with chronic CSC. All patients with chronic CSC were treated with a 577 nm micropulse laser. Individual power parameters for each patient were titrated in a micropulse mode. The primary outcome measure was best‐corrected visual acuity (BCVA) at 6‐month follow‐up. The secondary outcome measures were as follows: central retinal thickness (CRT) and maximum subretinal fluid height (SRFH) according to optical coherence tomography, number of laser sessions, and treatment safety at 6‐month follow‐up. Results. Before treatment, the mean BCVA was 0.35 ± 0.16, the mean CRT was 285 ± 76 µm, and the mean SRFH was 311 ± 85 µm. Six months after 577 nm SML therapy, there was a statistically significant increase in the mean BCVA with the maximum correction to 0.45 ± 0.15 (p = 0.001). The mean CRT and SRFH decreased significantly to 236 ± 45 μm (p = 0.003) and 45 ± 25 μm (p = 0.001), respectively. At the end of the follow‐up, complete resorption of the subretinal fluid was noted in 50% (15 eyes), and in 43% (13 eyes), a decrease in the SRFH was observed. During the entire observation period, 25 patients underwent 1 session of 577 nm SML therapy, 2 patients underwent 2 sessions, and 3 patients underwent the intervention three times. Conclusion. SML 577 nm therapy with individual selection of laser power in a micropulse mode is a safe and effective method of treating patients with chronic CSC. Further studies are needed to test the long‐term safety and efficacy of 577 nm SML therapy with individual power settings in chronic CSC.

An expert review of clozapine in Eastern European countries: Use, regulations and pharmacovigilance

ObjectivesTo compare the prevalence, regulations, and pharmacovigilance practices of clozapine use in Eastern European countries (except Russia). MethodsQuestionnaires and data from administrative databases (2016 and 2021), package inserts and national guidelines were collected from 21 co-authors from 21 countries. Reports of clozapine adverse drug reactions (ADRs) sent to the global pharmacovigilance database (VigiBase™) were analyzed from introduction to December 31, 2022. ResultsClozapine prescription among antipsychotics in 2021 varied six-fold across countries, from 2.8 % in the Czech Republic to 15.8 % in Montenegro. The utilization of antipsychotics in both 2016 and 2021 was highest in Croatia, and lowest in Serbia in 2016, and Montenegro in 2021, which had half the defined daily dose (DDD)/1000/day compared to the Croatian data. From 2016 to 2021, the prevalence of antipsychotic use increased in almost all countries; the proportion of clozapine use mainly remained unchanged. Differences were detected in hematological monitoring requirements and clozapine approved indications. Only a few national schizophrenia guidelines mention clozapine-induced myocarditis or individual titration schemes. The VigiBase search indicated major underreporting regarding clozapine and its fatal outcomes. By comparison, the United Kingdom had less than half the population of these Eastern European countries but reported to VigiBase more clozapine ADRs by 89-fold and clozapine fatal outcomes by almost 300-fold. ConclusionClozapine is under-utilized in Eastern European countries. Introducing individualized clozapine treatment schedules may help to maximize clozapine benefits and safety. Major improvement is needed in reporting clozapine ADRs and fatal outcomes in Eastern European countries.

Effect of individualized positive end-expiratory pressure based on electrical impedance tomography guidance on pulmonary ventilation distribution in patients who receive abdominal thermal perfusion chemotherapy.

Electrical impedance tomography (EIT) has been shown to be useful in guiding individual positive end-expiratory pressure titration for patients with mechanical ventilation. However, the appropriate positive end-expiratory pressure (PEEP) level and whether the individualized PEEP needs to be adjusted during long-term surgery (>6 h) were unknown. Meanwhile, the effect of individualized PEEP on the distribution of pulmonary ventilation in patients who receive abdominal thermoperfusion chemotherapy is unknown. The primary aim of this study was to observe the effect of EIT-guided PEEP on the distribution of pulmonary ventilation in patients undergoing cytoreductive surgery (CRS) combined with hot intraperitoneal chemotherapy (HIPEC). The secondary aim was to analyze their effect on postoperative pulmonary complications. A total of 48 patients were recruited and randomly divided into two groups, with 24 patients in each group. For the control group (group A), PEEP was set at 5 cm H2O, while in the EIT group (group B), individual PEEP was titrated and adjusted every 2 h with EIT guidance. Ventilation distribution, respiratory/circulation parameters, and PPC incidence were compared between the two groups. The average individualized PEEP was 10.3 ± 1.5 cm H2O, 10.2 ± 1.6 cm H2O, 10.1 ± 1.8 cm H2O, and 9.7 ± 2.1 cm H2O at 5 min, 2 h, 4 h, and 6 h after tracheal intubation during CRS + HIPEC. Individualized PEEP was correlated with ventilation distribution in the regions of interest (ROI) 1 and ROI 3 at 4 h mechanical ventilation and ROI 1 at 6 h mechanical ventilation. The ventilation distribution under individualized PEEP was back-shifted for 6 h but moved to the control group's ventral side under PEEP 5 cm H2O. The respiratory and circulatory function indicators were both acceptable either under individualized PEEP or PEEP 5 cm H2O. The incidence of total PPCs was significantly lower under individualized PEEP (66.7%) than PEEP 5 cm H2O (37.5%) for patients with CRS + HIPEC. The appropriate individualized PEEP was stable at approximately 10 cm H2O during 6 h for patients with CRS + HIPEC, along with better ventilation distribution and a lower total PPC incidence than the fixed PEEP of 5 cm H2O.Clinical trial registration: identifier ChiCTR1900023897.

#3041 DNAJB9 POSITIVE PRIMARY FIBRILLARY GLOMERULONEPHRITIS: TREATMENT WITH CORTICOSTEROID PULSES EXPERIENCE

Abstract Background and Aims Fibrillary glomerulonephritis (FGN) is a rare histological pattern. Electron microscopy is needed for diagnostic confirmation where predominantly mesangial fibrils are observed. To support the diagnosis; DNAJB9 is a biomarker that is 100% sensitive and 100% specific for FGN. To date, there is no defined therapeutic approach. Various immunosuppressants have been implemented to treat FGN showing poor renal response and approximately 50% progression to chronic kidney disease. Method Ambispective observational study. A protocol based on a bibliographic review was developed. The protocol included an induction therapy with methylprednisolone pulses (MTP), 500 mg a day for three days. Followed by oral prednisone at a dose of one mg/kg with an individual titration period considering the clinical evolution. Demographic, clinical, and pathological variables were extracted from the electronic health record. Results Case 1. Seventy-eight-year-old female. History of arterial hypertension (HT) treated with an angiotensin-converting enzyme inhibitor (ACEi). She debuted with a nephrotic syndrome characterized by proteinuria of 15 grams/day, hypoalbuminemia, and altered kidney function with creatinine (Cr) of 2.7 mg/dL. Secondary causes were rule out. The kidney biopsy showed mesangial expansion with mesangial deposition of IgG and C3 on the immunofluorescence. Congo red was negative. Positivity for DNAJB9 was observed. The electron microscopy (EM) showed 20-nanometer fibrils in the mesangium. The patient was initiated on the treatment protocol with a subsequent reduction of prednisone over a period of 24 weeks. Complete remission, defined as proteinuria &amp;lt;0.5g/day and reduction &amp;gt; 50% of Cr was achieved after 20 weeks of treatment. Case 2. Forty-seven-year-old female with a history of hypertension treated with ACEi. The patient presented with proteinuria 3.5g/d with a normal kidney function. Secondary causes were rule out. The kidney biopsy showed mesangial thickening with IgG, C3, C1q, Kappa, and lambda positivity on immunofluorescence. Congo red was negative. DNAJB9 was positive. An electron microscopy study showed randomly arranged mesangial fibrils. The treatment protocol was started. Prednisone was titrated over a period of 20 weeks. Partial remission was observed, defined by &amp;gt;50% reduction of proteinuria. Kidney function remained preserved. Conclusion Induction treatment based on steroid pulses followed by prednisone titration in patients with FGN with predominantly mesangial compromise was associated with a substantial reduction of proteinuria and stabilization of kidney function.

Hypoglycaemia frequency and physiological response after double or triple doses of once-weekly insulin icodec vs once-daily insulin glargine U100 in type 2 diabetes: a randomised crossover trial

Aims/hypothesisThis study compared the frequency of hypoglycaemia, time to hypoglycaemia and recovery from hypoglycaemia after double or triple doses of once-weekly insulin icodec vs once-daily insulin glargine U100. Furthermore, the symptomatic and counterregulatory responses to hypoglycaemia were compared between icodec and glargine U100 treatment.MethodsIn a randomised, single-centre (Department of Internal Medicine, Division of Endocrinology and Diabetology, Medical University of Graz, Graz, Austria), open-label, two-period crossover trial, individuals with type 2 diabetes (age 18–72 years, BMI 18.5–37.9 kg/m2, HbA1c ≤75 mmol/mol [≤9.0%]) treated with basal insulin with or without oral glucose-lowering drugs received once-weekly icodec (for 6 weeks) and once-daily glargine U100 (for 11 days). Total weekly doses were equimolar based on individual titration of daily glargine U100 during the run-in period (target fasting plasma glucose [PG]: 4.4–7.2 mmol/l). Randomisation was carried out by assigning a randomisation number to each participant in ascending order, which encoded to one of two treatment sequences via a randomisation list prepared prior to the start of the trial. At steady state, double and triple doses of icodec and glargine U100 were administered followed by hypoglycaemia induction: first, euglycaemia was maintained at 5.5 mmol/l by variable i.v. infusion of glucose; glucose infusion was then terminated, allowing PG to decrease to no less than 2.5 mmol/l (target PGnadir). The PGnadir was maintained for 15 min. Euglycaemia was restored by constant i.v. glucose (5.5 mg kg−1 min−1). Hypoglycaemic symptoms score (HSS), counterregulatory hormones, vital signs and cognitive function were assessed at predefined PG levels towards the PGnadir.ResultsHypoglycaemia induction was initiated in 43 and 42 participants after double dose of icodec and glargine U100, respectively, and in 38 and 40 participants after triple doses, respectively. Clinically significant hypoglycaemia, defined as PGnadir <3.0 mmol/l, occurred in comparable proportions of individuals treated with icodec vs glargine U100 after double (17 [39.5%] vs 15 [35.7%]; p=0.63) and triple (20 [52.6%] vs 28 [70.0%]; p=0.14) doses. No statistically significant treatment differences were observed in the time to decline from PG values of 5.5 mmol/l to 3.0 mmol/l (2.9–4.5 h after double dose and 2.2–2.4 h after triple dose of the insulin products). The proportion of participants with PGnadir ≤2.5 mmol/l was comparable between treatments after double dose (2 [4.7%] for icodec vs 3 [7.1%] for glargine U100; p=0.63) but higher for glargine U100 after triple dose (1 [2.6%] vs 10 [25.0%]; p=0.03). Recovery from hypoglycaemia by constant i.v. glucose infusion took <30 min for all treatments. Analyses of the physiological response to hypoglycaemia only included data from participants with PGnadir <3.0 mmol/l and/or the presence of hypoglycaemic symptoms; in total 20 (46.5%) and 19 (45.2%) individuals were included after a double dose of icodec and glargine U100, respectively, and 20 (52.6%) and 29 (72.5%) individuals were included after a triple dose of icodec and glargine U100, respectively. All counterregulatory hormones (glucagon, adrenaline [epinephrine], noradrenaline [norepinephrine], cortisol and growth hormone) increased during hypoglycaemia induction with both insulin products at both doses. Following triple doses, the hormone response was greater with icodec vs glargine U100 for adrenaline at PG3.0 mmol/l (treatment ratio 2.54 [95% CI 1.69, 3.82]; p<0.001), and cortisol at PG3.0 mmol/l (treatment ratio 1.64 [95% CI 1.13, 2.38]; p=0.01) and PGnadir (treatment ratio 1.80 [95% CI 1.09, 2.97]; p=0.02). There were no statistically significant treatment differences in the HSS, vital signs and cognitive function.Conclusions/interpretationDouble or triple doses of once-weekly icodec lead to a similar risk of hypoglycaemia compared with double or triple doses of once-daily glargine U100. During hypoglycaemia, comparable symptomatic and moderately greater endocrine responses are elicited by icodec vs glargine U100.Trial registrationClinicalTrials.gov NCT03945656.FundingThis study was funded by Novo Nordisk A/S.Graphical

Comparison of the neuromuscular effects of two infusion rates of rocuronium in anesthetized pigs

Background:Neuromuscular blocking agents are frequently administered to pigs used for research. In humans, administration of the drugs is not without risk and may result in accidental awareness under general anaesthesia and postoperative residual neuromuscular blockade that can lead to serious respiratory complications. Despite the extensive administration, the pharmacodynamics of neuromuscular blocking agents are not thoroughly studied in pigs. Therefore, this study investigates the neuromuscular response of two infusion rates of rocuronium, a commonly used non-depolarizing neuromuscular blocking agent. A group of 14 female Danish Landrace-Yorkshire-Duroc pigs used for supervised surgical training, weighing 40.3 ± 2.1 kg (mean ± SD), were included in the study. They received a loading dose of 0.85 mg/kg rocuronium intravenously followed by infusion of either 2.5 mg/kg/hour (L, low dose) or 5 mg/kg/hour (H, high dose) rocuronium for 30 min. Neuromuscular monitoring was performed with acceleromyography using train-of-four (TOF) stimulation. Onset time, time to reappearance of T1, T4, TOF ratio 90% and 100% were recorded.Results:All pigs in group H experienced loss of T1 throughout rocuronium infusion, whereas six out of seven pigs in group L had reappearance of T1 during rocuronium infusion, with additional reappearance of T4 in three of these pigs. The time to recovery of TOF ratio 90% was 14.0 ± 5.4 (L) and 21.7 ± 6.1 (H) minutes and recovery to TOF ratio 100% was 18.7 ± 6.5 (L) and 27.9 ± 9.2 min (H) (mean ± SD). Substantial inter-animal variation in neuromuscular recovery time was observed.ConclusionThe large inter-animal variation in pharmacodynamic profiles emphasizes that individual neuromuscular monitoring and titration to effect should be used routinely in research protocols that include rocuronium. In addition to other important measures, these actions are key in order to avoid overdosing and limit the risk of residual neuromuscular blockade.

Improving lithium dose prediction using population pharmacokinetics and pharmacogenomics: a cohort genome-wide association study in Sweden

Lithium is the most effective treatment for bipolar disorder, resulting in strong suicide prevention effects. The therapeutic range of lithium, however, is narrow and treatment initiation requires individual titration to address inter-individual variability. We aimed to improve lithium dose prediction using clinical and genomic data. We performed a population pharmacokinetic study followed by a genome-wide association study (GWAS), including two clinical Swedish cohorts. Participants in cohort 1 were from specialised outpatient clinics at Huddinge Hospital, in Stockholm, Sweden, and participants in cohort 2 were identified using the Swedish National Quality Registry for Bipolar disorder (BipoläR). Patients who received a lithium dose corresponding to at least one tablet of lithium sulphate (6 mmol) per day and had clinically relevant plasma concentrations of lithium were included in the study. Data on age, sex, bodyweight, height, creatinine concentration, estimated glomerular filtration rate (eGFR), lithium preparation, number of tablets of lithium per day, serum lithium concentration, and medications affecting kidney function (C09 antihypertensives, C03 [except C03D] sodium-retaining diuretics, and non-steroidal anti-inflammatory drugs) were obtained retrospectively for several timepoints when possible from electronic health records, BipoläR, and the Swedish prescription registry. The median time between timepoints was 1·07 years for cohort 1 and 1·09 years for cohort 2. The primary outcome of interest was the natural logarithm of total body clearance for lithium (CLLi) associated with the clinical variables. The residual effects after accounting for age and sex, representing the individual-level effects (CLLi,age/sex), were used as the dependent variable in a GWAS. 2357 patients who were administered lithium (1423 women [60·4%] and 934 men [39·6%]; mean age 53·6 years [range 17-89], mainly of European descent) were included and 5627 data points were obtained. Age (variance explained [R2]: R2cohort1=0·41 and R2cohort2=0·31; both p<0·0001), sex (R2cohort1=0·0063 [p=0·045] and R2cohort2=0·026 [p<0·0001]), eGFR (R2cohort1=0·38 and R2cohort2=0·20; both p<0·0001), comedication with diuretics (R2cohort1=0·0058 [p=0·014] and R2cohort2=0·0026 [p<0·0001]), and agents acting on the renin-aldosterone-angiotensin system (R2cohort1=0·028 and R2cohort2=0·015; both p<0·0001) were clinical predictors of CLLi. Notably, an association between CLLi and serum lithium was observed, with a lower CLLi being associated with higher serum lithium (R2cohort1=0·13 and R2cohort2=0·15; both p<0·0001). In a GWAS of CLLi,age/sex, one locus was associated with a change in CLLi (rs583503; β=-0·053 [95% CI -0·071 to -0·034]; p<0·00000005). We also found enrichment of the associations with genes expressed in the medulla (p=0·0014, corrected FDR=0·04) and cortex of the kidney (p=0·0015, corrected FDR=0·04), as well as associations with polygenic risk scores for eGFR (p value threshold: 0·05, p=0·01), body-mass index (p value threshold: 0·05, p=0·00025), and blood urea nitrogen (p value threshold: 0·001, p=0·00043). The model based on six clinical predictors explained 61·4% of the variance in CLLi in cohort 1 and 49·8% in cohort 2. Adding genetic markers did not lead to major improvement of the models: within the subsample of genotyped individuals, the variance explained only increased from 59·32% to 59·36% in cohort 1 and from 49·21% to 50·03% in cohort 2 when including rs583503 and the four first principal components. Our model predictors could be used clinically to better guide lithium dosage, shortening the time to reach therapeutic concentrations, thus improving care. Identification of the first genomic locus and PRS to be associated with CLLi introduces the opportunity of individualised medicine in lithium treatment. Stanley Medical Research Institute, Swedish Research Council, Swedish Foundation for Strategic Research, Swedish Brain Foundation, Swedish Research Council, Söderström-Königska Foundation, Bror Gadelius Minnesfond, Swedish Mental Health Fund, Karolinska Institutet and Hospital.

Individualized everolimus treatment for tuberous sclerosis-related angiomyolipoma promotes treatment adherence and response.

ABSTRACTBackgroundEverolimus is a potential alternative to embolization and nephrectomy for managing tuberous sclerosis complex (TSC)-associated renal angiomyolipoma (AML). In 2016, National Health Service England approved its use through regional centres for renal AML ≥30 mm showing interval growth. Evidence of lesion stabilization or reduction after 6 months is mandated for continuation of long-term treatment.MethodsFrom November 2016 to June 2021, all potentially eligible adult TSC patients with AML across Yorkshire and Humber were referred for assessment and monitoring. Eligible patients underwent baseline renal magnetic resonance imaging (MRI) assessment and a follow-up MRI scan after 6 months on everolimus. Dose titration was guided by trough levels and lesion responsiveness using a new 3D MRI volumetric protocol.ResultsOf 28 patients commencing treatment, 19 tolerated everolimus for >3 months. Overall, 11 patients (40%) discontinued treatment, mostly due to recurrent infections (42%) and allergic reactions (25%). Sixty-eight percent required dose adjustments from the initiating dose (10 mg) due to sub-optimal trough levels (38%), minimal AML response (15%) or adverse events (47%). 3D volumetric assessment confirmed a reduction in AML volume of a pre-selected index lesion in all treatment-naïve cases (n = 14), showing superiority over 2D measurements of lesion diameter.ConclusionIn this cohort, everolimus promoted AML regression in all patients who tolerated the drug for >6 months with stabilization observed over 3 years. Trough levels enabled individual dose titration to maximize responsiveness and minimize side effects. The use of 3D MRI assessment of lesion volume was superior to 2D measurements of lesion diameter in monitoring treatment response.

Intraoperative Oxygen Practices in Cardiac Surgery: A National Survey

To describe the current nationwide perspectives and practice regarding intraoperative oxygen titration in cardiac surgery. Prospective, observational survey. Hospitals across the United States. Cardiovascular anesthesiologists and perfusionists. Expert- and consensus-derived electronic surveys were sent to perfusionists and cardiac anesthesiologists to evaluate the current intraoperative practices around oxygen administration. Providers were asked about individual intraoperative oxygen titration practices used at different stages of cardiac surgical procedures. Anonymous responses were collected in the Research Electronic Data Capture (REDCap). A total of 3,335 providers were invited to participate, of whom 554 (317 anesthesiologists and 237 perfusionists) were included in the final analysis (17% response rate). During cardiopulmonary bypass (CPB), perfusionists reported a median (interquartile range [IQR]) target range from 150 (110-220)-to-325 mmHg (250-400), while anesthesiologists reported a significantly lower target range from 90 (70-150)-to-250 mmHg (158-400) (p values <0.0001 and 0.02, respectively). This difference was most pronounced at lower partial pressure of arterial oxygen (PaO2) ranges. The median PaO2 considered "too low" by perfusionists was 100 mmHg (IQR 80-125), whereas it was 60 mmHg (IQR 60-75) for anesthesiologists, who reported for both off and on bypass. The median PaO2 considered "too high" was 375 mmHg (IQR 300-400) for perfusionists and 300 mmHg (IQR 200-400) for anesthesiologists. Anesthesiologists, therefore, reported more comfort with significantly lower PaO2 values (p < 0.0001), and considered a higher PaO2 value less desirable compared with perfusionists (p < 0.0001). This survey demonstrated there was wide variation in oxygen administration practices between perfusionists and anesthesiologists. Hyperoxygenation was more common while on CPB.

ANI-моніторинг для оцінки ефективності варіантів анестезіологічного забезпечення пластичної хірургії носа

Метою роботи було вивчення ANI-моніторингу для оцінки періопераційної аналгезії і контролю балансу ноцицепції/антиноцицепції при різних варіантах анестезіологічного забезпечення пластичної хірургії носа. Матеріали та методи. Було обстежено 116 пацієнтів віком від 18 до 60 років з викривленням перегородки носа, яким проводилася септопластика в умовах комбінованої анестезії, що включала тотальну внутрішньовенну анестезію зі штучною вентиляцією легенів і місцевою анестезією лідокаїном. Усі пацієнти були розподілені на 4 групи: 1-ша група (n = 28) (контрольна) — зі стандартним комбінованим анестезіологічним забезпеченням; 2-га група (n = 31) — стандартне анестезіологічне забезпечення доповнювалося внутрішньовенною інфузією парацетамолу за 30 хвилин до початку операції в дозі 15 мг/кг (але не більше 1000 мг) одноразово; 3-тя група (n = 30) — проводилася інфузія дексмедетомідину, що починалася за 10 хвилин до індукції анестезії в дозі 0,7 мкг/кг/год і закінчувалася за 10 хвилин до завершення операції; 4-та група (n = 27) — проводилася інфузія дексмедетомідину, що починалася за 10 хвилин до індукції анестезії в дозі 0,7 мкг/кг/год і закінчувалася за 10 хвилин до завершення операції, в комбінації з внутрішньовенною інфузією парацетамолу за 30 хвилин до початку операції в дозі 15 мг/кг (але не більше 1000 мг) одноразово. Проводилася реєстрація АNI-індексу. Після операції реєструвалися рівень болю за візуально-аналоговою шкалою (ВАШ) і частота розвитку післяопераційної нудоти і блювання. Реєструвалася оцінка пацієнтами якості анестезії за допомогою шкали Iowa Satisfaction with Anesthesia Scale. Результати. У контрольній групі ANI-індекс на етапі інтубації, початку операції, на етапі найбільш травматичного моменту операції був нижче 50 одиниць, що, можливо, пов’язано з недостатнім рівнем аналгезії. У 2-й групі з використанням парацетамолу ANI-індекс в момент інтубації знижувався до 50 одиниць, але потім перебував у межах 50–70 одиниць. У 3-й групі з застосуванням дексмедетомідину ANI-індекс на етапі індукції анестезії та в момент пробудження пацієнта був вище 70 одиниць. У 4-й групі з комбінованим використанням дексмедетомідину і парацетамолу ANI-індекс на всіх етапах, крім початку операції, був вище 70 одиниць. При аналізі рівня післяопераційної аналгезії за ВАШ найбільш оптимальний рівень спостерігався у 2-й і 4-й групах пацієнтів. Частота розвитку післяопераційної нудоти і блювання була нижче в основних групах дослідження: 2-га група — 17 %, 3-тя група — 12 %, 4-та група — 14 % порівняно з пацієнтами контрольної групи — 20 %. При оцінці пацієнтами якості проведеної анестезії за Iowa Satisfaction with Anesthesia Scale кращі результати були отримані в 4-й групі пацієнтів, у якій 25 % оцінили якість анестезії як добру, а 75 % — як відмінну. Найгірші результати були отримані в 1-й групі пацієнтів, 30 % з яких оцінили якість анестезії як задовільну. Висновки. Використання АNI-індексу в анестезіологічній практиці дозволяє з високим ступенем специфічності в режимі онлайн мониторувати рівень сприйняття болю в інтра- і післяопераційному періоді і забезпечити поліпшення періопераційної аналгезії. Застосування парацетамолу і дексмедетомідину забезпечує більш надійну і повноцінну періопераційну аналгезію.

Early individualized positive end-expiratory pressure guided by electrical impedance tomography in acute respiratory distress syndrome: a randomized controlled clinical trial

BackgroundIndividualized positive end-expiratory pressure (PEEP) by electrical impedance tomography (EIT) has potential interest in the optimization of ventilation distribution in acute respiratory distress syndrome (ARDS). The aim of the study was to determine whether early individualized titration of PEEP with EIT improved outcomes in patients with ARDS.MethodsA total of 117 ARDS patients receiving mechanical ventilation were randomly assigned to EIT group (n = 61, PEEP adjusted based on ventilation distribution) or control group (n = 56, low PEEP/FiO2 table). The primary outcome was 28-day mortality. Secondary and exploratory outcomes were ventilator-free days, length of ICU stay, incidence of pneumothorax and barotrauma, and difference in Sequential Organ Failure Assessment (SOFA) score at day 1 (ΔD1-SOFA) and day 2 (ΔD2-SOFA) compared with baseline.Measurements and main resultsThere was no statistical difference in the value of PEEP between the EIT group and control group, but the combination of PEEP and FiO2 was different between groups. In the control group, a significantly positive correlation was found between the PEEP value and the corresponding FiO2 (r = 0.47, p < 0.00001) since a given matched table was used for PEEP settings. Diverse combinations of PEEP and FiO2 were found in the EIT group (r = 0.05, p = 0.68). There was no significant difference in mortality rate (21% vs. 27%, EIT vs. control, p = 0.63), ICU length of stay (13.0 (7.0, 25.0) vs 10.0 (7.0, 14.8), median (25th–75th percentile); p = 0.17), and ventilator-free days at day 28 (14.0 (2.0, 23.0) vs 19.0 (0.0, 24.0), p = 0.55) between the two groups. The incidence of new barotrauma was zero. Compared with control group, significantly lower ΔD1-SOFA and ΔD2-SOFA were found in the EIT group (p < 0.001) in a post hoc comparison. Moreover, the EIT group exhibited a significant decrease of SOFA at day 2 compared with baseline (paired t-test, difference by − 1 (− 3.5, 0), p = 0.001). However, the control group did show a similar decrease (difference by 1 (− 2, 2), p = 0.131).ConclusionOur study showed a 6% absolute decrease in mortality in the EIT group: a statistically non-significant, but clinically non-negligible result. This result along with the showed improvement in organ function might justify further reserach to validate the beneficial effect of individualized EIT-guided PEEP setting on clinical outcomes of patients with ARDS.Trial registration: ClinicalTrials, NCT02361398. Registered 11 February 2015—prospectively registered, https://clinicaltrials.gov/show/NCT02361398.

Optimal injection interval for testosterone undecanoate treatment of hypogonadal and transgender men.

ObjectiveTo define the optimized inter-injection interval of injectable testosterone undecanoate (TU) treatment for hypogonadal and transmen based on individual dose titration in routine clinical practice.Design and methodsA prolective observational study of consecutive TU injections in men undergoing testosterone replacement therapy for pathological hypogonadism or masculinization of female-to-male transgender (transmen) subject to individual dosing titration to achieve a stable replacement regimen.ResultsFrom 2006 to 2019, 6899 injections were given to 325 consecutive patients. After excluding the 6-week loading dose, 6300 injections were given to 297 patients who had at least three and a median of 14 injections. The optimal injection interval (mean of last three injection intervals) had a median of 12.0 weeks (interquartile range 10.4–12.7 weeks). The interval was significantly influenced by age and body size (body surface area, BSA) but not by diagnosis or trough serum LH, FSH, and SHBG. Longer (≥14 weeks; 68/297, 23%), but not shorter (≤10 weeks; 22/297, 7.4%), intervals were weakly correlated with age but not diagnosis or other covariables. Low blood hemoglobin increased with trough serum testosterone to reach plateau once testosterone was about 10 nmol/L or higher.ConclusionOptimal intervals between TU injection after individual titration resulted in the approved 12-week interval in 70% of patients with only minor influence for clinical application of BSA and not of trough serum LH, FSH, and SHBG. Individually optimized inter-injection interval did not differ between men with primary or secondary hypogonadism or transmen.

Safety and pharmacokinetic analysis of UGT1A1 genotype-guided dosing of irinotecan.

3574 Background: Irinotecan is commonly used in the treatment of advanced colorectal and pancreatic cancer. The polymorphisms UGT1A1*28 (7 TA repeats) and UGT1A1*93 (SNP -3156G &gt; A) are significantly associated with increased systemic exposure of irinotecan’s active metabolite SN-38 and subsequently severe irinotecan-associated adverse-events (AEs) including (febrile) neutropenia and diarrhea. Severe AEs may lead to hospitalization, loss of quality of life, treatment delay and/or treatment discontinuation. Nonetheless, prospective genetic screening is not yet routinely performed. The aim of this study was to determine the safety and pharmacokinetics of UGT1A1 genotype-guided dosing of irinotecan in UGT1A1 poor metabolizers (PMs), i.e. UGT1A1 *28/*28 and/or UGT1A1*93/*93 individuals, in order to reduce the incidence of severe irinotecan-associated AEs. Methods: A prospective, multi-center, non-randomized study was conducted in patients intended to be treated with irinotecan at a dose of ≥ 180 mg/m2 or 450-600 mg flat dose. All patients were pre-therapeutically genotyped for UGT1A1*28 and UGT1A1*93. In UGT1A1 PMs, an initial 30% dose reduction in the first cycle was applied followed by further individual dose titration based on neutrophil count and clinical tolerability. The primary endpoint was the incidence of febrile neutropenia in the first 2 cycles of irinotecan treatment. UGT1A1 PMs were compared to 1] historical control patients, i.e. homozygous polymorphic patients treated with full dose therapy identified from systematic literature review and to 2] UGT1A1 non-PMs treated with standard dose therapy. In addition, systemic SN-38 exposure (AUC0-500h) of reduced dosing in the UGT1A1 PM cohort was compared to a standard dosed irinotecan patient cohort [doi: 10.1200/JCO.2000.18.1.195] by an independent T-test. Results: A total of 349 patients were pre-therapeutically genotyped and included for analysis. Thirty-one (8.9%) patients were UGT1A1 PM, in whom an initial median 30% dose reduction was applied. The incidence of febrile neutropenia in this group was 6.5% compared to 24% in historical controls (n = 50) (p = 0.042) and comparable with the incidence (4.1%; p = 0.632) in UGT1A1 non-PMs treated with full dose therapy. The systemic exposure of SN-38 of reduced dosing in UGT1A1 PMs (n = 17) was comparable to the systemic exposure of the standard dosed irinotecan patient cohort (n = 46) with a relative difference of +24% (p = 0.054) with a geometric mean (CV) of SN-38 AUC0-500h of 391 (43.7%) versus 298 (75.3%) ng*h/mL, respectively. Conclusions: UGT1A1 genotype-guided dosing significantly reduces the incidence of febrile neutropenia in UGT1A1 PM patients treated with irinotecan. In addition, systemic drug exposure remained adequate, despite the 30% dose reduction. Therefore, UGT1A1 genotype-guided dosing of irinotecan should be considered standard of care in order to improve the individual patient safety. Clinical trial information: Trial NL6270 (NTR6612).

Alternative Procedure to Individual Nasal Pressure Titration for Sleep Apnea.

In the treatment of obstructive sleep apnea (OSA), the current standard of “CPAP titration” in the laboratory or at home is a resource demanding and costly approach that, in developed economies, markedly augments healthcare costs and in low resource economies precludes access to care altogether. Here, we discuss that current guidelines for titration of CPAP could be obviated by taking a different route that in many ways is similar to the institution of treatment in many other medical conditions. To this effect, we present novel population based data from 16,780 patients, showing that after individualized and labor-intensive and expensive CPAP titration, 86.4% of OSA patients are treated with nasal pressure settings within the range of 9 ± 2 cmH2O, and review the literature to justify the potential adoption of a standard therapeutic CPAP setting as the initial intervention which would be subsequently followed by any necessary adjustments in only a minority of patients who would not derive the necessary benefit from such standardized intervention. Assuming an 80–85% success rate as derived from our analyses, our personal view if extensively adopted could radically reduce healthcare costs and enable markedly improve access to diagnostics.

Current and evolving standards of care for patients with ARDS.

Care for patients with acute respiratory distress syndrome (ARDS) has changed considerably over the 50 years since its original description. Indeed, standards of care continue to evolve as does how this clinical entity is defined and how patients are grouped and treated in clinical practice. In this narrative review we discuss current standards – treatments that have a solid evidence base and are well established as targets for usual care – and also evolving standards – treatments that have promise and may become widely adopted in the future. We focus on three broad domains of ventilatory management, ventilation adjuncts, and pharmacotherapy. Current standards for ventilatory management include limitation of tidal volume and airway pressure and standard approaches to setting PEEP, while evolving standards might focus on limitation of driving pressure or mechanical power, individual titration of PEEP, and monitoring efforts during spontaneous breathing. Current standards in ventilation adjuncts include prone positioning in moderate-severe ARDS and veno-venous extracorporeal life support after prone positioning in patients with severe hypoxemia or who are difficult to ventilate. Pharmacotherapy current standards include corticosteroids for patients with ARDS due to COVID-19 and employing a conservative fluid strategy for patients not in shock; evolving standards may include steroids for ARDS not related to COVID-19, or specific biological agents being tested in appropriate sub-phenotypes of ARDS. While much progress has been made, certainly significant work remains to be done and we look forward to these future developments.

Transcription Factor Binding Affinities and DNA Shape Readout.

SummaryAn essential event in gene regulation is the binding of a transcription factor (TF) to its target DNA. Models considering the interactions between the TF and the DNA geometry proved to be successful approaches to describe this binding event, while conserving data interpretability. However, a direct characterization of the DNA shape contribution to binding is still missing due to the lack of accurate and large-scale binding affinity data. Here, we use a binding assay we recently established to measure with high sensitivity the binding specificities of 13 Drosophila TFs, including dinucleotide dependencies to capture non-independent amino acid-base interactions. Correlating the binding affinities with all DNA shape features, we find that shape readout is widely used by these factors. A shape readout/TF-DNA complex structure analysis validates our approach while providing biological insights such as positively charged or highly polar amino acids often contact nucleotides that exhibit strong shape readout.