Ultrasound-guided bilateral greater occipital nerve block on headache seen after endovascular treatment of ruptured or unruptured intracranial aneurysms: A case report.

Headache is a common symptom in subarachnoid hemorrhage (SAH). Often, pain control is difficult and opioid use can have a complicated effect on the patient's state of consciousness. In this study of 2 cases, opioid consumption was reduced while effective pain control of headache occurring after endovascular treatment of an intracranial aneurysm was achieved using an ultrasound-guided, bilateral greater occipital nerve (GON) block. Case 1 was a 59-year-old male patient with a Glasgow Coma Scale (GCS) of 13 who was diagnosed with Fisher scale grade 3 SAH. Coiling and stenting were performed for an anterior communicating artery aneurysm. Cerebrospinal fluid drainage was provided with a lumbar spinal catheter. Case 2 was a 55-yearold male patient with a GCS of 15 who underwent coiling of a fusiform aneurysm in the left basilar artery and stenting of the stenotic region due to a basilar artery aneurysm. After the procedure, the visual analog score (VAS) of the patients was 9 and 7, respectively, and a bilateral GON block was performed with ultrasound guidance. The VAS score of both patients decreased to 3 and did not exceed 3 during follow-up in the intensive care unit, eliminating the need for additional analgesics. A bilateral GON block provided effective analgesia and significantly reduced the need for other pain relief in both cases.

The effect of pregabalin on tourniquet-induced ischemia-reperfusion injury: a prospective randomized study

Background/aim: The aim of this study was to investigate the efficacy of pregabalin on ischemia-reperfusion injuries. Materials and methods: Fifty-four patients were randomly assigned into 2 groups. A 150-mg tablet of pregabalin was given the night before and then 1 h before the operation for patients in Group P (pregabalin group, n = 27). A placebo was given to patients in Group C (control group, n = 27) at the same times. After combined spinal-epidural anesthesia was performed, venous blood samples were taken before tourniquet inflation (t1), just before tourniquet deflation (t2), and 20 min after tourniquet deflation (t3) for the analysis of total antioxidant status (TAS), total oxidant status (TOS), catalase (CAT), and ischemia-modified albumin (IMA). Results: There was no significant difference in TAS levels between the groups for the t3 period. However, the TAS in Group P was significantly higher in the t3 period than the t2 period (mean ± SD, 0.46 ± 0.1 vs. 0.38 ± 0.2 mmol of Trolox equivalent/L, respectively; P < 0.05). The CAT level in the t3 period was significantly higher in Group P than Group C (mean ± SD, 53.04 ± 32.1 vs. 35.46 ± 17.2 µmol/ formaldehyde, respectively; P < 0.05). In the t3 period, the TOS was significantly lower in Group P than Group C (mean ± SD, 11.97 ± 5 vs. 18.29 ± 9.9 pg/mL, respectively; P < 0.05). The TOS in Group P was significantly lower in the t3 period than the t2 period (mean ± SD, 11.97 ± 5 vs. 18.98 ± 10.7 pg/mL, respectively; P < 0.0001). Conclusion: Pregabalin has no marked antioxidant activity, but it contributes to the antioxidant defense system of an organism.

Ultrasound-Guided versus Conventional Caudal Block in Children: A Prospective Randomized Study.

BACKGROUND: Injection to the accurate area without any complications is the main factor for the efficiencies of caudal block. The aim of this study was to compare success and the complications of conventional and ultrasound method for caudal block in children. MATERIALS AND METHODS: Two-hundred sixty-six American Society of Anesthesiologists (ASA) category 1 children aged between 6 months and 6 years undergoing hypospadias, circumcision, or both surgeries were randomly allocated two groups (Group C or Group H, n = 133). About 0.25% bupivacaine with 1/200000 adrenaline (total volume: 0.5 mL/kg) was injected after the needle was inserted into the sacral canal in Group C, or right after the needle pierced the sacrococcygeal ligament under longitudinal ultrasound view in Group H. Success rate of block, block performing time, number of needle puncture, success at first puncture, complication rate, age and weight of the patients encountering these complications were recorded. RESULTS: The success rate of block was similar between two groups (94.7% in Group C vs 96.2% in Group U, p > 0.05). Success at first puncture was higher in Group U than in Group C (90.2 vs 66.2%, respectively; p < 0.001). Number of needle puncture, blood aspiration, subcutaneous bulging, and bone contact was higher in Group C but none in Group U (p < 0.001) and these complications were occurred in children weighing < 16 kg and less younger than 6 years old. CONCLUSION: We observed that the complications were not encountered, number of needle puncture was lesser, and the success rate of first puncture was higher under ultrasound with longitudinal view.

Effects of Single-Dose Preemptive Pregabalin and Intravenous Ibuprofen on Postoperative Opioid Consumption and Acute Pain after Laparoscopic Cholecystectomy.

PURPOSE: Non-opioid medications as a part of multimodal analgesia has been increasingly suggested in the management of acute post-surgical pain. The present study was planned to compare the efficacy of the combination of pregabalin plus iv ibuprofen. METHODS: 58 patients were included in this prospective, randomized, double-blinded study. The pregabalin group (Group P, n = 29) received 150 mg pregabalin, the pregabalin plus ibuprofen group (Gropu PI, n = 29) received 150 mg pregabalin and 400mg iv ibuprofen before surgery. Postoperative fentanyl consumption, additional analgesia requirements and PACU stay were recorded. Postoperative analgesia was performed with patient-controlled IV fentanyl. RESULTS: VAS scores in the group PI were statistically lower at PACU, 1and 2 hours at rest, at PACU, 1, 2, 4, 12 and 24 hours on movement compared to the group P (P < 0.05). Opioid consumption was statistically significantly higher in the group P compared to the group PI (130.17 ± 60.27 vs 78.45 ± 60.40 µq, respectively, P < 0.001) and reduced in the 4th 24 hours by 55% in group PI. Rescue analgesia usage was statistically significantly higher in the group P than in the group PI (16/29 vs 7/29, respectively, P < 0.001). Four patient in the group PI did not need any opioid drug. Besides, PACU stay was shorter in the group PI than the group P (10.62 ± 2.38 vs 15.59 ± 2.11 min, respectively, P < 0.001). CONCLUSION: Preemptive pregabalin plus iv ibuprofen in laparoscopic cholecystectomy reduced postoperative opioid consumption. This multimodal analgesic aproach generated lower pain scores in the postoperative period.

The efficacy of ultrasound-guided type-I and type-II pectoral nerve blocks for postoperative analgesia after breast augmentation: A prospective, randomised study.

PURPOSE: The present study was planned to evaluate the efficacy and safety of ultrasound-guided Pecs I and II blocks for postoperative analgesia after sub-pectoral breast augmentation. METHODS: Fifty-four adult female patients undergoing breast augmentation were randomly divided into two groups: the control group (Group C, n=27) who were not subjected to block treatment and Pecs group (Group P, n=27) who received Pecs I (bupivacain 0.25%, 10mL) and Pecs II (bupivacain 0.25%, 20mL) block. Patient-controlled fentanyl analgesia was used for postoperative pain relief in both groups, and the patients were observed for the presence of any block-related complications. RESULTS: The 24-h fentanyl consumption was smaller in Group P [mean±SD, 378.7±54.0µg and 115.7±98.1µg, respectively; P<0.001]. VAS scores in Group P were significantly lower at the time of admission to the post-anaesthetic care unit and at 1, 2, 4, 8, 12, and 24h (P<0.001). The rates of nausea and vomiting were higher in Group C than in Group P (9 vs 2, P=0.018). Hospital stay duration was shorter in Group P than in Group C (24.4±1.2h vs 27.0±3.1h, P<0.001). No block-related complications were recorded. CONCLUSIONS: Combine used of Pecs I and II blocks provide superior postoperative analgesia in patients undergoing breast augmentation and shortens hospital stay.

Laparoscopic gastrostomy under awake thoracic epidural anesthesia: A successful experience.

General anesthesia is the first choice as an anesthesia method particularly for abdominal operations. However, because neuromuscular blockade induced during general anesthesia will increase atelectasis in a patient with pulmonary disease, it will also increase postoperative ventilator dependence, which will be even more apparent in cases of chronic obstructive pulmonary disease (COPD) that pose a risk, particularly for postoperative complications. Herein, thoracic epidural anesthesia (TEA) was found to be a better option for our patient with severe COPD and stage IV lung cancer, as it provided sufficient anesthesia and better postoperative care for laparoscopic gastrostomy.

The effect of spinal versus general anesthesia on intraocular pressure in lumbar disc surgery in the prone position: A randomized, controlled clinical trial.

OBJECTIVE: To compare IOP changes between spinal anesthesia (SA) and general anesthesia (GA) in patients who underwent lumbar disc surgery in the prone position. DESIGN: Prospective, randomized, controlled trial. SETTING: Operating room. PATIENTS: Forty ASA I-II patients scheduled for lumbar disc surgery in prone position. INTERVENTION: Patients were randomly allocated to the SA or GA groups. MEASUREMENTS: IOP was measured before anesthesia (IOP1), 10 min after spinal or general anesthesia in supine position (IOP2), 10 min after being placed in the prone position (IOP3), and at the end of the operation in the prone position (IOP4). MAIN RESULTS: There was no significant difference between baseline IOP1 (group GA = 19.4 ±â€¯3.2 mmHg; group SA = 18.6 ±â€¯2.4 mmHg) and IOP2 values (group GA = 19.7 ±â€¯4.1 mmHg; group SA = 18.4 ±â€¯1.9 mmHg) between and within the groups. IOP values after prone positioning and group GA measurements (IOP3 = 21.6 ±â€¯3.1 mmHg; IOP4 = 33.9 ±â€¯3.1 mmHg) were significantly higher when compared with the SA group (IOP3 = 19.3 ±â€¯2.7 mmHg, IOP4 = 26.9 ±â€¯2.4 mmHg) (p = 0.018 and p < 0.001, respectively). Furthermore, IOP3 was significantly increased when compared with IOP2 in the GA group but not in the SA group (p = 0.019 and p = 0.525, respectively). In both groups, IOP4 values were significantly higher than the other three measurements (p < 0.001). CONCLUSION: The results indicated that IOP increase is significantly less in patients who undergo lumbar disc surgery in the prone position under SA compared with GA.

What happened? An inexplicable case: Accidental subdural block.

Epidural block is an appropriate anesthesia method for outpatient operation. This technique is generally safe and efficient. We present the case of a 20-year-old female patient with accidental subdural block after a single dose of epidural block for pilonidal sinus surgery. Sudden apnea, unconsciousness, and bilateral mydriasis occurred within a few minutes after injection. Within 80 minutes after injection, the patient regained full consciousness and spontaneous respiration, with motor block in lower extremities and sensory block until the T4 level. Motor block continued until 165 minutes after injection, whereas sensory block ended 225 minutes later.

Higher dose intra-arterial milrinone and intra-arterial combined milrinone-nimodipine infusion as a rescue therapy for refractory cerebral vasospasm.

Background Cerebral vasospasm (CV) is a major cause of delayed morbidity and mortality in patients with subarachnoid hemorrhage (SAH). Various cerebral protectants have been tested in patients with aneurysmal SAH. We aimed to research the success rate of treatment of CV via intra-arterial milrinone injection and aggressive pharmacological therapy for refractory CV. Methods A total of 25 consecutive patients who received intra-arterial milrinone and nimodipine treatment for CV following SAH between 2014 and 2017 were included in the study. Patients who underwent surgical clipping were excluded. Refractory vasospasm was defined as patients with CV refractory to therapies requiring ≥3 endovascular interventions. Overall, six patients had refractory CV. Long-term neurological outcome was assessed 6-18 months after SAH using a modified Rankin score and Barthel index. Results The median modified Rankin scores were 1 (min: 0, max: 3) and Barthel index scores were 85 (min: 70, max: 100) From each vasospastic territory maximal 10-16 mg milrinone was given to patients; a maximum of 24 mg milrinone was given to each patient in a session and a maximum of 42 mg milrinone was given to a patient in a day. Both milrinone and nimodipine were given to three patients. There was a large vessel diameter increase after milrinone and nimodipine injections. No patient died due to CV; only one patient had motor dysfunction on the right lower extremity. Conclusion Higher doses of milrinone can be used effectively to control refractory CV. For exceptional patients with refractory CV, high dose intra-arterial nimodipine and milrinone infusion can be used as a rescue therapy.

Effects of Addition of Preoperative Intravenous Ibuprofen to Pregabalin on Postoperative Pain in Posterior Lumbar Interbody Fusion Surgery.

OBJECTIVE: Ibuprofen and pregabalin both have independent positive effects on postoperative pain. The aim of the study is researching effect of 800 mg i.v. ibuprofen in addition to preoperative single dose pregabalin on postoperative analgesia and morphine consumption in posterior lumbar interbody fusion surgery. MATERIALS AND METHODS: 42 adult ASA I-II physical status patients received 150 mg oral pregabalin 1 hour before surgery. Patients received either 250 ml saline with 800 mg i.v. ibuprofen or saline without ibuprofen 30 minutes prior to the surgery. Postoperative analgesia was obtained by morphine patient controlled analgesia (PCA) and 1 g i.v. paracetamol every six hours. PCA morphine consumption was recorded and postoperative pain was evaluated by Visual Analog Scale (VAS) in postoperative recovery room, at the 1st, 2nd, 4th, 8th, 12th, 24th, 36th, and 48th hours. RESULTS: Postoperative pain was significantly lower in ibuprofen group in recovery room, at the 1st, 2nd, 36th, and 48th hours. Total morphine consumption was lower in ibuprofen group at the 2nd, 4th, 8th, 12th, and 48th hours. CONCLUSIONS: Multimodal analgesia with preoperative ibuprofen added to preoperative pregabalin safely decreases postoperative pain and total morphine consumption in patients having posterior lumbar interbody fusion surgery, without increasing incidences of bleeding or other side effects.

Smartphone use habits of anesthesia providers during anesthetized patient care: a survey from Turkey.

BACKGROUND: Smartphones are used in many areas of anesthesia practice. However, recent editorial articles have expressed concerns about smartphone uses in the operating room for non-medical purposes. We performed a survey to learn about the smartphone use habits and views of Turkish anesthesia providers. METHODS: A questionnaire consisting of 14 questions about smartphone use habits during anesthesia care was sent anesthesia providers. RESULTS: In November-December 2015, a total of 955 participants answered our survey with 93.7 % of respondents responding that they used smartphones during the anesthetized patient care. Phone calls (65.4 %), messaging (46.4 %), social media (35.3 %), and surfing the internet (33.7 %) were the most common purposes. However, 96.7 % of respondents indicated that smartphones were either never or seldom used during critical stages of anesthesia. Most respondents (87.3 %) stated that they were never distracted because of smartphone use; however, 41 % had witnessed their collagues in such a situation at least once. CONCLUSIONS: According to the results of the survey, smartphones are used in the operating room often for non-medical purposes. Distraction remains a concern but evidence-based data on whether restrictions to smartphone use are required are not yet available.

The effect of pneumoperitoneum on the cross-sectional areas of internal jugular vein and subclavian vein in laparoscopic cholecystectomy operation.

BACKGROUND: Increased central venous pressure secondary to an increase in intraabdominal pressure has been reported during laparoscopic surgery. However, no study has yet determined the effect of pneumoperitoneum on cross-sectional area (CSA) of central veins by ultrasonography during laparoscopic cholecystectomy. Herein, we aimed to quantify changes in CSAs of internal jugular (IJV) and subclavian veins (SCV) by ultrasonography during this surgery. METHODS: This study included 60 ASA I-II patients scheduled for laparoscopic cholecystectomy surgery under general anesthesia. Pneumoperitoneum was performed with CO2 at 12 mmHg. The CSAs of right IJV and right SCV were measured using a 6 Mhz ultrasonography transducer in supine and neutral positions before anesthesia induction (T1), 5 min after connecting to mechanical ventilator (T2), 5 min after creation of pneumoperitoneum (T3), at the end of pneumoperitoneum (T4), and 5 min after desufflation and before extubation (T5) both at end-expiration and end-inspiration. RESULTS: The comparison of IJV CSA at inspiration showed significant increase in T3 value compared to T2 value (p < 0.001). Similarly the expiratory measurements of IJV CSA demonstrated significant increase in T3 value compared to T2 value (p < 0.001). The comparison of inspiratory CSA measurements of SCV showed significantly increased in T3 (p = 0.009) than T2 value. In expiratory measurements there was a significant increase in T3 (p = 0.032) value compared to T2. All measurements of IJV and SCV SCAs both end-inspiration and end-expiration T5 values significantly decreased compared to T4 values (p < 0.001). CONCLUSIONS: Pneumoperitoneum with an intraabdominal pressure of 12 mmHg produces significant increases in IJV and SCV CSAs during laparoscopic cholecystectomy procedure. We believe that this finding may enhance our understanding of pneumoperitoneum-induced hemodynamic changes and facilitate catheterization attempts. TRIAL REGISTRATION: Date of registration 21/07/2016, ISRCTN Registry ( No: ISRCTN15164056 , registered retrospectively).

Spinal anesthesia is an efficient and safe anesthetic method for percutaneous nephrolithotomy.

OBJECTIVE: To investigate the effect of spinal anesthesia (SA) vs general anesthesia (GA) administration on the safety and efficiency of percutaneous nephrolithotomy (PCNL). METHODS: We retrospectively evaluated 1478 patients who underwent PCNL in our clinic between 2004 and 2011. We excluded the patients with bilateral PCNL, renal abnormality, or solitary kidney. The remaining 1004 adult patients were divided into 2 groups according to anesthesia administration as GA (n = 564) or SA (n = 440). The groups were compared according to operative and postoperative properties. Complications of PCNL were evaluated according to the modified Clavien classification. Independent t test, chi-square test, and analysis of covariance were used for the comparison of groups. RESULTS: The durations of hospitalization, operation, and fluoroscopy of patients in the SA group were significantly shorter than that of the patients in the GA group (P <.01). The number of patients with postoperative requirement of narcotic analgesic and blood transfusion was significantly higher in the GA group (P <.01). The GA group had more grades 2, 3a, 3b, and 4b complications according to modified Clavien classification (P <.05). The significant differences in postoperative analgesic requirement and hospitalization duration between the groups did not affect postoperative urinary drainage (P <.01; adjusted r(2) = 0.064). CONCLUSION: PCNL with SA demonstrated shorter hospitalization, operation, and fluoroscopy durations. GA has some disadvantages as a greater requirement of narcotic analgesic and greater frequency of major complications. SA administration is a safe and effective method in appropriately selected patients with PCNL.

Mild carbon monoxide poisoning impairs left ventricular diastolic function.

RATIONALE: Carbon monoxide (CO) poisoning is associated with direct cardiovascular toxicity. In mild CO poisoning in which cardiovascular life support is not required, the effects of CO on left and right ventricular functions are unknown in patients without cardiac failure. OBJECTIVES: Echocardiography was used to determine whether or not mild CO poisoning impairs ventricular function. Twenty otherwise healthy patients with CO poisoning and 20 age- and gender-matched controls were studied. Echocardiographic examinations were performed at the time of admission and 1 week after poisoning. RESULTS: The impairment observed in the left and right ventricular diastolic function at the time of admission was greater than the impairment 1 week after poisoning. Mild CO poisoning did not have a significant effect on systolic function. Carboxyhemoglobin levels were positively correlated with left ventricular diastolic dysfunction, whereas the levels were not correlated with right ventricular diastolic function. CONCLUSIONS: In CO intoxication, the development of left and right ventricular diastolic dysfunction precedes systolic abnormality. Patients with mild CO poisoning do not manifest cardiovascular symptoms; however, it should be borne in mind that most of these patients have myocardial involvement.

Gastrointestinal hemorrhage caused by rupture of a pseudoaneurysm of the hepatic artery.

Gastrointestinal bleeding secondary to rupture of a hepatic artery pseudoaneurysm is rare. We report the case of a 61-year-old woman, who was admitted to our institution with hematemesis and melena. Upper gastrointestinal endoscopy and flexible sigmoidoscopy failed to reveal any significant abnormality. Computed tomography scan showed an aneurysm arising from the hepatic artery. A selective angiography showed a ruptured pseudoaneurysm originating from the right hepatic artery with extravasation. It was decided to embolize the pseudoaneurysm, and the neck of the pseudoaneurysm was occluded successfully with two microcoils. While these investigations and interventions were being performed, disseminated intravascular coagulation and acute hepatic failure occurred due to the massive blood transfusion and gross intrahepatic hematoma. Consequently, the patient died 10 days after admission. In this case, we observed that delayed diagnosis of hepatic artery aneurysm rupture may lead to a life-threatening situation. Thus, computed tomography and selective angiography should be obtained immediately. The percutaneous super-selective angiographic embolization of intrahepatic aneurysms is a promising form of treatment, with low risk.

Comparison of sedative drugs under peribulbar or topical anesthesia during phacoemulsification.

BACKGROUND AND OBJECTIVE: To compare dexmedetomidine and midazolam+fentanyl sedation primarily based on patient satisfaction during phacoemulsification under topical and peribulbar anesthesia. PATIENTS AND METHODS: Prospective, randomized, and double-blind study of 80 American Society of Anesthesiology grade I-II patients who underwent phacoemulsification with local anesthesia under sedation. Patients were divided into four groups (20 patients for each): dexmedetomidine and topical anesthesia, dexmedetomidine and peribulbar anesthesia, midazolam+fentanyl and topical anesthesia, and midazolam+fentanyl and peribulbar anesthesia. Patient and surgeon satisfaction were determined on a 5-point scale. The pain was determined by verbal pain scale intraoperatively and postoperatively. Drugs were given to a Ramsay sedation scale of 3. Topical and peribulbar anesthesia were performed by an ophthalmologist. Hemodynamic, respiratory, and intraocular pressure monitoring was done. Operative and recovery times were recorded. RESULTS: In the midazolam+fentanyl groups, better patient and surgeon satisfaction scores were obtained (P < .005), verbal pain scale scores were significantly lower (P < .001), and patients needed less postoperative analgesia. Ramsay sedation scale scores were between 3 and 4 in all patients and there were no significant differences. Intraocular pressure alterations were similar between groups. Recovery time was longer in the dexmedetomidine groups (P < .05). CONCLUSION: The study demonstrated that the midazolam+fentanyl combination provided high-level patient satisfaction scores, low-level pain scores, and shorter recovery time. Also, both of the peribulbar and topical anesthesia procedures showed similar efficiency.

Comparison of local anaesthesia with dexmedetomidine sedation and general anaesthesia during septoplasty.

BACKGROUND AND OBJECTIVE: To compare general anaesthesia and local anaesthesia with dexmedetomidine on the basis of postoperative pain and surgical bleeding after septoplasties. METHOD: Sixty patients with ASA 1 or 2 were divided into the local anaesthesia with dexmedetomidine (LAD) group (n = 30) and the general anaesthesia group (n = 30). Heart rate (HR), SBP and DBP were monitored. The amount of surgical bleeding, duration of surgery and recovery, postoperative pain evaluations [by visual analogue scale (VAS)] and nausea-vomiting were also recorded. Patients' satisfaction with anaesthesia and quality of breathing was questioned 1 week after discharge. RESULTS: HR values were significantly higher in the general anaesthesia group than in the LAD group at the 15th min and at the end of surgery. The SBP value at the 30th min was significantly higher in the LAD group than in the general anaesthesia group. No difference was observed between the groups with respect to the DBP value. Surgical bleeding and the duration of recovery were significantly less in the LAD group. The postoperative VAS scores were significantly higher in the general anaesthesia group than in the LAD group. Postoperative nausea-vomiting was also significantly greater in the general anaesthesia group. Although more patients in the LAD group preferred this anaesthetic procedure to general anaesthesia, the quality of breathing was better in both groups after surgery. CONCLUSION: Septoplasty performed under local anaesthesia with dexmedetomidine sedation resulted in less surgical bleeding, less postoperative pain, a more stable haemodynamic state, less nausea-vomiting, a shorter recovery period and a higher level of anaesthesia satisfaction.

Effects of the application of intra-abdominal low pressure on laparoscopic cholecystectomy on acid-base equilibrium.

The objective of this study was to determine the effects of low-pressure intra-abdominal application on laparoscopic cholecystectomy on acid-base equilibrium. Thirty patients were included in this study. Group 1 patients had 8 mmHg intra-abdominal pressure and Group 2 had 12 mmHg intra-abdominal pressure when they were operated on. There were no significant differences between the groups in terms of their age, sex, body mass index, insufflation and operation time, and anesthesia duration. The acid-base equilibrium situations were similar. Short-term metabolic, respiratory, and mix-type acidosis was observed during the operation and becomes normal in the recovery room. Acidosis is more likely related to the absorption of CO2 in the peritoneum rather than to secondary changes caused by intra-abdominal pressure increases. No positive effects of the application of intra-abdominal low pressure on laparoscopic cholecystectomy on acid-base equilibrium were observed in our study.