Assessment of Procalcitonin to Predict Outcome in Hypothermia-Treated Patients after Cardiac Arrest

Objective. Determine the potential of procalcitonin (PCT) to predict neurological outcome after hypothermia treatment following cardiac arrest.Methods. Retrospective analysis of patient data over a 2-year period. Mortality and neurological outcome of survivors were determined 6 months after cardiac arrest using the Cerebral Performance Category (CPC) score.Results. Data from 53 consecutive patients were analyzed. Median age was 63 (54–71) and 79% were male. Twenty-seven patients had good outcome (CPC ≤ 2) whereas 26 had severe neurological sequelae or died (CPC 3–5). At 48 h, after regaining normothermia, PCT was significantly higher in patients with bad outcome compared to those with good outcome: 3.38 (1.10–24.48) versus 0.28 (0–0.75) ng/mL (). PCT values correlated with bad neurological outcome (, ) and predicted outcome with an area under the curve of 0.84 (95% CI 0.73–0.96). A cutoff point of 1 ng/mL provided a sensitivity of 85% and a specificity of 81%. Above a PCT level of 16 ng/mL, no patient regained consciousness. PCT provided an additive value over simplified acute physiology score II.Conclusions. PCT might be an ancillary marker for outcome prediction after cardiac arrest treated by induced hypothermia.

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Abstract 199: Pulmonary Embolism and Accidental Hypothermia Have a Favorable Outcome in Cardiac Arrest With PEA Treated by ECPR

Circulation ◽

10.1161/circ.138.suppl_2.199 ◽

2018 ◽

Vol 138 (Suppl_2) ◽

Author(s):

Shinichi Ijuin ◽

Akihiko Inoue ◽

Nobuaki Igarashi ◽

Shigenari Matsuyama ◽

Tetsunori Kawase ◽

...

Keyword(s):

Pulmonary Embolism ◽

Cardiac Arrest ◽

Neurological Outcome ◽

Cerebral Performance Category ◽

Accidental Hypothermia ◽

Neurological Outcomes ◽

Good Outcome ◽

Group B ◽

Favorable Neurological Outcome ◽

Hospital Cardiac Arrest

Introduction: We have reported previously a favorable neurological outcome by extracorporeal cardiopulmonary resuscitation (ECPR) for out of hospital cardiac arrest. However, effects of ECPR on patients with prolonged pulseless electrical activity (PEA) are unclear. We analyzed etiology of patients with favorable neurological outcomes after ECPR for PEA with witness. Methods: In this single center retrospective study, from January 2007 to May 2018, we identified 68 patients who underwent ECPR for PEA with witness. Of these, 13 patients (19%) had good neurological outcome at 1 month (Glasgow-Pittsburgh Cerebral Performance Category (CPC):1-2, Group G), and 55 patients (81%) had unfavorable neurological outcome (CPC:3-5, Group B). We compared courses of treatment and causes/places of arrests between two groups. Results are expressed as mean ± SD. Results: Patient characteristics were not different between the two groups. Time intervals from collapse to induction of V-A ECMO were also not significantly different (Group G; 46.1 ± 20.2 min vs Group B; 46.8 ± 21.7 min, p=0.92). Ten patients achieved favorable neurological outcome among 39 (26%) with non-cardiac etiology. In cardiac etiology, only 3 of 29 patients (9%) had a good outcome at 1 month (p=0.08). In particular, 5 patients of 10 pulmonary embolism, and 4 of 4 accidental hypothermia responded well to ECPR with a favorable neurological outcome. Additionally, 6 of 13 (46%), who had in hospital cardiac arrest, had good outcome, whereas 7 of 55 (15%) who had out of hospital cardiac arrest, had good outcome (p=0.02). Conclusions: In our small cohort of cardiac arrest patients with pulmonary embolism or accidental hypothermia and PEA with witness, EPCR contributed to favorable neurological outcomes at 1 month.

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Prediction of regaining consciousness despite an early epileptiform EEG after cardiac arrest

Neurology ◽

10.1212/wnl.0000000000009283 ◽

2020 ◽

Vol 94 (16) ◽

pp. e1675-e1683 ◽

Cited By ~ 3

Author(s):

Giuseppina Barbella ◽

Jong Woo Lee ◽

Vincent Alvarez ◽

Jan Novy ◽

Mauro Oddo ◽

...

Keyword(s):

Cardiac Arrest ◽

Operating Characteristic ◽

Neuronal Damage ◽

Cerebral Performance Category ◽

Neuron Specific Enolase ◽

Area Under The Curve ◽

Performance Category ◽

Receiver Operating Characteristic Curves ◽

Normal Background ◽

Serum Neuron Specific Enolase

ObjectiveAfter cardiac arrest (CA), epileptiform EEG, occurring in about 1/3 of patients, often but not invariably heralds poor prognosis. We tested the hypothesis that a combination of specific EEG features identifies patients who may regain consciousness despite early epileptiform patterns.MethodsWe retrospectively analyzed a registry of comatose patients post-CA (2 Swiss centers), including those with epileptiform EEG. Background and epileptiform features in EEGs 12–36 hours or 36–72 hours from CA were scored according to the American Clinical Neurophysiology Society nomenclature. Best Cerebral Performance Category (CPC) score within 3 months (CPC 1–3 vs 4–5) was the primary outcome. Significant EEG variables were combined in a score assessed with receiver operating characteristic curves, and independently validated in a US cohort; its correlation with serum neuron-specific enolase (NSE) was also tested.ResultsOf 488 patients, 107 (21.9%) had epileptiform EEG <72 hours; 18 (17%) reached CPC 1–3. EEG 12–36 hours background continuity ≥50%, absence of epileptiform abnormalities (p < 0.00001 each), 12–36 and 36–72 hours reactivity (p < 0.0001 each), 36–72 hours normal background amplitude (p = 0.0004), and stimulus-induced discharges (p = 0.0001) correlated with favorable outcome. The combined 6-point score cutoff ≥2 was 100% sensitive (95% confidence interval [CI], 78%–100%) and 70% specific (95% CI, 59%–80%) for CPC 1–3 (area under the curve [AUC], 0.98; 95% CI, 0.94–1.00). Increasing score correlated with NSE (ρ = −0.46, p = 0.0001). In the validation cohort (41 patients), the score was 100% sensitive (95% CI, 60%–100%) and 88% specific (95% CI, 73%–97%) for CPC 1–3 (AUC, 0.96; 95% CI, 0.91–1.00).ConclusionPrognostic value of early epileptiform EEG after CA can be estimated combining timing, continuity, reactivity, and amplitude features in a score that correlates with neuronal damage.

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Circulating Levels of miR-574-5p Are Associated with Neurological Outcome after Cardiac Arrest in Women: A Target Temperature Management (TTM) Trial Substudy

Disease Markers ◽

10.1155/2019/1802879 ◽

2019 ◽

Vol 2019 ◽

pp. 1-10 ◽

Cited By ~ 2

Author(s):

Adeline Boileau ◽

Antonio Salgado Somoza ◽

Josef Dankiewicz ◽

Pascal Stammet ◽

Patrik Gilje ◽

...

Keyword(s):

Cardiac Arrest ◽

Neurological Outcome ◽

Cerebral Performance Category ◽

Temperature Management ◽

Target Temperature Management ◽

Target Temperature ◽

Circulating Micrornas ◽

Performance Category ◽

Poor Neurological Outcome ◽

Circulating Levels

Purpose. Postresuscitation neuroprognostication is guided by neurophysiological tests, biomarker measurement, and clinical examination. Recent investigations suggest that circulating microRNAs (miRNA) may help in outcome prediction after cardiac arrest. We assessed the ability of miR-574-5p to predict neurological outcome after cardiac arrest, in a sex-specific manner. Methods. In this substudy of the Target Temperature Management (TTM) Trial, we enrolled 590 cardiac arrest patients for which blood samples were available. Expression levels of miR-574-5p were measured by quantitative PCR in plasma samples collected 48 h after cardiac arrest. The endpoint of the study was poor neurological outcome at 6 months (cerebral performance category scores 3 to 5). Results. Eighty-one percent of patients were men, and 49% had a poor neurological outcome. Circulating levels of miR-574-5p at 48 h were higher in patients with a poor neurological outcome at 6 months (p<0.001), both in women and in men. Circulating levels of miR-574-5p were univariate predictors of neurological outcome (odds ratio (OR) [95% confidence interval (CI)]: 1.5 [1.26-1.78]). After adjustment with clinical variables and NSE, circulating levels of miR-574-5p predicted neurological outcome in women (OR [95% CI]: 1.9 [1.09-3.45]), but not in men (OR [95% CI]: 1.0 [0.74-1.28]). Conclusion. miR-574-5p is associated with neurological outcome after cardiac arrest in women.

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Post-resuscitation partial pressure of arterial carbon dioxide and outcome in patients with out-of-hospital cardiac arrest: a multicenter retrospective cohort study

10.21203/rs.3.rs-882819/v1 ◽

2021 ◽

Author(s):

Nobunaga Okada ◽

Tasuku Matsuyama ◽

Yohei Okada ◽

Asami Okada ◽

Kenji Kandori ◽

...

Keyword(s):

Cardiac Arrest ◽

Neurological Outcome ◽

Cerebral Performance Category ◽

Multivariate Logistic Regression Analysis ◽

Spontaneous Circulation ◽

Performance Category ◽

Neurological Outcomes ◽

Significant Difference ◽

Poor Neurological Outcome ◽

Hospital Cardiac Arrest

Abstract We aimed to estimate the association between PaCO2 level in the patient after out-of-hospital cardiac arrest (OHCA) resuscitation with patient outcome based on a multicenter prospective cohort registry in Japan between June 2014 and December 2015.Based on the PaCO2 within 24-h after return of spontaneous circulation (ROSC), patients were divided into six groups as follow; severe hypocapnia (<25mmHg), mild hypocapnia (25–35mmHg,), normocapnia (35–45mmHg), mild hypercapnia (45–55mmHg), severe hypercapnia (>55mmHg), exposure to both hypocapnia and hypercapnia. Multivariate logistic regression analysis was conducted to calculate the adjusted odds ratios (aORs) and 95% confidence interval (CI) for the 1-month poor neurological outcome (Cerebral Performance Category ≥3). Among the 13491 OHCA patients, 607 were included. Severe hypocapnia, mild hypocapnia, severe hypercapnia, and exposure to both hypocapnia and hypercapnia were associated with a higher rate of 1-month poor neurological outcome compared with mild hypercapnia (aOR 6.68 [95% CI 2.16–20.67], 2.56 [1.30–5.04], 2.62 [1.06–6.47], 5.63 [2.21–14.34]; respectively). There was no significant difference between the outcome of patients with normocapnia and mild hypercapnia. In conclusion, maintaining normocapnia and mild hypercapnia during the 24-h after ROSC was associated with better neurological outcomes than other PaCO2 abnormalities in this study.

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Prediction of Neurologically Intact Survival in Cardiac Arrest Patients without Pre-Hospital Return of Spontaneous Circulation: Machine Learning Approach

Journal of Clinical Medicine ◽

10.3390/jcm10051089 ◽

2021 ◽

Vol 10 (5) ◽

pp. 1089

Author(s):

Dong-Woo Seo ◽

Hahn Yi ◽

Hyun-Jin Bae ◽

Youn-Jung Kim ◽

Chang-Hwan Sohn ◽

...

Keyword(s):

Machine Learning ◽

Cardiac Arrest ◽

Neurological Outcome ◽

Cerebral Performance Category ◽

Area Under The Curve ◽

Spontaneous Circulation ◽

Good Neurological Outcome ◽

Return Of Spontaneous Circulation ◽

Neurological Outcomes ◽

Neurologically Intact

Current multimodal approaches for the prognostication of out-of-hospital cardiac arrest (OHCA) are based mainly on the prediction of poor neurological outcomes; however, it is challenging to identify patients expected to have a favorable outcome, especially before the return of spontaneous circulation (ROSC). We developed and validated a machine learning-based system to predict good outcome in OHCA patients before ROSC. This prospective, multicenter, registry-based study analyzed non-traumatic OHCA data collected between October 2015 and June 2017. We used information available before ROSC as predictor variables, and the primary outcome was neurologically intact survival at discharge, defined as cerebral performance category 1 or 2. The developed models’ robustness were evaluated and compared with various score metrics to confirm their performance. The model using a voting classifier had the best performance in predicting good neurological outcome (area under the curve = 0.926). We confirmed that the six top-weighted variables predicting neurological outcomes, such as several duration variables after the instant of OHCA and several electrocardiogram variables in the voting classifier model, showed significant differences between the two neurological outcome groups. These findings demonstrate the potential utility of a machine learning model to predict good neurological outcome of OHCA patients before ROSC.

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l-arginine, asymmetric and symmetric dimethylarginine for early outcome prediction in unselected cardiac arrest victims: a prospective cohort study

Internal and Emergency Medicine ◽

10.1007/s11739-021-02767-z ◽

2021 ◽

Author(s):

Beata Csiszar ◽

Zsolt Marton ◽

Janos Riba ◽

Peter Csecsei ◽

Lajos Nagy ◽

...

Keyword(s):

Cardiac Arrest ◽

Neurological Outcome ◽

Plasma Concentrations ◽

Cerebral Performance Category ◽

Simplified Acute Physiology Score ◽

Characteristic Analysis ◽

Symmetric Dimethylarginine ◽

Failure Assessment ◽

Poor Neurological Outcome ◽

Hospital Cardiac Arrest

AbstractEarly prediction of the mortality, neurological outcome is clinically essential after successful cardiopulmonary resuscitation. To find a prognostic marker among unselected cardiac arrest survivors, we aimed to evaluate the alterations of the l-arginine pathway molecules in the early post-resuscitation care. We prospectively enrolled adult patients after successfully resuscitated in- or out-of-hospital cardiac arrest. Blood samples were drawn within 6, 24, and 72 post-cardiac arrest hours to measure asymmetric and symmetric dimethylarginine (ADMA and SDMA) and l-arginine plasma concentrations. We recorded Sequential Organ Failure Assessment, Simplified Acute Physiology Score, and Cerebral Performance Category scores. Endpoints were 72 h, intensive care unit, and 30-day mortality. Among 54 enrolled patients [median age: 67 (61–78) years, 48% male], the initial ADMA levels were significantly elevated in those who died within 72 h [0.88 (0.64–0.97) µmol/L vs. 0.55 (0.45–0.69) µmol/L, p = 0.001]. Based on receiver operator characteristic analysis (AUC = 0.723; p = 0.005) of initial ADMA for poor neurological outcome, the best cutoff was determined as > 0.65 µmol/L (sensitivity = 66.7%; specificity = 81.5%), while for 72 h mortality (AUC = 0.789; p = 0.001) as > 0.81 µmol/L (sensitivity = 71.0%; specificity = 87.5%). Based on multivariate analysis, initial ADMA (OR = 1.8 per 0.1 µmol/L increment; p = 0.002) was an independent predictor for 72 h mortality. Increased initial ADMA predicts 72 h mortality and poor neurological outcome among unselected cardiac arrest victims.

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Serum Neurofilament Measurement Improves Clinical Risk Score for Outcome Prediction After Cardiac Arrest: Results of A Prospective Study

10.21203/rs.3.rs-92711/v1 ◽

2020 ◽

Author(s):

Sabina Hunziker ◽

Adrian Quinto ◽

Maja Ramin-Wright ◽

Christoph Becker ◽

Katharina Beck ◽

...

Keyword(s):

Cardiac Arrest ◽

Single Molecule ◽

Neurological Outcome ◽

Outcome Prediction ◽

Cerebral Performance Category ◽

Neuron Specific Enolase ◽

Risk Scores ◽

Neurofilament Light Chain ◽

Clinical Risk ◽

Poor Neurological Outcome

Abstract Background: A recent study found serum neurofilament light chain (NfL) levels to be strongly associated with poor neurological outcome in patients after cardiac arrest. Our aim was to confirm these findings in an independent validation study and to investigate whether NfL improves the prognostic value of two cardiac arrest risk scores.Methods: This prospective, single-center study included 164 consecutive adult cardiac arrest patients upon intensive care unit admission. We calculated two clinical risk scores (OHCA, CAHP) and measured NfL on admission using the single molecule array NF-light® assay. The primary endpoint was neurological outcome at hospital discharge assessed with the cerebral performance category (CPC) score.Results: Poor neurological outcome (CPC≥3) was found in 60% (98/164) of patients, and 55% (91/164) died. Compared to patients with favorable outcome, NfL was 14-times higher in patients with poor neurological outcome (685±1787 vs. 49±111pg/mL), with an adjusted odds ratio of 3.4 (95%CI 2.1 to 5.6, p<0.001) and an area under the curve (AUC) of 0.82. Adding NfL to the clinical risk scores significantly improved discrimination of both the OHCA score (from AUC 0.82 to 0.89, p<0.001) and CAHP score (from AUC 0.89 to 0.92, p<0.05). Admission NfL showed better outcome prediction compared to neuron-specific enolase (NSE) (AUC 0.84 vs.0.69, p=0.01).Conclusions: This study confirms the high performance of admission NfL alone and in combination with two clinical risk scores to prognosticate clinical outcome in patients after cardiac arrest. NfL should be considered as a standard laboratory measures in the evaluation of cardiac arrest patients.

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Serum neurofilament measurement improves clinical risk scores for outcome prediction after cardiac arrest: results of a prospective study

Critical Care ◽

10.1186/s13054-021-03459-y ◽

2021 ◽

Vol 25 (1) ◽

Author(s):

Sabina Hunziker ◽

Adrian Quinto ◽

Maja Ramin-Wright ◽

Christoph Becker ◽

Katharina Beck ◽

...

Keyword(s):

Cardiac Arrest ◽

Single Molecule ◽

Neurological Outcome ◽

Cerebral Performance Category ◽

Area Under The Curve ◽

Risk Scores ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Clinical Risk ◽

Poor Neurological Outcome

Abstract Background A recent study found serum neurofilament light chain (NfL) levels to be strongly associated with poor neurological outcome in patients after cardiac arrest. Our aim was to confirm these findings in an independent validation study and to investigate whether NfL improves the prognostic value of two cardiac arrest-specific risk scores. Methods This prospective, single-center study included 164 consecutive adult after out-of-hospital cardiac arrest (OHCA) patients upon intensive care unit admission. We calculated two clinical risk scores (OHCA, CAHP) and measured NfL on admission within the first 24 h using the single molecule array NF-light® assay. The primary endpoint was neurological outcome at hospital discharge assessed with the cerebral performance category (CPC) score. Results Poor neurological outcome (CPC > 3) was found in 60% (98/164) of patients, with 55% (91/164) dying within 30 days of hospitalization. Compared to patients with favorable outcome, NfL was 14-times higher in patients with poor neurological outcome (685 ± 1787 vs. 49 ± 111 pg/mL), with an adjusted odds ratio of 3.4 (95% CI 2.1 to 5.6, p < 0.001) and an area under the curve (AUC) of 0.82. Adding NfL to the clinical risk scores significantly improved discrimination of both the OHCA score (from AUC 0.82 to 0.89, p < 0.001) and CAHP score (from AUC 0.89 to 0.92, p < 0.05). Adding NfL to both scores also resulted in significant improvement in reclassification statistics with a Net Reclassification Index (NRI) of 0.58 (p < 0.001) for OHCA and 0.83 (p < 0.001) for CAHP. Conclusions Admission NfL was a strong outcome predictor and significantly improved two clinical risk scores regarding prognostication of neurological outcome in patients after cardiac arrest. When confirmed in future outcome studies, admission NfL should be considered as a standard laboratory measures in the evaluation of OHCA patients.

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Impact of the cardiopulmonary resuscitation-related injuries on the prognosis after cardiac arrest

European Heart Journal ◽

10.1093/ehjci/ehaa946.1819 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

C Merino Argos ◽

I Marco Clement ◽

S.O Rosillo Rodriguez ◽

L Martin Polo ◽

E Arbas Redondo ◽

...

Keyword(s):

Cardiac Arrest ◽

Cardiopulmonary Resuscitation ◽

Cerebral Performance Category ◽

University Hospital ◽

Temperature Management ◽

Performance Category ◽

Neurological Outcomes ◽

Cardiac Care Unit ◽

Sternal Fractures

Abstract Background Cardiopulmonary resuscitation (CPR) manoeuvres involve vigorous compressions with the proper depth and rate in order to keep sufficient perfusion to organs, especially the brain. Accordingly, high incidences of CPR-related injuries (CPR-RI) have been observed in survivors after cardiac arrest (CA). Purpose To analyse whether CPR-related injuries have an impact on the survival and neurological outcomes of comatose survivors after CA. Methods Observational prospective database of consecutive patients (pts) admitted to the acute cardiac care unit of a tertiary university hospital after in-hospital and out-of-hospital CA (IHCA and OHCA) treated with targeted temperature management (TTM 32–34°) from August 2006 to December 2019. CPR-RI were diagnosed by reviewing medical records and analysing image studies during hospitalization. Results A total of 498 pts were included; mean age was 62.7±14.5 years and 393 (78.9%) were men. We found a total of 145 CPR-RI in 109 (21.9%) pts: 79 rib fractures, 20 sternal fractures, 5 hepatic, 5 gastrointestinal, 3 spleen, 1 kidney, 26 lung and 6 heart injuries. Demographic characteristics and cardiovascular risk factors did not differ between the non-CPR-RI group and CPR-RI group. Also, we did not find differences in CA features (Table 1). Survival at discharge was higher in the CPR-RI group [74 (67.8%) vs 188 (48.3%); p<0.001]. Moreover, Cerebral Performance Category (CPC) 1–2 within a 3-month follow-up was significantly higher in the CPR-RI group [(71 (65.1%) vs 168 (43.2%); p<0.001; Figure 1]. Finally, pts who recieved blood transfusions were proportionally higher in the CPR-RI group [34 (32.1%) vs 65 (16.7%)]; p=0.004). Conclusions In our cohort, the presence of CPR-RI was associated with higher survival at discharge and better neurological outcomes during follow-up. Figure 1 Funding Acknowledgement Type of funding source: None

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Abstract 115: One-Year Outcomes in Individual Domains of the Cerebral Performance Category Extended

Circulation ◽

10.1161/circ.138.suppl_2.115 ◽

2018 ◽

Vol 138 (Suppl_2) ◽

Author(s):

Katharyn L Flickinger ◽

Melissa J Repine ◽

Stephany Jaramillo ◽

Allison C Koller ◽

Margo Holm ◽

...

Keyword(s):

Cardiac Arrest ◽

Return To Work ◽

Short Term Memory ◽

Demographic Data ◽

Cerebral Performance Category ◽

Logical Thinking ◽

Short Term ◽

Performance Category ◽

Term Memory

Introduction: Cognitive and physical impairments are common in cardiac arrest survivors. Global measures including the Modified Rankin Scale (mRS), Cerebral Performance Category (CPC) and the 10-domain CPC-Extended (CPC-E) tend to improve over 1 year. The CPC-E is scored from 1-5 with higher scores signifying greater impairment. However, with the CPC-E, individual functional domains (alertness, logical thinking, attention, motor skills, short-term memory, basic and complex activities of daily living (ADL), mood, fatigue, and return to work) may recover at different rates. Hypothesis: We hypothesized that patients would have recovery in all domains of the CPC-E at 1 year after index cardiac arrest. Methods: A prospective cohort study of cardiac arrest survivors was conducted between 2/1/16 and 5/31/17. Chart review was done for baseline demographic data. Outcome measures including mRS, CPC, and CPC-E scores were assessed at discharge, 3 months, 6 months, and 1 year. We defined recovery of a CPC-E domain when >90% of patients had scores of 1-2 in that domain. Results: Of 71 subjects, 35 completed the CPC-E at discharge, 35 at 3 months, 25 at 6 months and 31 at 1 year. The most common reasons for exclusion were patient declined or were lost to follow up. The majority (N=37; 52%) were female, with a mean (SD) age of 58(17) years. Most arrests occurred out of hospital (N= 49; 69%), 27 (38%) had a shockable rhythm and the majority (N=37; 54%) were discharged home. CPC-E domains of alertness (N=35, 100%) logical thinking (N=35; 100%), and attention (N=33; 94%) recovered by hospital discharge. BADLs were recovered by 3 months (N=33; 94%). The majority of patients (N=24;77%) experienced slight-to-no disability or symptoms (mRS 0-2 / CPC 1-2) at 1 year follow up. CPC-E short term memory (67%), motor (87%), mood (87%), fatigue (13%), complex ADL (74%), and return to work (55%) did not recover fully by 1 year. Conclusions: In survivors of cardiac arrest, CPC-E domains of alertness, logical thinking, and attention recover rapidly, while domains of short term memory, motor, mood, fatigue, complex ADL and ability to return to work are chronically impaired 1 year after arrest. Interventions to improve recovery in these domains are needed.

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