Competition between Allowed and First-Forbidden ß Decay: The Case of

The ß decay of ^{208}Hg into the one-proton hole, one neutron-particle _{81}^{208}Tl_{127} nucleus was investigated at CERN-ISOLDE. Shell-model calculations describe well the level scheme deduced, validating the proton-neutron interactions used, with implications for the whole of the N>126, Z<82 quadrant of neutron-rich nuclei. While both negative and positive parity states with spin 0 and 1 are expected within the Q_{ß} window, only three negative parity states are populated directly in the ß decay. The data provide a unique test of the competition between allowed Gamow-Teller and Fermi, and first-forbidden ß decays, essential for the understanding of the nucleosynthesis of heavy nuclei in the rapid neutron capture process. Furthermore, the observation of the parity changing 0^{+}→0^{-}ß decay where the daughter state is core excited is unique, and can provide information on mesonic corrections of effective operators.

Using local knowledge and sustainable transport to promote a greener city: The case of Bucharest, Romania.

Cities undergoing climate change and rapid urbanization are faced with significant transformational processes that affect the environment and society, challenging them to become more sustainable and resilient. The promotion of nature-based solutions represents an efficient approach to meet sustainability targets in cities and improve the quality of life of citizens. The association of large components of green infrastructure, such as urban parks, with physical activity can counteract the sedentary lifestyle endemic to cities and improve the overall health and well-being of individuals (Carrus et al., 2013; Scopelliti et al., 2016). By promoting a sustainable means of transport and connecting green spaces within a highly urbanized city, bicycle lanes represent an effective tool for associating physical activity with nature in cities allowing bicycle users to benefit from the positive health effects of nature-based solutions. Our study focuses on the potential of bicycle lanes to improve functional connectivity among green spaces. We administered 820 questionnaires in 34 green spaces (i.e., urban parks) in Bucharest, Romania, to identify the factors influencing the use of bicycle lanes connecting urban parks and to understand which planning criteria for bicycle lanes are considered as the most important by park visitors. We applied binary and ordinal logistic regressions and found that the factors affecting bicycle lane use are illegally parked cars and lack of accessibility to urban parks. The criteria preferred by park visitors for bicycle lane planning are determined by experience level and frequency of bicycle use. To develop a functional and integrated bicycle lane network that can make cities healthier and more sustainable, policy makers are advised to engage in a public participatory process and focus on the needs of bicycle users.

European Society of Endocrine Surgeons (ESES) and European Network for the Study of Adrenal Tumours (ENSAT) recommendations for the surgical management of adrenocortical carcinoma.

BACKGROUND: Radical surgery provides the best chance of cure for adrenocortical carcinoma (ACC), but perioperative surgical care for these patients is yet to be standardized. METHODS: A working group appointed jointly by ENSAT and ESES used Delphi methodology to produce evidence-based recommendations for the perioperative surgical care of patients with ACC. Papers were retrieved from electronic databases. Evidence and recommendations were classified according to the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system, and were discussed until consensus was reached within the group. RESULTS: Twenty-five recommendations for the perioperative surgical care of patients with ACC were formulated. The quality of evidence is low owing to the rarity of the disease and the lack of prospective surgical trials. Multi-institutional prospective cohort studies and prospective RCTs are urgently needed and should be strongly encouraged. CONCLUSION: The present evidence-based recommendations provide comprehensive advice on the optimal perioperative care for patients undergoing surgery for ACC.

Multifaceted Quadruplet of Low-Lying Spin-Zero States in

A search for shape isomers in the ^{66}Ni nucleus was performed, following old suggestions of various mean-field models and recent ones, based on state-of-the-art Monte Carlo shell model (MCSM), all considering ^{66}Ni as the lightest nuclear system with shape isomerism. By employing the two-neutron transfer reaction induced by an ^{18}O beam on a ^{64}Ni target, at the sub-Coulomb barrier energy of 39 MeV, all three lowest-excited 0^{+} states in ^{66}Ni were populated and their γ decay was observed by γ-coincidence technique. The 0^{+} states lifetimes were assessed with the plunger method, yielding for the 0_{2}^{+}, 0_{3}^{+}, and 0_{4}^{+} decay to the 2_{1}^{+} state the B(E2) values of 4.3, 0.1, and 0.2 Weisskopf units (W.u.), respectively. MCSM calculations correctly predict the existence of all three excited 0^{+} states, pointing to the oblate, spherical, and prolate nature of the consecutive excitations. In addition, they account for the hindrance of the E2 decay from the prolate 0_{4}^{+} to the spherical 2_{1}^{+} state, although overestimating its value. This result makes ^{66}Ni a unique nuclear system, apart from ^{236,238}U, in which a retarded γ transition from a 0^{+} deformed state to a spherical configuration is observed, resembling a shape-isomerlike behavior.

Diagnosis, treatment and outcome of adrenocortical cancer.

BACKGROUND: Adrenocortical cancer (ACC) is a rare disease with a dismal prognosis. The majority of patients are diagnosed with advanced disease and raise difficult management challenges. METHODS: All references identified in PubMed, published between 2004 and 2014, using the keywords 'adrenocortical cancer' or 'adrenal surgery' or both, were uploaded into a database. The database was interrogated using keywords specific for each field studied. RESULTS: In all, 2049 publications were identified. There is ongoing debate about the feasibility and oncological outcomes of laparoscopic adrenalectomy for small ACCs, and data derived from institutional case series have failed to provide an evidence level above expert opinion. The use of mitotane (1-(2-chlorophenyl)-1-(4-chlorophenyl)-2,2-dichloroethane) in combination with chemotherapy in the treatment of metastatic disease has been assessed in an international randomized trial (FIRM-ACT trial) involving patients with ACC. Based on this trial, mitotane plus etoposide, doxorubicin and cisplatin is now the established first-line cytotoxic therapy owing to a higher response rate and longer median progression-free survival than achieved with streptozocin-mitotane. For patients with tumours smaller than 5 cm and with no signs of lymph node or distant metastases, survival is favourable with a median exceeding 10 years. However, the overall 5-year survival rate for all patients with ACC is only 30 per cent. CONCLUSION: Open and potentially laparoscopic adrenalectomy for selected patients is the main treatment for non-metastatic ACC, but the overall 5-year survival rate remains low.

Surgery for phaeochromocytomas and paragangliomas: Current practice in the United Kingdom.

INTRODUCTION: There is wide variability in the perioperative management of phaeochromocytoma and paraganglioma (PPGL) in different centres. This study aimed to summarise the management of PPGLs as reported in the United Kingdom Registry for Endocrine and Thyroid Surgery (UKRETS) database and to determine current perioperative management of PPGLs by surveying UK clinicians. METHODS: Data recorded on UKRETS from 2005 to 2021 were subjected to descriptive analyses. British Association of Endocrine and Thyroid Surgeons members were invited to participate in an open survey relating to the perioperative management of patients with PPGLs. RESULTS: A total of 2,007 operations for PPGL from 49 participating centres were included. The median annual workload in each centre was four cases. Operations were performed predominantly laparoscopically (69%). The median length of stay (4 days) was the same in groups of surgeons stratified by volume. The survey had 29 respondents from 22 centres across the UK, and a formal protocol for perioperative management exists in 48% of the centres. Phenoxybenzamine (72%) was preferred for alpha-blockade. The practice of admitting patients for optimisation from 1 to 7 days before the day of surgery was common (62%). Central venous pressure and blood glucose monitoring were mentioned as routine intraoperative adjuncts by 72% of the responders. CONCLUSIONS: There is significant variation in the workload and perioperative management of PPGLs in the UK. This is potentially detrimental to patient outcomes and a consensus document might be beneficial to harmonise practice across the UK.

Unveiling the Unexpected: Co-occurrence of Acute Pancreatitis and Riedel's Lobe.

Riedel's lobe is a rare anatomical variant of the liver, more often being diagnosed incidentally, with the patient being investigated for other underlying pathology. As regards acute pancreatitis, this represents one of the most treated diseases worldwide in gastroenterology with a variable severity and outcome. Here, we report a case of a non-palpable Riedel's lobe in a 47-year-old man, smoker, and chronic alcohol consumer, who presented to the hospital with epigastric pain radiating in the right hypochondrium, accompanied by nausea. Based on his clinical examination, laboratory, and imaging findings, he was admitted in the gastroenterology department with the diagnosis of alcohol-related acute pancreatitis. The computed tomography scan emphasized the presence of Riedel's lobe, causing an increased anterior diameter of the liver. Riedel's lobe is, in most cases, an unforeseen radiologic disclosure, which can remain clinically latent, or it can raise confusion regarding the differential diagnosis.

Risk of malignancy in thyroid nodules with indeterminate (THY3f) cytology.

BACKGROUND: Fine-needle aspiration cytology (FNAC) is an integral part of thyroid nodule assessment. Nodules with an indeterminate cytology (THY3a-f) require formal histological assessment to confirm benign or malignant pathology. This study aimed to provide data for an evidence-based approach for management of patients with THY3f nodules. METHODS: Retrospective review of patients who had a thyroid FNAC reported as suspicious of follicular neoplasm (THY3f) or showing atypia (THY3a) were identified, and clinical, operative and outcomes data were analysed. RESULTS: Between 2018 and 2020, 200 patients (167F:33M, median age 51 years (range:18-86 years)) had a THY3f cytology. Most presented with a palpable nodule (n=104; 68.4%). Overall, 152 (76.0%;130F:23M) underwent surgery and 31 (20.4%) were found to have a thyroid carcinoma (22 follicular carcinomas, 7 papillary carcinomas, 1 medullary thyroid carcinoma and 1 metastatic renal carcinoma). An additional incidental carcinoma (size: 0.7-13mm) was found in seven (4.6%). Among those with cancer, a completion thyroidectomy and radioactive iodine treatment was indicated in nine (<6% of the entire cohort). Previously suggested risk factors for malignancy, eg male gender, large tumour size (>4cm) or age, were not found to be associated with increased risk. During the same period, THY3a cytology was reported in 53 patients, of whom 29 underwent diagnostic surgery and 4 patients were found to have a thyroid cancer (follicular, n=3 and medullary, n=1). CONCLUSION: One in five patients with features suspicious of a follicular neoplasm (THY3f) has a thyroid carcinoma. This risk is much lower for THY3a. This study reinforces the current recommendation for thyroid surgery in all patients with a reliable THY3f cytology, as no further stratifying risk factors could be identified.

Thyroid lobectomy for low-risk thyroid cancers.

BACKGROUND: The 2016 American Thyroid Association (ATA) guidelines proposed thyroid lobectomy for low-risk differentiated thyroid cancer (DTC); however, this approach is yet to be widely adopted. The aim of the study was to review our practice over three years following the publication of these guidelines identifying patients who underwent lobectomy-only for low-risk DTC in two regional units in the same multidisciplinary team (MDT). METHOD: A retrospective review of patients who were operated between January 2016 and December 2018 was carried out. RESULTS: In total, 288 patients undergoing thyroid surgery were included. The preoperative distribution of cytology was: Thy 1 or 2 in 46, THY3a in 57, THY3f in 154, THY4 in 18 and THY5 in 13 patients. Median size of nodules was 26mm (range 1-70mm). DTC was diagnosed in 95 patients (33%). Overall, 39% (n = 37) of patients underwent completion thyroidectomy according to ATA recommendations on size or adverse histological features. The only variable associated with likelihood of completion was tumour size (p < 0.05, OR 1.14). Ten patients were discharged following surgery with no further follow-up as they had T1a/b well-differentiated DTC with no high-risk histological features. CONCLUSION: Lobectomy-only appears to be the current surgical practice in two-thirds of patients presenting to our regional units with differentiated thyroid carcinoma. In the context of the current drive to reduce the extent of treatment for low-risk thyroid cancer, there is a need for a more homogeneous approach to these patients and for protocols for long-term follow-up after lobectomy-only.

Post-thyroidectomy tracheomalacia: minimal risk despite significant tracheal compression.

BACKGROUND: Tracheomalacia is a feared complication of goitre surgery, but considered rare in the Western World. This study aimed to estimate the risk of tracheomalacia in a contemporary series of patients with goitres causing significant tracheal compression. METHODS: A retrospective review was conducted of thyroidectomies performed in a UK tertiary referral centre over a 30 month period. Anaesthetic, operative, radiological, and pathological data were obtained from medical notes and hospital software systems. RESULTS: Of 334 patients who underwent thyroid surgery, preoperative CT scan was performed in 101 (30%). Tracheal compression was reported in 62 patients (19%) with minimum tracheal diameter ranging from 2 to 15 mm (mean 7.6 mm) due to multinodular goitre (n=50), malignancy (n=10), or thyroiditis (n=2). Critical compression <5 mm was observed in 18 patients (6%) and 35 patients had compression to 6-10 mm. Awake fibreoptic intubation was performed in eight patients (six of those with tracheas <5 mm) and asleep fibreoptic intubation was performed in one. Standard intubation was performed otherwise. All patients were recovered on a general surgical ward. None required tracheostomy or tracheal stenting. The incidence of tracheomalacia was 0 (95% confidence interval 0.0-4.8%). Mean length of stay was 2.4 days in those with tracheas <5 mm and 2.0 days in those >5 mm. CONCLUSIONS: We found no evidence of tracheomalacia in high-risk patients with significant tracheal compression. This supports prior work on retrosternal goitres suggesting that the risk of tracheomalacia is minimal in modern thyroid surgery. For risk management, however, we would still advocate that such patients be managed in units with multispeciality support.

Comparative performances of nomograms and conditional survival after resection of adrenocortical cancer.

BACKGROUND: Adrenocortical carcinomas (ACCs) carry a poor prognosis. This study assessed the comparative performance of existing nomograms in estimating the likelihood of survival, along with the value of conditional survival estimation for patients who had already survived for a given length of time after surgery. METHODS: This was an observational study based on a prospectively developed departmental database that recorded details of patients operated for ACC in a UK tertiary referral centre. RESULTS: Of 74 patients with ACC managed between 2001 and 2020, data were analysed for 62 patients (32 women and 30 men, mean(s.d.) age 51(17) years) who had primary surgical treatment in this unit. Laparoscopic (9) or open adrenalectomies (53) were performed alone or in association with a multivisceral resection (27). Most of the tumours were left-sided (40) and 18 were cortisol-secreting.Overall median survival was 33 months, with 1-, 3- and 5-year survival rates of 79, 49, and 41 per cent respectively. Age over 55 years, higher European Network for Study of Adrenal Tumours stage, and cortisol secretion were associated with poorer survival in univariable analyses. Four published nomograms suggested widely variable outcomes that did not correlate with observed overall survival at 1, 3 or 5 years after operation. The 3-year conditional survival at 2 years (probability of surviving to postoperative year 5) was 65 per cent, compared with a 5-year actuarial survival rate of 41 per cent calculated from the time of surgery. CONCLUSION: Survival of patients with ACC correlates with clinical parameters but not with published nomograms. Conditional survival might provide a more accurate estimate of survival for patients who have already survived for a certain amount of time after resection.

A novel calibration for L-shell x-ray fluorescence measurements of bone lead concentration using the strontium Kß/Kαratio.

Objective. Lead (Pb) is a well-known toxic element.In vivobone Pb concentration measurement is a long-term exposure metric complementary to blood Pb concentration measurement which is a metric of recent exposure.In vivohuman tibia bone Pb measurements using Pb K-shell or L-shell x-ray fluorescence (KXRF or LXRF) emissions were developed in the 1980s. KXRF bone Pb measurements using Cd-109 gamma rays and coherent-to-fluorescence ratio to account for differences between phantom andin vivomeasurements, was employed in human studies. Bone Pb LXRF method employed x-ray tubes. However, calibration procedures using ultrasound measurements of the soft tissue thickness (STT) proved inaccurate.Approach. In this study, bone and soft tissue (ST) phantoms simulatedin vivobone Pb measurements. Seven plaster-of-Paris cylindrical bone phantoms containing 1.01 mg g-1of strontium (Sr) were doped with Pb in 0, 8, 16, 29, 44, 59, and 74 µg g-1concentrations. Polyoxymethylene (POM), resin, and wax were each used to fabricate four ST phantoms in the approximate 1-4 mm thickness range. Pb LXRF measurements were performed using a previously developed optimal grazing incidence position method.Main results. Linear attenuation coefficients measurements of ST materials indicated that POM and resin mimicked well attenuation of Pb x-rays in skin and adipose tissue, respectively. POM and resin data indicated a bone Pb detection limit of 20 µg g-1for a 2 mm STT. Derived relationships between the Pb concentration, Pb LXRF and Sr Kß/Kαratio data did not require STT knowledge. Applied to POM and resin data, the new calibration method yielded unbiased results.Significance.In vivobone Pb measurements in children were suggested following considerations of radiation dose, STT, detectability and distribution of Pb and Sr in bone. This research meets with the concerns regarding the negative effects of low levels of Pb exposure on neurodevelopment of children.

Hypoxia stimulates angiogenesis and a metabolic switch in human parathyroid adenoma cells.

Hypoxia, a primary stimulus for angiogenesis, is important for tumour proliferation and survival. The effects of hypoxia on parathyroid tumour cells, which may also be important for parathyroid autotransplantation in patients, are, however, unknown. We, therefore, assessed the effects of hypoxia on gene expression in parathyroid adenoma (PA) cells from patients with primary hyperparathyroidism. Cell suspensions from human PAs were cultured under normoxic or hypoxic conditions and then subjected to cDNA expression analysis. In total, 549 genes were significantly upregulated and 873 significantly downregulated. The most highly upregulated genes (carbonic anhydrase 9 (CA9), Solute carrier family 2A1 (SLC2A1) and hypoxia-inducible lipid droplet-associated protein (HIG2)) had known involvement in hypoxia responses. Dysregulation of oxidative phosphorylation and glycolysis pathway genes were also observed, consistent with data indicating that cells shift metabolic strategy of ATP production in hypoxic conditions and that tumour cells predominantly utilise anaerobic glycolysis for energy production. Proliferation- and angiogenesis-associated genes linked with growth factor signalling, such as mitogen-activated protein kinase kinase 1 (MAP2K1), Jun proto-oncogene (JUN) and ETS proto-oncogene 1 (ETS1), were increased, however, Ras association domain family member 1 (RASSF1), an inhibitor of proliferation was also upregulated, indicating these pathways are unlikely to be biased towards proliferation. Overall, there appeared to be a shift in growth factor signalling pathways from Jak-Stat and Ras signaling to extracellular signal-regulated kinases (ERKs) and hypoxia-inducible factor (HIF)-1α signalling. Thus, our data demonstrate that PAs, under hypoxic conditions, promote the expression of genes known to stimulate angiogenesis, as well as undergoing a metabolic switch.

Litigation related to airway and respiratory complications of anaesthesia: an analysis of claims against the NHS in England 1995-2007.

Claims notified to the NHS Litigation Authority in England between 1995 and 2007 and filed under anaesthesia were analysed to explore patterns of injury and cost related to airway or respiratory events. Of 841 interpretable claims the final dataset contained 96 claims of dental damage, 67 airway-related claims and 24 respiratory claims. Claims of dental damage contributed a numerically important (11%), but financially modest (0.5%) proportion of claims. These claims predominantly described injury during tracheal intubation or extubation; a minority associated with electroconvulsive therapy led to substantial cost per claim. The total cost of (non-dental) airway claims was 4.9 million pounds (84% closed, median cost 30,000 pounds) and that of respiratory claims was 3.3 million pounds (81% closed, median 27,000 pounds). Airway and respiratory claims account for 12% of anaesthesia-related claims, 53% of deaths, 27% of cost and ten of the 50 most expensive claims in the dataset. Airway claims most frequently described events at induction of anaesthesia, involved airway management with a tracheal tube and typically led to hypoxia and patient death or brain injury. Airway trauma accounted for one third of airway claims and these included deaths from mediastinal injury at intubation. Pulmonary aspiration and tube misplacement, including oesophageal intubation, led to several claims. Among respiratory claims, ventilation problems, combined with hypoxia, were an important source of claims. Although limited clinical details hamper analysis, the data suggest that most airway and respiratory-related claims arise from sentinel events. The absence of clinical detail and denominators limit opportunities to learn from such events; much more could be learnt from a closed claim or sentinel event analysis scheme.

Litigation related to regional anaesthesia: an analysis of claims against the NHS in England 1995-2007.

We analysed 366 claims related to regional anaesthesia and analgesia from the 841 anaesthesia-related claims handled by the National Health Service Litigation Authority between 1995 and 2007. The majority of claims (281/366, 77%) were closed at the time of analysis. The total cost of closed claims was pound12,724,017 (34% of the cost of the anaesthesia dataset) with a median (IQR [range]) of pound4772 (pound0-28,907 [pound0-2,070,092]). Approximately half of the claims (186/366; 51%) were related to obstetric anaesthesia and analgesia and of the non-obstetric claims, the majority (148/180; 82%) were related to neuraxial block. The total cost for obstetric closed claims was pound5,433,920 (median (IQR [range]) pound5678 (pound0-27,690 [pound0-1,597,565]) while that for non-obstetric closed claims was pound7,290,097 (pound3337 (pound0-31,405 [pound0-2,070,062]). Non-obstetric claims were more likely to relate to severe outcomes than obstetric ones. The maximum values of claims were higher for claims related to neuraxial blocks and eye blocks than for peripheral nerve blocks. Despite many limitations, including lack of clinical detail for each case, the dataset provides a useful overview of the extent, patterns and cost associated with the claims.

Probing Trace Elements in Human Tissues with Synchrotron Radiation.

For the past several decades, synchrotron radiation has been extensively used to measure the spatial distribution and chemical affinity of elements found in trace concentrations (

Litigation related to inadequate anaesthesia: an analysis of claims against the NHS in England 1995-2007.

Inadequate anaesthesia may cause distress to the patient and lead to medical litigation. All claims made to the NHS Litigation Authority 1995-2007 were obtained and the data was examined independently by all authors and classified. In a dataset of 1067 claims there were 161 cases of inadequate anaesthesia and data were suitable for analysis in 159: intra-operative awareness (79), brief awake paralysis (20) and inadequate regional anaesthesia (60). The total cost of closed claims was pound 3.2 m. Cost was incurred in 100% of claims of brief awake paralysis, 87% of claims of awareness and 80% of claims of inadequate regional blockade. Mean cost of closed claims was pound 32,680 for anaesthetic awareness, pound 29,345 for inadequate regional blockade and pound 24,364 for brief awake paralysis. Inadequate anaesthesia accounts for 19% of anaesthesia-related claims in the NHS in England. Strategies that reduce anaesthetic awareness, drug errors and inadequate regional blockade are known and their improved implementation is likely to reduce such claims.

Litigation related to anaesthesia: an analysis of claims against the NHS in England 1995-2007.

The distribution of medico-legal claims in English anaesthetic practice is unreported. We studied National Health Service Litigation Authority claims related to anaesthesia since 1995. All claims were reviewed by three clinicians and variously categorised, including by type of incident, claimed outcome and cost. Anaesthesia-related claims account for 2.5% of all claims and 2.4% of the value of all claims. Of 841 relevant claims 366 (44%) were related to regional anaesthesia, 245 (29%) obstetric anaesthesia, 164 (20%) inadequate anaesthesia, 95 (11%) dental damage, 71 (8%) airway (excluding dental damage), 63 (7%) drug related (excluding allergy), 31 (4%) drug allergy related, 31 (4%) positioning, 29 (3%) respiratory, 26 (3%) consent, 21 (2%) central venous cannulation and 18 (2%) peripheral venous cannulation. Defining which cases are, from a medico-legal viewpoint, 'high risk' is uncertain, but the clinical categories with the largest number of claims were regional anaesthesia, obstetric anaesthesia, inadequate anaesthesia, dental damage and airway, those with the highest overall cost were regional anaesthesia, obstetric anaesthesia, and airway and those with the highest mean cost per closed claim were respiratory, central venous cannulation and drug error excluding allergy. The data currently available have limitations but offer useful information. A closed claims analysis similar to that in the USA would improve the clinical usefulness of analysis.

Pharmacokinetic-pharmacodynamic modeling in anesthesia, intensive care and pain medicine.

PURPOSE OF REVIEW: Studies from the anesthesiology literature published in the last 2 years were selected to illustrate the most important developments in the field of pharmacokinetic-pharmacodynamic modeling. RECENT FINDINGS: The pharmacokinetic models focused on incorporating covariate, especially age for pediatric-geriatric use, and altered physiological states. The pharmacodynamic models studied the effect of rate of anesthetic administration, age, experimental conditions, and delay within the monitor on estimation of drug concentration in the biophase. Models for the surrogate measure of the components of general anesthesia, hypnosis (bispectral index scale, entropy), immobility (limb tetanic stimulus-induced withdrawal reflex) and antinociception (surgical stress index, skin conductance algesimeter) were developed and validated. Response surface models were used to study drug interactions for important end-points during surgery and also to optimize dosing of anesthetic agents to maximize the desired/undesired effect ratio. The models for target-controlled infusions were improved by incorporating more covariates, and the closed-loop system was refined by using adaptive controllers that individualize the pharmacokinetic/pharmacodynamic parameters to the particular patient by using Bayesian, Kalman filters, fuzzy logic or neural networks. SUMMARY: Progress was made by improving population pharmacokinetic/pharmacodynamic models, developing new indexes to measure drug effect and using them in an adaptive delivery system to the individual patient.