Effective data sampling strategies and boundary condition constraints of physics-informed neural networks for identifying material properties in solid mechanics

Material identification is critical for understanding the relationship between mechanical properties and the associated mechanical functions.However,material identification is a challenging task,especially when the characteristic of the material is highly nonlinear in nature,as is common in biological tissue.In this work,we identify unknown material properties in continuum solid mechanics via physics-informed neural networks(PINNs).To improve the accuracy and efficiency of PINNs,we develop efficient strategies to nonuniformly sample observational data.We also investigate different approaches to enforce Dirichlet-type boundary conditions(BCs)as soft or hard constraints.Finally,we apply the proposed methods to a diverse set of time-dependent and time-independent solid mechanic examples that span linear elastic and hyperelastic material space.The estimated material parameters achieve relative errors of less than 1%.As such,this work is relevant to diverse applications,including optimizing structural integrity and developing novel materials.

Effect of acetyl-L-carnitine on hypersensitivity in acute recurrent caerulein-induced pancreatitis and microglial activation along the brain’s pain circuitry

BACKGROUND Acute pancreatitis(AP)and recurring AP are serious health care problems causing excruciating pain and potentially lethal outcomes due to sepsis.The validated caerulein-(CAE)induced mouse model of acute/recurring AP produces secondary persistent hypersensitivity and anxiety-like behavioral changes for study.AIM To determine efficacy of acetyl-L-carnitine(ALC)to reduce pain-related behaviors and brain microglial activation along the pain circuitry in CAE-pancreatitis.METHODS Pancreatitis was induced with 6 hly intraperitoneal(i.p.)injections of CAE(50μg/kg),3 d a week for 6 wk in male C57BL/6J mice.Starting in week 4,mice received either vehicle or ALC until experiment’s end.Mechanical hypersensitivity was assessed with von Frey filaments.Heat hypersensitivity was determined with the hotplate test.Anxiety-like behavior was tested in week 6 using elevated plus maze and open field tests.Microglial activation in brain was quantified histologically by immunostaining for ionized calcium-binding adaptor molecule 1(Iba1).RESULTS Mice with CAE-induced pancreatitis had significantly reduced mechanical withdrawal thresholds and heat response latencies,indicating ongoing pain.Treatment with ALC attenuated inflammation-induced hypersensitivity,but hypersensitivity due to abdominal wall injury caused by repeated intraperitoneal injections persisted.Animals with pancreatitis displayed spontaneous anxiety-like behavior in the elevated plus maze compared to controls.Treatment with ALC resulted in increased numbers of rearing activity events,but time spent in“safety”was not changed.After all the abdominal injections,pancreata were translucent if excised at experiment’s end and opaque if excised on the subsequent day,indicative of spontaneous healing.Post mortem histopathological analysis performed on pancreas sections stained with Sirius Red and Fast Green identified wide-spread fibrosis and acinar cell atrophy in sections from mice with CAE-induced pancreatitis that was not rescued by treatment with ALC.Microglial Iba1 immunostaining was significantly increased in hippocampus,thalamus(intralaminar nuclei),hypothalamus,and amygdala of mice with CAE-induced pancreatitis compared to naïve controls but unchanged in the primary somatosensory cortex compared to naïves.CONCLUSION CAE-induced pancreatitis caused increased pain-related behaviors,pancreatic fibrosis,and brain microglial changes.ALC alleviated CAE-induced mechanical and heat hypersensitivity but not abdominal wall injury-induced hypersensitivity caused by the repeated injections.

Intraoperative glycemic control procedures and the use of an artificial pancreas

Strict intraoperative glycemic control can significantly decrease the incidence of postoperative infection; however, anesthesiologists must carefully control blood glucose levels as well as properly manage the respiratory and cardiovascular systems. However, standard blood glucose measurement systems and insulin dosing algorithms, which are necessary for achieving strict glycemic control, have not yet been developed. An artificial pancreas (STG-22TM; Nikkiso Co., Tokyo, Japan) is considered a highly accurate blood glucose monitoring system capable of closed-loop control of blood glucose. The device has, however, many problems to be addressed since it is a large and expensive system with little versatility, and it requires a large amount of blood to be collected. Therefore, the development of less invasive and inexpensive systems with future technological progress is greatly anticipated.

Electrical stimulation of cortical neurons promotes oligodendrocyte development and remyelination in the injured spinal cord

Background and early studies： Endogenous tri-potential neural stem cells （NSCs） exist in the adult mammalian central nervous system （CNS）. In the spinal cord, NSCs distribute throughout the entire cord, but exist predominately in white matter tracts. The phenotypic fate of these cells in white matter is glial, largely oligodendrocyte, but not neuronal.

The Effects of Glucose Load on Catabolism during Remifentanil-Based Anesthesia in Patients with Diabetes Mellitus: A Prospective Randomized Trial

Background: General anesthesia using remifentanil may suppress the unwanted metabolic changes caused by surgical stress including hyperglycemia and ketogenesis. Surgery-related changes in catabolism can be attenuated with low-dose glucose load, without causing hyperglycemia. However, the impact of glucose load in diabetic patients during surgery is unknown. In this study, we investigated the effect of glucose load on catabolism during remifentanil-based anesthesia in patients with diabetes mellitus. Methods: Twenty-nine patients with diabetes mellitus undergoing elective surgery were randomly assigned to receive a glucose load (1.5 mg/kg/min) or not. Plasma levels of glucose, insulin, cortisol, dopamine, adrenaline, noradrenaline, acetoacetic acid, free fatty acid, ketone bodies, 3-hydroxybutyric acid, and 3-methylhistidine/creatinine, a marker of protein catabolism were measured at the start of surgery and 3 h after the start of surgery. Results: Glucose and insulin levels were significantly higher in patients who received a glucose load than in those who did not. Cortisol levels decreased at 3 h after the start of surgery in both groups whereas the levels of catecholamines were unchanged. Acetoacetic acid and total ketone body levels were significantly lower in patients given a glucose load than in those who were not 3 h after the start of surgery. The difference in the 3 methylhistidine/creatinine ratio between the two groups was not significant. Conclusions: The infusion of glucose suppressed lipid catabolism in diabetic patients under remifentanil-based anesthesia during surgery. Our study also suggests that in patients with diabetes mellitus, protein sparing is inhibited by remifentanil-based anesthesia, regardless of the glucose load. Trial registration: the University Hospital Medical Information Network identifier: UMIN000010914.

Intraoperative Gastric Tube Intubation: A Summary of Case Studies and Review of the Literature

Study Objective: Establish complications and risk factors that are associated with blind tube insertion, evaluate the validity of correct placement verification methods, establish the rationales supporting its employment by anesthesia providers, and describe various deployment facilitators described in current literature. Measurements: An exhaustive literature review of the databases Medline, CINAHL, Cochrane Collaboration, Scopus, and Google Scholar was performed applying the search terms “gastric tube”, “complications”, “decompression”, “blind insertion”, “perioperative”, “intraoperative” in various order sequences. A five-year limit was applied to limit the number and timeliness of articles selected. Main Results: Patients are exposed to potentially serious morbidity and mortality from blindly inserted gastric tubes. Risk factors associated with malposition include blind insertion, the presence of endotracheal tubes, altered sensorium, and previous tube misplacements. Pulmonary aspiration risk prevention remains the only indication for anesthesia-related intraoperative use. There are no singularly effective tools that predict or verify the proper placement of blindly inserted gastric tubes. Current placement facilitation techniques are perpetuated through anecdotal experience and technique variability warrants further study. Conclusion: In the absence of aspiration risk factors or the need for surgical decompression in ASA classification I & II patients, a moratorium should be instituted on the elective use of gastric tubes.

Effects of Glucose Load on Catabolism during Propofol-Based Anesthesia with Remifentanil in Patients with Diabetes Mellitus: A Prospective Randomized Trial

Background: Perioperative exacerbation of hyperglycemia and insulin resistance is associated with increased complications in patients with diabetes mellitus. We recently reported that glucose load during anesthesia with sevoflurane suppressed lipid catabolism in diabetic patients. In contrast to inhaled anesthetics, propofol solution contains triglycerides, which can be an energy source during surgery. However, the clinical relevance of glucose load under propofol-based anesthesia in diabetic patients is unknown. Therefore, we investigated the effect of intraoperative glucose load on catabolism during propofol-based anesthesia in patients with diabetes mellitus. Methods: Twenty-three patients with diabetes mellitus undergoing elective surgery with propofol-remifentanil-based anesthesia were randomly assigned to receive a glucose load (1.5 mg/kg/ min) or not. Plasma levels of glucose, insulin, cortisol, catecholamines, acetoacetic acid, free fatty acids, ketone bodies, 3-hydroxybutyric acid, and 3-methylhistidine/creatinine, used as a marker for protein catabolism, were measured at the start of surgery and 3 h later. Results: Glucose and insulin levels were significantly higher in patients who received a glucose load than in those who did not. Nonetheless, the levels of cortisol and catecholamines were unchanged during surgery. Similarly, the difference in the levels of markers for lipid as well as protein catabolism was not significant between the groups at 3 h after the start of surgery. Conclusions: Changes in lipid as well as protein catabolism were not altered by glucose load in diabetic patients under propofol-based anesthesia with remifentanil. Our study suggested that continuous infusion of propofol at a clinical dose is sufficient to reduce the requirement for glucose infusion during surgery in patients with diabetes.

Heart‘omicsin’AGEing (HOMAGE):design,research objectives and characteristics of the common database

Heart failure is common in older people and its prevalence is increasing.The Heart ＇omics＇ in AGEing（HOMAGE） project aims to provide a biomarker approach that will improve the early diagnosis of heart failure.A large clinical database,based on（1） prospective population studies or（2） cross-sectional,prospective studies or randomized controlled trials（RCTs） of patients at risk for or with overt cardiovascular disease will be constructed to determine most promising ＇omics＇-based biomarkers to identify the risk of developing heart failure and/or comorbidities.Population studies,patient cohorts and RCTs are eligible for inclusion in the common database,if they received ethical approval to obtain and share data and have baseline information on cardiovascular risk factors.Currently,the HOMAGE database includes 43,065 subjects,from 20 studies in eight European countries,including healthy subjects from three population studies in France,Belgium and Italy（n = 7,124）,patients with heart failure（n = 4,312） from four cohorts in the UK,Spain and Switzerland and patients at high risk for cardiovascular disease（n = 31,629） in 13 cohorts.It is anticipated that more partners will join the consortium and enlarge the pooled data.This large merged database will be a useful resource with which to identify candidate biomarkers that play a role in the mechanism underlying the onset and progression of heart failure.

Remifentanil Has Sufficient Hypnotic and Amnesic Effect for Induction of Anesthesia by Itself

With a small-dose remifentanil, some patients showed no reaction and did not remember it postoperatively. We, therefore, hypothesized that remifentanil may decrease the level of consciousness and/or exhibit amnesic effect when stimulations are avoided. Thirty-patients were divided into two groups: non-stimulation group and stimulation group. Anesthesia was induced with 1 micro-g·kg?1·min?1 of remifentanil using no additional hypnotic agent. In the non-stimulation group, patients were left free from any stimulation except non-invasive blood pressure monitoring. In the stimulation group, patients were asked to follow verbal commands. The level of consciousness was evaluated with electroencephalogram and BIS-value derived from it. In the non-stimulation group, all patients reached the decreased level of consciousness in 5 minutes. In the stimulation group, however, 14 patients were judged to be still conscious. 10 patients could open their mouth at the 5th minute, but 9 of these 10 patients did not remember it postoperatively. In conclusion, remifentanil, with no additional anesthetics, exhibited hypnotic and amnesic effects when stimulations were kept minimal.

Recent evidence for subcutaneous drains to prevent surgical site infections after abdominal surgery:A systematic review and metaanalysis

BACKGROUND Surgical site infections(SSIs)increase mortality,hospital stays,additional medical treatment,and medical costs.Subcutaneous drains prevent SSIs in gynecological and breast surgeries;however,their clinical impact in abdominal surgery remains unclear.AIM To investigate whether subcutaneous drains were beneficial in abdominal surgery using a systematic review and meta-analysis.METHODS The database search used PubMed,MEDLINE,and the Cochrane Library.The following inclusion criteria were set for the systematic review:(1)Randomized controlled trial studies comparing SSIs after abdominal surgery with or without subcutaneous drains;and(2)Studies that described clinical outcomes,such as SSIs,seroma formation,the length of hospital stays,and mortality.RESULTS Eight studies were included in this meta-analysis.The rate of total SSIs was significantly lower in the drained group(54/771,7.0%)than in the control group(89/759,11.7%),particularly in gastrointestinal surgery.Furthermore,the rate of superficial SSIs was slightly lower in the drained group(31/517,6.0%)than in the control group(49/521,9.4%).No significant differences were observed in seroma formation between the groups.Hospital stays were shorter in the drained group than in the control group.CONCLUSION Subcutaneous drains after abdominal surgery prevented SSIs and reduced hospital stays but did not significantly affect seroma formation.The timing of drain removal needs to be reconsidered in future studies.

Conditioned medium from human dental pulp stem cells treats spinal cord injury by inhibiting microglial pyroptosis

Human dental pulp stem cell transplantation has been shown to be an effective therapeutic strategy for spinal cord injury.However,whether the human dental pulp stem cell secretome can contribute to functional recovery after spinal cord injury remains unclear.In the present study,we established a rat model of spinal cord injury based on impact injury from a dropped weight and then intraperitoneally injected the rats with conditioned medium from human dental pulp stem cells.We found that the conditioned medium effectively promoted the recovery of sensory and motor functions in rats with spinal cord injury,decreased expression of the microglial pyroptosis markers NLRP3,GSDMD,caspase-1,and interleukin-1β,promoted axonal and myelin regeneration,and inhibited the formation of glial scars.In addition,in a lipopolysaccharide-induced BV2 microglia model,conditioned medium from human dental pulp stem cells protected cells from pyroptosis by inhibiting the NLRP3/caspase-1/interleukin-1βpathway.These results indicate that conditioned medium from human dental pulp stem cells can reduce microglial pyroptosis by inhibiting the NLRP3/caspase-1/interleukin-1βpathway,thereby promoting the recovery of neurological function after spinal cord injury.Therefore,conditioned medium from human dental pulp stem cells may become an alternative therapy for spinal cord injury.

Use of venous-to-arterial carbon dioxide tension difference to guide resuscitation therapy in septic shock

The mixed venous-to-arterial carbon dioxide(CO_2)tension difference[P(v-a) CO_2]is the difference between carbon dioxide tension(PCO_2) in mixed venous blood(sampled from a pulmonary artery catheter) and the PCO_2 in arterial blood.P(v-a) CO_2 depends on the cardiac output and the global CO_2 production,and on the complex relationship between PCO_2 and CO_2 content.Experimental and clinical studies support the evidence that P(v-a) CO_2 cannot serve as an indicator of tissue hypoxia,and should be regarded as an indicator of the adequacy of venous blood to wash out the total CO_2generated by the peripheral tissues.P(v-a) CO_2 can be replaced by the central venous-to-arterial CO_2 difference(△PCO_2),which is calculated from simultaneous sampling of central venous blood from a central vein catheter and arterial blood and,therefore,more easy to obtain at the bedside.Determining the △PCO_2 during the resuscitation of septic shock patients might be useful when deciding when to continue resuscitation despite a central venous oxygen saturation(SCVO_2) > 70%associated with elevated blood lactate levels.Because high blood lactate levels is not a discriminatory factor in determining the source of that stress,an increased △PCO_2(> 6 mmHg)could be used to identify patients who still remain inadequately resuscitated.Monitoring the △PCO_2 from the beginning of the reanimation of septic shock patients might be a valuable means to evaluate the adequacy of cardiac output in tissue perfusion and,thus,guiding the therapy.In this respect,it can aid to titrate inotropes to adjust oxygen delivery to CO_2 production,or to choose between hemoglobin correction or fluid/inotrope infusion in patients with a too low ScvO_2 related to metabolic demand.The combination of P(v-a) CO_2 or △PCO_2 with oxygen-derived parameters through the calculation of the P(v-a) CO_2 or △PCO_2/arteriovenous oxygen content difference ratio can detect the presence of global anaerobic metabolism.

Brain-lung crosstalk: Implications for neurocritical care patients

Major pulmonary disorders may occur after brain injuries as ventilator-associated pneumonia, acute respiratory distress syndrome or neurogenic pulmonary edema. They are key points for the management of brain-injured patients because respiratory failure and mechanical ventilation seem to be a risk factor for increased mortality, poor neurological outcome and longer intensive care unit or hospital length of stay. Brain and lung strongly interact via complex pathways from the brain to the lung but also from the lung to the brain. Several hypotheses have been proposed with a particular interest for the recently described "double hit" model. Ventilator setting in brain-injured patients with lung injuries has been poorly studied and intensivists are often fearful to use some parts of protective ventilation in patients with brain injury. This review aims to describe the epidemiology and pathophysiology of lung injuries in brain-injured patients, but also the impact of different modalities of mechanical ventilation on the brain in the context of acute brain injury.

Endoscopic retrograde cholangiopancreatography-induced and non-endoscopic retrograde cholangiopancreatographyinduced acute pancreatitis:Two distinct clinical and immunological entities?

Acute pancreatitis(AP) is common gastrointestinal disease of varied aetiology. The most common cause of AP is gallstones, followed by alcohol abuse as an independent risk factor. With the increased need for invasive techniques to treat pancreatic and bile duct pathologies such as endoscopic retrograde cholangiopancreatography(ERCP), AP has emerged as the most frequent complication. While severe AP following ERCP is rare(0.5%), if it does develop it has a greater severity index compared to non-ERCP AP. Development of a mild form of AP after ERCP is not considered a clinically relevant condition. Differences in the clinical presentation and prognosis of the mild and severe forms have been found between non-ERCP AP and postendoscopic pancreatitis(PEP). It has been proposedthat AP and PEP may also have different immunological responses to the initial injury. In this review, we summarise the literature on clinical and inflammatory processes in PEP vs non-ERCP AP.

Accuracy of training blood volume quantifi cation using a visual estimation tool

BACKGROUND:We investigated whether the use of a specially designed visual estimation tool may improve accuracy in quantifying blood volumes related to surface spreading.METHODS:A prospective,paired-control,single-blinded experimental study was performed at a medical university.Anesthesiologists and emergency medical personnel estimated various blood volumes on surfaces with varying absorptivity(carpet,towel,polyvinyl chloride,wooden fl ooring)in an experimental setting.We assessed the sensitivity of training blood volume quantifi cation using a self-designed visual estimation tool by comparing the accuracy of visual blood volume estimations before and after practical training with the tool.RESULTS:A total of 352 estimations by 44 participants were evaluated.Accurate estimations improved significantly from pre-training to post-training(P<0.05).The sensitivity of blood volume quantifi cation was 33.0%after training with the visual estimation tool.Estimations did not depend on age,profession,gender or years of the estimator’s professional experience.CONCLUSIONS:Training with a visual estimation tool by professional rescuers can improve the estimation accuracy of blood volumes spread on surfaces with varying absorptivity.

Melatonin for the treatment of spinal cord injury

Spinal cord injury（SCI） from trauma or disease severely impairs sensory and motor function. Neurorehabilitation after SCI is a complex medical process that focuses on improving neurologic function and repairing damaged connections in the central nervous system. An increasing number of preclinical studies suggest that melatonin may be useful for the treatment of SCI. Melatonin is an indolamine that is primarily secreted by the pineal gland and known to be regulated by photoperiodicity. However, it is also a versatile hormone with antioxidative, antiapoptotic, neuroprotective, and anti-inflammatory properties. Here, we review the neuroprotective properties of melatonin and the potential mechanisms by which it might be beneficial in the treatment of SCI. We also describe therapies that combine melatonin with exercise, oxytetracycline, and dexamethasone to attenuate the secondary injury after SCI and limit potential side effects. Finally, we discuss how injury at different spinal levels may differentially affect the secretion of melatonin.

Effect of microenvironment modulation on stem cell therapy for spinal cord injury pain

Spinal cord injury （SCI） currently ranks second after mental retarda- tion among neurological disorders in terms of cost to society. Pain is a debilitating consequence of SCI related to the nature of the lesion, neurological structures damaged, and secondary pathophysiological changes of surviving tissues （Yezierski, 2005; D＇Angelo et al., 2013）.

Stability of cirrhotic systemic hemodynamics ensures sufficient splanchnic blood flow after living-donor liver transplantation in adult recipients with liver cirrhosis

AIM: To investigate the correlation between systemic hemodynamics and splanchnic circulation in recipients with cirrhosis undergoing living-donor liver transplantation (LDLT), and to clarify how systemic hemodynamics impact on local graft circulation after LDLT. METHODS: Systemic hemodynamics, indocyanine green (ICG) elimination rate (KICG) and splanchnic circulation were simultaneously and non-invasively investigated by pulse dye densitometry (PDD) and ultrasound. Accurate estimators of optimal systemic hyperdynamics after LDLT [i.e., balance of cardiac output (CO) to blood volume (BV) and mean transit time (MTT), defined as the timerequired for half the administered ICG to pass through an attached PDD sensor in the first circulation] were also measured. Thirty recipients with cirrhosis were divided into two groups based on clinical outcomes corresponding to postoperative graft function. RESULTS: Cirrhotic systemic hyperdynamics characterized by high CO, expanded BV and low total peripheral resistance (TPR) were observed before LDLT. TPR reflecting cirrhotic vascular alterations was slowly restored after LDLT in both groups. Although no significant temporal differences in TPR were detected between the two groups, CO/BV and MTT differed significantly. Recipients with good outcomes showed persistent cirrhotic systemic hyperdynamics after LDLT, whereas recipients with poor outcomes presented with unstable cirrhotic systemic hyperdynamics and severely decreased KICG. Systemic hyperdynamic disorders after LDLT impacted on portal venous flow but not hepatic arterial flow. CONCLUSION: We conclude that subtle systemic hyperdynamics disorders impact on splanchnic circulation, and that an imbalance between CO and BV decreases portal venous flow, which results in critical outcomes.

Assessment of cardiac output in liver transplantation recipients

BACKGROUND:Liver cirrhosis causes peculiar systemic hemodynamics,and accurate evaluation of systemic hemodynamic state is important for cirrhotic recipients who underwent living donor liver transplantation(LDLT). We investigated the clinical advantages of a novel non- invasive method for measuring systemic hemodynamic parameters using indocyanine green(ICG). METHODS:Twenty-eight LDLT recipients were evaluated. Simultaneous measurements of cardiac output(CO)using Swan-Ganz catheters and pulse dye densitometry(PDD) were performed every 12 hours after LDLT.A total of 155 sets of simultaneous CO measurements were obtained. RESULTS:The CO values obtained by PDD correlated well with those obtained by the invasive catheter technique.In addition,none of the recipients developed any side-effects, and we verified the safety of repeated ICG injections.ICG is safe,even for repeated use over time in the same recipient. Moreover,PDD can measure the blood volume(BV).CONCLUSIONS:Since the cirrhotic systemic hemody- namics characterized by high CO and large BV remains, even after LDLT,the ability to measure CO and BV in a non-invasive,simple and real-time manner using PDD has advantages for cirrhotic LDLT recipients.

Conversion from prolonged intravenous fentanyl infusion to enteral methadone in critically ill children

AIM To describe our institutional experience with conversion from intravenous(IV) fentanyl infusion directly to enteral methadone and occurrence of withdrawal in critically ill mechanically ventilated children exposed to prolonged sedation and analgesia.METHODS With Institutional Review Board approval,we retrospectively studied consecutively admitted invasively mechanically ventilated children(0-18 years) sedated with IV fentanyl infusion > 5 d and subsequently converted directly to enteral methadone.Data were obtained onsubject demographics,illness severity,daily IV fentanyl and enteral methadone dosing,time to complete conversion,withdrawal scores(WAT-1),pain scores,and need for rescue opioids.Patients were classified as rapid conversion group(RCG) if completely converted ≤ 48 h and slow conversion group(SCG) if completely converted in > 48 h.Primary outcome was difference in WAT-1 scores at 7 d.Secondary outcomes included differences in overall pain scores,and differences in daily rescue opioids.RESULTS Compared to SCG(n = 21),RCG(n = 21) had lower median WAT-1 scores at 7 d(2.5 vs 5,P = 0.027).Additionally,RCG had lower overall median pain scores(3 vs 6,P = 0.007),and required less median daily rescue opioids(3 vs 12,P = 0.003) than SCG.The starting daily median methadone dose was 2.3 times the daily median fentanyl dose in the RCG,compared to 1.1 times in the SCG(P = 0.049).CONCLUSION We observed wide variation in conversion from IV fentanyl infusion directly to enteral methadone and variability in withdrawal in critically ill mechanically ventilated children exposed to prolonged sedation.In those children who converted successfully from IV fentanyl infusion to enteral methadone within a period of 48 h,a methadone:fentanyl dose conversion ratio of approximately 2.5:1 was associated with less withdrawal and reduced need for rescue opioids.