Procedural Sedation With Dexmedetomidine in Combination With Ketamine in the Emergency Department.

BACKGROUND: Dexmedetomidine is an alternative agent for procedural sedation in the emergency department thanks to its ability to maintain hemodynamic and respiratory stability. Dexmedetomidine must, however, be combined with a powerful analgesic. OBJECTIVE: Our aim was to evaluate the quality and safety of procedural sedation using the combination of dexmedetomidine and ketamine for patients undergoing painful procedures in the emergency department. METHODS: This prospective interventional single-center study was conducted in an academic emergency department of an urban hospital in Brussels, Belgium. Patients received a bolus injection of 1 µg/kg dexmedetomidine over 10 min and then a continuous infusion of 0.6 µg/kg/h followed by a bolus of 1 mg/kg ketamine. The painful procedure was carried out 1 min later. The level of pain was evaluated with a numerical rating scale from 0 (no pain) to 10 (maximal pain). The level of patient comfort for the procedure was measured using a comfort scale. RESULTS: Thirty patients were included. Overall, 90% of patients felt little or no pain (n = 29 of 30) or discomfort (n = 28 of 30) during the procedure. One patient experienced apnea with desaturation, which was resolved by a jaw-thrust maneuver. Although 23% of patients had significant arterial hypertension, none required drug treatment. CONCLUSIONS: The combination of dexmedetomidine and ketamine provides conscious sedation, bringing comfort and pain relief to patients in optimal conditions for respiratory and hemodynamic safety. However, sedation and recovery times are longer than with conventional drug combinations. The dexmedetomidine-ketamine combination should therefore be recommended for nonurgent procedures and fragile patients.

Enhanced Fear Memories and Altered Brain Glucose Metabolism (18F-FDG-PET) following Subanesthetic Intravenous Ketamine Infusion in Female Sprague-Dawley Rats.

Although women and men are equally likely to receive ketamine following traumatic injury, little is known regarding sex-related differences in the impact of ketamine on traumatic memory. We previously reported that subanesthetic doses of an intravenous (IV) ketamine infusion following fear conditioning impaired fear extinction and altered regional brain glucose metabolism (BGluM) in male rats. Here, we investigated the effects of IV ketamine infusion on fear memory, stress hormone levels, and BGluM in female rats. Adult female Sprague-Dawley rats received a single IV ketamine infusion (0, 2, 10, or 20 mg/kg, over a 2-h period) following auditory fear conditioning (three pairings of tone and footshock). Levels of plasma stress hormones, corticosterone (CORT) and progesterone, were measured after the ketamine infusion. Two days after ketamine infusion, fear memory retrieval, extinction, and renewal were tested over a three-day period. The effects of IV ketamine infusion on BGluM were determined using 18F-fluoro-deoxyglucose positron emission tomography (18F-FDG-PET) and computed tomography (CT). The 2 and 10 mg/kg ketamine infusions reduced locomotor activity, while 20 mg/kg infusion produced reduction (first hour) followed by stimulation (second hour) of activity. The 10 and 20 mg/kg ketamine infusions significantly elevated plasma CORT and progesterone levels. All three doses enhanced fear memory retrieval, impaired fear extinction, and enhanced cued fear renewal in female rats. Ketamine infusion produced dose-dependent effects on BGluM in fear- and stress-sensitive brain regions of female rats. The current findings indicate that subanesthetic doses of IV ketamine produce robust effects on the hypothalamic-pituitary-adrenal (HPA) axis and brain energy utilization that may contribute to enhanced fear memory observed in female rats.

Intriguing Cytotoxicity of the Street Dissociative Anesthetic Methoxphenidine: Unexpected Impurities Spotted.

The black market for new psychoactive substances has been constantly evolving and the substances that appear on this market cause a considerable number of issues, in extreme cases leading to human deaths. While monitoring the drug black market, we detected a sample of a dissociative anesthetic methoxphenidine, the salt of which contained an unusual anion in the form of bromo- and chloro-zincate complex. Concerning the unknown and potentially hazardous properties of this sample, we performed an in vitro cytotoxicity screening in cell lines of various origins (e.g., kidney, liver, bladder) which was compared with the toxicity results of the methoxphenidine standard prepared for this purpose. The street methoxphenidine sample exhibited markedly higher toxicity than the standard, which was probably caused by the anion impurity. Since it is not usual to analyze anions in salts of novel psychoactive substances, but such samples may be commonly available at the drug black market, we have developed a method for their identification with X-ray powder diffraction (XRPD), which also enabled us to distinguish between different polymorphs/solvates of methoxphenidine that were crystallized in the laboratory. XRPD offers additional data about samples, which may not be discovered by routine techniques, and in some cases, they may help to find out essential information.

Harm related to recreational ketamine use and its relevance for the clinical use of ketamine. A systematic review and comparison study.

BACKGROUNDS: Ketamine is a dissociative anesthetic that is currently considered for several new indications. AIM: To deduce the safety of long-term ketamine treatment using the harm of heavy recreational (non-medical) ketamine use as a proxy for maximal possible harm of ketamine treatment. METHODS: Systematic literature review according to PRISMA guidelines to identify controlled studies on ketamine-related harm in heavy recreational ketamine users. Results were compared with serious adverse events (SAEs) in patients treated with ketamine according to three systematic reviews considering dosing regimen and cumulative dose. RESULTS: The systematic search yielded 25 studies. Heavy recreational ketamine use can escalate to ketamine dependency and was often dose-dependently associated with other SAEs, including cognitive and mental disorders, and gastrointestinal and urinary tract symptoms, which disappeared upon marked reduction of ketamine use. Heavy ketamine users have a much higher cumulative exposure to ketamine than ketamine treated patients (>90 times), which may explain why SAEs in the clinical context are mostly mild and reversible and why ketamine dependence was not reported in these patients. CONCLUSION: Treatment of patients with ketamine is not associated with ketamine dependency or SAEs. However, caution is needed since data on long-term clinical ketamine use with a long-term follow-up is lacking.

[History of Ketamine: An ancient molecule that is still popular today]. / Histoire de la kétamine : une molécule ancienne qui a toujours la cote.

The history of ketamine begins in 1962, when Calvin Stevens of the pharmaceutical laboratory Parke-Davis synthesizes it from phencyclidine, a molecule with psychodysleptic, hallucinogenic and dissociative properties. Following the first administration of ketamine to humans in 1964 in Jackson prison (Michigan, USA), its dissociative effects associated with short anaesthesia were reported, and a patent for its human use was filed in 1966. In the 1990s, the discovery of opioid-induced hyperalgesia sparked interest in ketamine as an analgesic. In recent years, the human use of ketamine, and in particular its esketamine enantiomer, has shifted towards the treatment of depression. The first cases of ketamine abuse were reported in 1992 in France, leading to special surveillance by the health authorities, and its inclusion in the list of narcotic drugs in 1997. Today, ketamine has become an attractive substance for recreational use, gradually emerging from alternative techno circles to spread to more commercial party scenes. These elements represent a public health concern, associated with the risk of developing new chemically synthesized analogues, the harmful effects of which are still little known.

Apnea with ketamine sedation in a patient with severe anorexia nervosa: A case report.

BACKGROUND: There is a paucity of literature around sedation and anesthesia in patients with severe anorexia nervosa. Chronically malnourished patients are known to have myopathy, neuropathy, and altered neurotransmitter signaling. Ketamine is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist that is an established general anesthetic and short-acting dissociative analgesic agent. It generally has a reassuring adverse event profile and rarely has been reported to result in apnea. We aim to raise awareness of this untoward adverse event in patients with severe anorexia nervosa among sedation providers and those referring patients for hospitalization or sedation. CASE PRESENTATION: We describe an episode of apnea, a rare adverse event of ketamine, which was given for procedural sedation to a severely malnourished 13-year-old female with anorexia nervosa, generalized anxiety disorder, and high-functioning autism spectrum disorder. She had no history of apnea nor of ketamine sedation. She was given a standard dose of ketamine and had no other central nervous system depressants within 24 h. Within 1 min after slow medication administration, she had a 9-min period of apnea without laryngospasm. She was supported with bag-valve-mask ventilation throughout this period and did not require intubation. She returned to baseline shortly after procedural sedation. CONCLUSIONS: This case describes apnea after ketamine sedation in a patient with severe anorexia nervosa. It supports the importance of a thorough pre-procedure review of a patient's underlying medical problems and the consideration of how sedatives may interact with these conditions. We aim to alert those who care for this complex population of the possible altered neurotransmitters, myopathy, and adverse response to sedation, anesthetics, and analgesics.

Long-term increase in sensitivity to ketamine's behavioral effects in mice exposed to mild blast induced traumatic brain injury.

Neurobehavioral deficits emerge in nearly 50% of patients following a mild traumatic brain injury (TBI) and may persist for months. Ketamine is used frequently as an anesthetic/analgesic and for management of persistent psychiatric complications. Although ketamine may produce beneficial effects in patients with a history of TBI, differential sensitivity to its impairing effects could make the therapeutic use of ketamine in TBI patients unsafe. This series of studies examined male C57BL/6 J mice exposed to a mild single blast overpressure (mbTBI) for indications of altered sensitivity to ketamine at varying times after injury. Dystaxia (altered gait), diminished sensorimotor gating (reduced prepulse inhibition) and impaired working memory (step-down inhibitory avoidance) were examined in mbTBI and sham animals 15 min following intraperitoneal injections of saline or R,S-ketamine hydrochloride, from day 7-16 post injury and again from day 35-43 post injury. Behavioral performance in the forced swim test and sucrose preference test were evaluated on day 28 and day 74 post injury respectively, 24 h following drug administration. Dynamic gait stability was compromised in mbTBI mice on day 7 and 35 post injury and further exacerbated following ketamine administration. On day 14 and 42 post injury, prepulse inhibition was robustly decreased by mbTBI, which ketamine further reduced. Ketamine-associated memory impairment was apparent selectively in mbTBI animals 1 h, 24 h and day 28 post shock (tested on day 15/16/43 post injury). Ketamine selectively reduced immobility scores in the FST in mbTBI animals (day 28) and reversed mbTBI induced decreases in sucrose consumption (Day 74). These results demonstrate increased sensitivity to ketamine in mice when tested for extended periods after TBI. The results suggest that ketamine may be effective for treating neuropsychiatric complications that emerge after TBI but urge caution when used in clinical practice for enhanced sensitivity to its side effects in this patient population.

Ketamine Alleviates Depressive Symptoms in Patients Undergoing Intracranial Tumor Resection: A Randomized Controlled Trial.

BACKGROUND: Depressive symptoms occur in over 40% of neurosurgical patients during the perioperative period. However, no measure has been suggested to have a rapid effect on depressive surgical patients during increasingly shorter stays in the hospital. This study aimed to determine whether ketamine could improve depressive symptoms rapidly and safely during the hospital stay. METHODS: This was a randomized, placebo-controlled, and double-blinded trial. Patients with moderate-to-severe depressive symptoms undergoing elective supratentorial brain tumor resection were randomized to intravenously receive either (1) 0.5 mg·kg-1 ketamine for 40 minutes or (2) an identical volume of normal saline. The primary outcome was treatment response on postoperative day 3, defined as a ≥50% reduction from the baseline depressive score. The secondary outcomes included the rate of remission and safety outcomes. The Montgomery-Åsberg Depression Rating Scale was applied by trained psychiatrists to evaluate depressive symptoms. RESULTS: A total of 84 neurosurgical patients were enrolled in the trial. The response rate was increased by the administration of ketamine (41.5% [17/41] vs 16.3% [7/43]; relative risk [RR]: 2.51, 95% confidence interval [CI], 1.18-5.50) relative to the administration of placebo at 3 days. Furthermore, the remission rate at discharge (29.3% [12/41] vs 7.0% [3/43]; RR: 4.20, 95% CI, 1.28-13.80) was also improved by ketamine. No psychotic symptoms or adverse events were reported to be substantially higher in the ketamine group. CONCLUSIONS: The trial indicates that the intraoperative administration of ketamine could alleviate moderate-to-severe depressive symptoms in neurosurgical patients without worsening safety.

Outcomes Associated with Lower Doses of Ketamine by Emergency Medical Services for Profound Agitation.

INTRODUCTION: Ketamine is commonly used to treat profound agitation in the prehospital setting. Early in ketamine's prehospital use, intubation after arrival in the emergency department (ED) was frequent. We sought to measure the frequency of ED intubation at a Midwest academic medical center after prehospital ketamine use for profound agitation, hypothesizing that intubation has become less frequent as prehospital ketamine has become more common and prehospital dosing has improved. METHODS: We conducted a retrospective cohort study of adult patients receiving ketamine in the prehospital setting for profound agitation and transported to a midwestern, 60,000-visit, Level 1 trauma center between January 1, 2017-March 1, 2021. We report descriptive analyses of patient-level prehospital clinical data and ED outcomes. The primary outcome was proportion of patients intubated in the ED. RESULTS: A total of 78 patients received ketamine in the prehospital setting (69% male, mean age 36 years). Of the 42 (54%) admitted patients, 15 (36% of admissions) were admissions to the intensive care unit. Overall, 12% (95% confidence interval [CI]), 4.5-18.6%)] of patients were intubated, and indications included agitation (n = 4), airway protection not otherwise specified (n = 4), and respiratory failure (n = 1). CONCLUSION: Endotracheal intubation in the ED after prehospital ketamine use for profound agitation in our study sample was found to be less than previously reported.

A comparative study of dexmedetomidine and propofol to prevent recovery agitation in adults undergoing procedural sedation with ketamine: A randomized double-blind clinical trial.

BACKGROUND: The present study was designed to evaluate the effect of dexmedetomidine and propofol on ketamine-induced recovery agitation in adults when used as co-administration with ketamine. METHODS: In this prospective, randomized, and double-blind clinical trial, 93 patients aged 18 years or older who were candidates for painful procedures in the emergency department (ED) were enrolled and assigned into three equal groups to receive either ketadex (dexmedetomidine 0.7 µg/kg and ketamine 1 mg/kg), ketofol (propofol 0.5 mg/kg and ketamine 0.5 mg/kg) or ketamine alone (1 mg/kg) intravenously. Incidence and severity of recovery agitation were evaluated using the Richmond Agitation-Sedation Scale and compared between groups. RESULTS: There were no significant differences in demographic characteristics, procedures, pain scores, pre-sedation agitation, and duration of procedure between the three groups. The incidence of recovery agitation was 26% in the Ketadex group, 29% in the Ketofol group, and 58% in the Ketamine group. The difference in incidence of recovery agitation between Ketadex group and Ketamine group was 32% (95% confidence interval (CI), 9 to 56]) and between Ketofol group and Ketamine group was 29% (95% CI, 6 to 53). The severe agitation was significantly higher in Ketamine group, with a difference between Ketamine and Ketadex group of 19% (95% CI, 6 to 33), and a difference between Ketamine and Ketofol group of 16% (95% CI, 1 to 31). CONCLUSIONS: In this study, a combination of ketamine-dexmedetomidine and ketamine-propofol reduced the incidence and severity of ketamine-induced recovery agitation in adults undergoing procedural sedation in the ED.

The Effect of Low-Dose Intraoperative Ketamine on Closed-Loop-Controlled General Anesthesia: A Randomized Controlled Equivalence Trial.

BACKGROUND: Closed-loop control of propofol-remifentanil anesthesia using the processed electroencephalography depth-of-hypnosis index provided by the NeuroSENSE monitor (WAVCNS) has been previously described. The purpose of this placebo-controlled study was to evaluate the performance (percentage time within ±10 units of the setpoint during the maintenance of anesthesia) of a closed-loop propofol-remifentanil controller during induction and maintenance of anesthesia in the presence of a low dose of ketamine. METHODS: Following ethical approval and informed consent, American Society of Anesthesiologist (ASA) physical status I-II patients aged 19-54 years, scheduled for elective orthopedic surgery requiring general anesthesia for >60 minutes duration, were enrolled in a double-blind randomized, placebo-controlled, 2-group equivalence trial. Immediately before induction of anesthesia, participants in the ketamine group received a 0.25 mg·kg-1 bolus of intravenous ketamine over 60 seconds followed by a continuous 5 µg·kg-1·min-1 infusion for up to 45 minutes. Participants in the control group received an equivalent volume of normal saline. After the initial study drug bolus, closed-loop induction of anesthesia was initiated; propofol and remifentanil remained under closed-loop control until the anesthetic was tapered and turned off at the anesthesiologist's discretion. An equivalence range of ±8.99% was assumed for comparing controller performance. RESULTS: Sixty patients participated: 41 males, 54 ASA physical status I, with a median (interquartile range [IQR]) age of 29 [23, 38] years and weight of 82 [71, 93] kg. Complete data were available from 29 cases in the ketamine group and 27 in the control group. Percentage time within ±10 units of the WAVCNS setpoint was median [IQR] 86.6% [79.7, 90.2] in the ketamine group and 86.4% [76.5, 89.8] in the control group (median difference, 1.0%; 95% confidence interval [CI] -3.6 to 5.0). Mean propofol dose during maintenance of anesthesia for the ketamine group was higher than for the control group (median difference, 24.9 µg·kg-1·min-1; 95% CI, 6.5-43.1; P = .005). CONCLUSIONS: Because the 95% CI of the difference in controller performance lies entirely within the a priori equivalence range, we infer that this analgesic dose of ketamine did not alter controller performance. Further study is required to confirm the finding that mean propofol dosing was higher in the ketamine group, and to investigate the implication that this dose of ketamine may have affected the WAVCNS.

Safety and Efficacy of the Combination of Propofol and Ketamine for Procedural Sedation/Anesthesia in the Pediatric Population: A Systematic Review and Meta-analysis.

BACKGROUND: Drugs such as propofol and ketamine are used alone or in combination to provide sedation for medical procedures in children. The purpose of this systematic review was to compare the safety and effectiveness of propofol and ketamine to other drug regimens. METHODS: We searched Medline, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Database of Systematic Reviews (CDSR), Web of Science, and the grey literature (meta-Register of Controlled Trials, ClinicalTrials.gov, and Google Scholar) for randomized controlled studies comparing intravenous propofol and ketamine to any other single or combination drug regimen administered to children undergoing diagnostic or therapeutic procedures. Meta-analyses were performed for primary (hemodynamic and respiratory adverse events) and secondary outcomes using RevMan 5.3. We assessed the risk of bias and the certainty (quality) evidence for all outcomes using Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. RESULTS: Twenty-nine studies were included for analysis. Based on low-to-moderate quality evidence, we concluded that the use of propofol and ketamine may result in a slight-to-small reduction in the risk of hypotension, bradycardia, and apnea, and a slight increase in the risk of tachycardia, hypertension, and other respiratory adverse events, such as cough or laryngospasm. The ratio of propofol to ketamine and comparator drug regimen subgroups effects were important for desaturation and some secondary outcomes. CONCLUSIONS: The use of propofol and ketamine had a minimal effect on the incidence of adverse events and other secondary outcomes. Large-scale studies are required to more accurately estimate adverse event rates and the effects of propofol and ketamine on patient-important outcomes.

Recreational ketamine-induced cholangiopathy and ulcerative cystitis.

Ketamine is a versatile analgesic that has become an increasingly popular recreational drug. Chronic ketamine use has been found to cause biliary duct damage and bladder dysfunction. Ketamine-induced cholangiopathy and ulcerative cystitis are uncommon diagnoses presenting with nonspecific symptoms, creating diagnostic challenges for emergency physicians. We report a case of a teenage patient with the rare simultaneous presentation of ketamine-induced cholangiopathy and ulcerative cystitis. Due to increased recreational and chronic ketamine use, cases of ketamine-induced cholangiopathy and ulcerative cystitis are likely to rise with the increased knowledge, awareness, and reporting of these entities by radiologists and emergency physicians.

Subcutaneous ketamine prolongs the analgesic effect of local infiltration of plain Bupivacaine in children undergoing inguinal herniotomy.

BACKGROUND: Inguinal herniotomy is one of the commonest paediatric surgical procedures at the University of Benin Teaching Hospital. Incisional infiltration with plain bupivacaine has been used to provide postoperative analgesia for this procedure but with a short duration of action, 4-6 hours. AIMS/OBJECTIVES: The aim of this study therefore was to evaluate the efficacy of subcutaneous ketamine on post-operative analgesia in children undergoing unilateral inguinal herniotomy. METHODS: Forty-six (46) ASA I or II patients aged three to seven years scheduled for unilateral inguinal herniotomy were recruited. The patients were randomized to receive surgical wound site infiltration with plain bupivacaine plus subcutaneous injection of ketamine for group I or surgical wound site infiltration plain bupivacaine plus 2ml of saline subcutaneously for group II at the end of surgery. Data obtained were analyzed using SPSS version 20. Continuous data were compared using student t-test while categorical data were compared using Chi-square or Fisher's exact test. P-value <0.05 was considered statistically significant. RESULTS: In group, I, the mean time to first analgesic request was 667.7 minutes (11.12 hours) and in group II, it was 371.3 minutes (6.2 hours) with p<0.001. The pain scores were better and more favourable in group I from the 8th hour and above of the assessment period. The mean post-operative analgesic consumption in 24 hours was less in group I (19.35±5.4mg) than in group II (27.32±5.8 mg) with p-value <0.001. CONCLUSION: The study showed that subcutaneous ketamine prolonged the analgesic effect of plain bupivacaine surgical wound site infiltration in children undergoing unilateral inguinal herniotomy.

Rescue Intubation in the Emergency Department After Prehospital Ketamine Administration for Agitation.

OBJECTIVE: Prehospital intramuscular (IM) ketamine is increasingly used for chemical restraint of agitated patients. However, few studies have assessed emergency department (ED) follow-up of patients receiving prehospital ketamine for this indication, with previous reports suggesting a high rate of post-administration intubation. This study examines the rate of and reasons for intubation and other airway interventions in agitated patients who received ketamine by Emergency Medical Services (EMS). METHODS: This retrospective cohort study included patients who received prehospital ketamine for agitation and were transported to two community hospital EDs. Charts were reviewed for demographics, ketamine dose, and airway intervention by EMS or in the ED. Characteristics of patients who were intubated versus those who did not receive airway intervention were analyzed. RESULTS: Over 28 months, 86 patients received ketamine for agitation. Fourteen (16.3%) underwent endotracheal intubation. Patients with a higher temperature and a lower Glasgow Coma Score (GCS) were more likely to require intubation. There was no age or dose-dependent association on intubation rate. Intubated patients averaged 39 years old versus 44 for patients not intubated (negative five-year difference; 95% CI, -16 to 6). The mean ketamine dose was 339.3mg in patients intubated versus 350.7mg in patients not (-11.4mg difference; 95% CI, -72.4 to 49.6). The mean weight-based ketamine dose was 4.44mg/kg in patients intubated versus 4.96mg/kg in patients not (-0.53mg/kg difference; 95% CI, -1.49 to 0.43). CONCLUSIONS: The observed rate of intubation in patients receiving prehospital ketamine for agitation was 16.3%. Study data did not reveal an age or dose-dependent rate of intubation. Further research should be conducted to compare the airway intervention rate of agitated patients receiving ketamine versus other sedatives in a controlled fashion.

Ketamine-induced neuromuscular reactivity is associated with aging in female rhesus macaques.

Rhesus macaques represent an important species for translational and pre-clinical research studies across a multitude of disease and injury models, including aging. Ketamine anesthesia is used in humans and non-human primates but may be associated with adverse effects, including neuromuscular reactions. The effects of aging on ketamine adverse effects is not well characterized. Urodynamic recordings and electromyography (EMG) studies were performed in aged (>20 years old) and adult (3.9-14.9 years old) female rhesus macaques under an equal and light plane of sedation by constant rate infusion (CRI) of ketamine. A total of 4 of 41 adult subjects (9.7%) showed clinical signs of ketamine-induced abnormal neuromuscular reactivity, whereas a larger portion of 14 of 26 aged subjects showed similar ketamine-induced neuromuscular reactivity (53.8%; P< 0.001). The ketamine CRI rate was 19.8±0.9 mg/kg/h in adults and lower in aged subjects at 16.5±1.4 mg/kg/h (P<0.05). The ketamine CRI rate was negatively correlated with age (r = -0.30, P<0.05, n = 64). The incidence of ketamine reactivity or CRI rate was not different between aged pre-and post-menopausal females. EMG recordings during neuromuscular reactivity showed coordinated activation of multiple muscles, suggesting a central nervous system (CNS) mechanism for ketamine-associated neuromuscular reactivity. The incidence of ketamine-induced neuromuscular reactivity is age related but not affected by the estrous cycle in female rhesus macaques. A coordinated activation of multiple muscles, innervated by different peripheral nerves, suggests that ketamine-induced neuromuscular reactivity originates in the CNS.