Outpatient Treatment With Gabapentin in Women With Severe Acute Pain After Cesarean Delivery Is Ineffective: A Randomized, Double-Blind, Placebo-Controlled Trial.

BACKGROUND: Most of the 1.1 million women who deliver by cesarean in the United States each year have an uncomplicated recovery. However, severe pain resistant to standard multimodal therapy within the first days after surgery is associated with an increased risk for prolonged pain and opioid use. The best outpatient management for parturients with severe resistant early onset pain is not known. METHODS: We performed a prospective, double-blind, placebo-controlled, randomized trial of up to 12 weeks of outpatient treatment with gabapentin to evaluate its effectiveness to facilitate opioid cessation in women with at least 2 reports of severe pain during the immediate postpartum period resistant to standard multimodal pain management. Time to opioid cessation was the primary outcome. Time to pain resolution; time to discontinuation of gabapentin, acetaminophen, and ibuprofen; time to self-reported recovery; and National Institute of Health Patient-Reported Outcomes System (PROMIS) surveys for anxiety, depression, fatigue, and physical function were assessed as secondary outcomes. RESULTS: There was no difference in time to opioid cessation between patients who were randomly assigned to be treated with gabapentin (Kaplan-Meier estimated median of 2 [25th-75th percentiles of 1-3] weeks, n = 35) versus those who were treated with placebo (2 [1-3] weeks, n = 35). The hazard ratio was 1.1 (95% confidence interval [CI], 0.67-1.8), P = .65. There were no differences in any secondary end points between the study groups. CONCLUSIONS: Outpatient supplementation with gabapentin did not reduce time to opioid cessation, pain, anxiety, depression, fatigue, or improve physical function in women with severe pain after cesarean delivery. Gabapentin should not be routinely added to the standard outpatient multimodal regimen of ibuprofen, acetaminophen, and opioids.

The Effect of Night Float Rotation on Resident Sleep, Activity, and Well-Being.

BACKGROUND: Night float call systems are becoming increasingly common at training programs with the goal of reducing fatigue related to sleep deprivation and sleep disturbance. Previous studies have shown that trainees obtain less sleep during the night float rotation and have decreased sleep efficiency for several days after the rotation. The impact on physical and emotional well-being has not been documented. METHODS: Twenty-seven anesthesia residents were enrolled in a study using wearable sleep and activity trackers and National Institutes of Health Patient-Reported Outcome Measurement Information System (NIH PROMIS) surveys for sleep disturbance, fatigue, and positive affect to record data the week before ("baseline"), during ("night float"), and 1 week after ("recovery") their night float rotation. Each subject's data during the night float week and recovery week were compared to his or her own baseline week data using a paired, nonparametric analysis. The primary outcome variable was the change in average daily sleep hours during the night float week compared to the baseline week. Average daily rapid eye movement (REM) sleep, daily steps, and NIH PROMIS scores comparing night float and recovery weeks to baseline week were prespecified secondary outcomes. NIH PROMIS scores range from 0 to 100 with 50 as the national mean and more of the construct having a higher score. RESULTS: There was no difference in average daily sleep hours between the night float and the baseline weeks (6.7 [5.9-7.8] vs 6.7 [5.5-7.7] hours, median [interquartile range]; P = .20). Residents had less REM sleep during the night float compared to the baseline weeks (1.1 [0.7-1.5] vs 1.4 [1.1-1.9] hours, P = .002). NIH PROMIS fatigue scores were higher during the night float than the baseline week (58.8 [54.6-65.1] vs 48.6 [46.0-55.1], P = .0004) and did not return to baseline during the recovery week (51.0 [48.6-58.8], P = .029 compared to baseline). Sleep disturbance was not different among the weeks. Positive affect was reduced after night float compared to baseline (39.6 [35.0-43.5] vs 44.8 [40.1-49.6], P = .0009), but returned to baseline during the recovery week (43.6 [39.6-48.2], P = .38). CONCLUSIONS: The residents slept the same number of total hours during their night float week but had less REM sleep, were more fatigued, and had less positive affect. All of these resolved to baseline except fatigue, that was still greater than the baseline week. This methodology appears to robustly capture psychophysiological data that might be useful for quality initiatives.

A Brief Screening Tool for Opioid Use Disorder: EMPOWER Study Expert Consensus Protocol.

Growing concerns about the safety of long-term opioid therapy and its uncertain efficacy for non-cancer pain have led to relatively rapid opioid deprescribing in chronic pain patients who have been taking opioid for years. To date, empirically supported processes for safe and effective opioid tapering are lacking. Opioid tapering programs have shown high rates of dropouts and increases in patient distress and suicidal ideation. Therefore, safe strategies for opioid deprescribing that are more likely to succeed are urgently needed. In response to this demand, the EMPOWER study has been launched to examine the effectiveness of behavioral medicine strategies within the context of patient-centered opioid tapering in outpatient settings (https://empower.stanford.edu/). The EMPOWER protocol requires an efficient process for ensuring that collaborative opioid tapering would be offered to the most appropriate patients while identifying patients who should be offered alternate treatment pathways. As a first step, clinicians need a screening tool to identify patients with Opioid Use Disorder (OUD) and to assess for OUD severity. Because such a tool is not available, the study team composed of eight chronic pain and/or addiction experts has extended a validated screening instrument to develop a brief and novel consensus screening tool to identify OUD and assess for OUD severity for treatment stratification. Our screening tool has the potential to assist busy outpatient clinicians to assess OUD among patients receiving long-term opioid therapy for chronic pain.

Factors associated with persistent pain after childbirth: a narrative review.

A systematic literature search was performed to identify studies that reported risk factors for persistent pain after childbirth. Many studies have sought to identify risk factors for post-delivery pain in different populations, using different methodologies and different outcome variables. Studies of several different but interrelated post-partum pain syndromes have been conducted. Factors strongly and specifically associated with persistent incisional scar pain after Caesarean delivery include a coexisting persistent pain problem in another part of the body and severe acute postoperative pain. For persistent vaginal and perineal pain, operative vaginal delivery and the magnitude of perineal trauma have been consistently linked. History of pregnancy-related and pre-pregnancy back pain and heavier body weight are robust risk factors for persistent back pain after pregnancy. Unfortunately, limitations, particularly small samples and lack of a priori sample size calculation designed to detect specific effect sizes for risk of persistent pain outcomes, preclude definitive conclusions about many other predictors and the strength of outcome associations. In future studies, assessments of specific phenotypes using a rigorous analysis with appropriate predetermined sample sizes and validated instruments are needed to allow elucidation of stronger and reliable associations. Interventional studies targeting the most robustly associated, modifiable risk factors, such as acute post-partum pain, may lead to solutions for the prevention and treatment of these common problems that impact a large population.

Women's health in Northwestern Syria: Findings from Healthy-Syria 2017 study.

OBJECTIVES: Since the uprising in 2011, there have been limited health-care data from inside Syria regarding women's health. This study aimed to provide an updated account of women's health, including pregnancy, perinatal care, childbirth, and other conditions to identify obstacles and challenges to health-care delivery in Northwestern Syria. METHODS: This is a prospective data registry study, using a medical electronic records system that builds on the International Classification of Diseases, Tenth Revision (ICD-10) codes. We collected data from one medical center in Northwestern Syria during 2017. We conducted a survey to understand patients' knowledge of and barriers limiting antenatal care (ANC). RESULTS: We studied 7213 patients' health status and surveyed 134 regarding ANC. Prenatal care, delivery, and miscarriage treatment represented the most common (70%) reasons for women's health-care visits, followed by menstrual disorders (17%). From 2057 delivery records, 70% delivered vaginally and 30% required cesarean delivery. Our findings showed that 1169 (24%) of the pregnant women (4936) in 2017 were adolescents, of them 22 (0.44%) were 14 years old. Regarding ANC visits, 85% of respondents did not have a single ANC visit in the first trimester, 82% had no visits in the second trimester, and 44% had no visits in the third trimester. Thirty-one percent had no ANC visit throughout the entire pregnancy. Only 13% had postnatal care (PNC) visits. Women who live in the refugee camp are 2.7 times less likely to meet the World Health Organization (WHO) criteria for focused ANC (FANC = 4 visits) compared to those who reside in town (P < 0.001), with only 14% having met the FANC. The major barrier to ANC is related to transportation (34%), followed by factors related to the study center (29%) and knowledge and education (19%). We estimated the number of obstetrics-gynecology doctors per 1000 populations to be 0.02. CONCLUSIONS: We found a huge deficiency in ANC and PNC visits, a high adolescent birth rate, and a higher cesarean-to-vaginal delivery ratio than what is recommended by the WHO. We also found a severe shortage in the number of obstetrician-gynecologists serving this population.

Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU.

OBJECTIVE: To update and expand the 2013 Clinical Practice Guidelines for the Management of Pain, Agitation, and Delirium in Adult Patients in the ICU. DESIGN: Thirty-two international experts, four methodologists, and four critical illness survivors met virtually at least monthly. All section groups gathered face-to-face at annual Society of Critical Care Medicine congresses; virtual connections included those unable to attend. A formal conflict of interest policy was developed a priori and enforced throughout the process. Teleconferences and electronic discussions among subgroups and whole panel were part of the guidelines' development. A general content review was completed face-to-face by all panel members in January 2017. METHODS: Content experts, methodologists, and ICU survivors were represented in each of the five sections of the guidelines: Pain, Agitation/sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption). Each section created Population, Intervention, Comparison, and Outcome, and nonactionable, descriptive questions based on perceived clinical relevance. The guideline group then voted their ranking, and patients prioritized their importance. For each Population, Intervention, Comparison, and Outcome question, sections searched the best available evidence, determined its quality, and formulated recommendations as "strong," "conditional," or "good" practice statements based on Grading of Recommendations Assessment, Development and Evaluation principles. In addition, evidence gaps and clinical caveats were explicitly identified. RESULTS: The Pain, Agitation/Sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption) panel issued 37 recommendations (three strong and 34 conditional), two good practice statements, and 32 ungraded, nonactionable statements. Three questions from the patient-centered prioritized question list remained without recommendation. CONCLUSIONS: We found substantial agreement among a large, interdisciplinary cohort of international experts regarding evidence supporting recommendations, and the remaining literature gaps in the assessment, prevention, and treatment of Pain, Agitation/sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption) in critically ill adults. Highlighting this evidence and the research needs will improve Pain, Agitation/sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption) management and provide the foundation for improved outcomes and science in this vulnerable population.

Methodologic Innovation in Creating Clinical Practice Guidelines: Insights From the 2018 Society of Critical Care Medicine Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption Guideline Effort.

OBJECTIVES: To describe novel guideline development strategies created and implemented as part of the Society of Critical Care Medicine's 2018 clinical practice guidelines for pain, agitation (sedation), delirium, immobility (rehabilitation/mobility), and sleep (disruption) in critically ill adults. DESIGN: We involved critical illness survivors from start to finish, used and expanded upon Grading of Recommendations, Assessment, Development and Evaluation methodology for making recommendations, identified evidence gaps, and developed communication strategies to mitigate challenges. SETTING/SUBJECTS: Thirty-two experts from five countries, across five topic-specific sections; four methodologists, two medical librarians, four critical illness survivors, and two Society of Critical Care Medicine support staff. INTERVENTIONS: Unique approaches included the following: 1) critical illness survivor involvement to help ensure patient-centered questions and recommendations; 2) qualitative and semiquantitative approaches for developing descriptive statements; 3) operationalizing a three-step approach to generating final recommendations; and 4) systematic identification of evidence gaps. MEASUREMENTS AND MAIN RESULTS: Critical illness survivors contributed to prioritizing topics, questions, and outcomes, evidence interpretation, recommendation formulation, and article review to ensure that their values and preferences were considered in the guidelines. Qualitative and semiquantitative approaches supported formulating descriptive statements using comprehensive literature reviews, summaries, and large-group discussion. Experts (including the methodologists and guideline chairs) developed and refined guideline recommendations through monthly topic-specific section conference calls. Recommendations were precirculated to all members, presented to, and vetted by, most members at a live meeting. Final electronic voting provided links to all forest plots, evidence summaries, and "evidence to decision" frameworks. Written comments during voting captured dissenting views and were integrated into evidence to decision frameworks and the guideline article. Evidence gaps, reflecting clinical uncertainty in the literature, were identified during the evidence to decision process, live meeting, and voting and formally incorporated into all written recommendation rationales. Frequent scheduled "check-ins" mitigated communication gaps. CONCLUSIONS: Our multifaceted, interdisciplinary approach and novel methodologic strategies can help inform the development of future critical care clinical practice guidelines.

Recovery after Nulliparous Birth: A Detailed Analysis of Pain Analgesia and Recovery of Function.

BACKGROUND: The majority of parturients in the United States first return for evaluation by their obstetric practitioner 6 weeks after delivery. As such, there is little granular data on the pain experience, analgesic requirements, and functional recovery during the postpartum period. This prospective observational study was performed to evaluate these factors to provide expectations for patients. METHODS: A total of 213 nulliparous women were enrolled and assessed daily until they completed 3 outcomes: (1) pain resolution; (2) opioid cessation; and (3) self-assessed functional recovery from delivery. The primary endpoint, pain- and opioid-free functional recovery, was the time required to reach all three of the endpoints. Pain burden was assessed as the area under the curve created by plotting the daily numerical pain rating scale against the days required to attain pain resolution. Times to attain study endpoints after cesarean delivery and vaginal delivery were compared using survival analysis. RESULTS: After vaginal delivery, days required for pain and opioid-free functional recovery (median [interquartile range (IQR)]) were 19 [11 to 26], for opioid cessation 0 [0 to 2], termination of all analgesic (including nonsteroidal antiinflammatories and acetaminophen) 11 [5 to 17], and pain resolution 14 [7 to 24]. Achievement of these endpoints after cesarean delivery required 27 [19 to 40], 9 [5 to 12], 16 [11 to 24], and 21 [14 to 27] days, respectively. CONCLUSIONS: There is clinically significant variability between healthy nulliparous parturients in the pain experience, opioid use, and functional recovery after childbirth following vaginal and cesarean delivery. Recovery to predelivery function is similar after vaginal and cesarean delivery, and approximately half of the variance was explained by pain burden.

Inhibition Mediated by Glycinergic and GABAergic Receptors on Excitatory Neurons in Mouse Superficial Dorsal Horn Is Location-Specific but Modified by Inflammation.

The superficial dorsal horn is the synaptic termination site for many peripheral sensory fibers of the somatosensory system. A wide range of sensory modalities are represented by these fibers, including pain, itch, and temperature. Because the involvement of local inhibition in the dorsal horn, specifically that mediated by the inhibitory amino acids GABA and glycine, is so important in signal processing, we investigated regional inhibitory control of excitatory interneurons under control conditions and peripheral inflammation-induced mechanical allodynia. We found that excitatory interneurons and projection neurons in lamina I and IIo are dominantly inhibited by GABA while those in lamina IIi and III are dominantly inhibited by glycine. This was true of identified neuronal subpopulations: neurokinin 1 receptor-expressing (NK1R+) neurons in lamina I were GABA-dominant while protein kinase C gamma-expressing (PKCγ+) neurons at the lamina IIi-III border were glycine-dominant. We found this pattern of synaptic inhibition to be consistent with the distribution of GABAergic and glycinergic neurons identified by immunohistochemistry. Following complete Freund's adjuvant injection into mouse hindpaw, the frequency of spontaneous excitatory synaptic activity increased and inhibitory synaptic activity decreased. Surprisingly, these changes were accompanied by an increase in GABA dominance in lamina IIi. Because this shift in inhibitory dominance was not accompanied by a change in the number of inhibitory synapses or the overall postsynaptic expression of glycine receptor α1 subunits, we propose that the dominance shift is due to glycine receptor modulation and the depressed function of glycine receptors is partially compensated by GABAergic inhibition.SIGNIFICANCE STATEMENT Pain associated with inflammation is a sensation we would all like to minimize. Persistent inflammation leads to cellular and molecular changes in the spinal cord dorsal horn, including diminished inhibition, which may be responsible for enhance excitability. Investigating inhibition in the dorsal horn following peripheral inflammation is essential for development of improved ways to control the associated pain. In this study, we have elucidated regional differences in inhibition of excitatory interneurons in mouse dorsal horn. We have also discovered that the dominating inhibitory neurotransmission within specific regions of dorsal horn switches following peripheral inflammation and the accompanying hypersensitivity to thermal and mechanical stimuli. Our novel findings contribute to a more complete understanding of inflammatory pain.

Impact of cervical effacement and fetal station on progress during the first stage of labor: a biexponential model.

OBJECTIVE: To develop a model that uses cervical effacement, fetal station, and parity to predict progress during the first stage of labor. STUDY DESIGN: This was a secondary analysis of a cohort of 1,128 parturients delivering after 34 weeks. Timed cervical exams from each patient were fit with a biexponential model. Methods for consideration of fetal station, cervical effacement and parity were developed and validated. RESULTS: The biexponential model fit the data in an unbiased manner with a median absolute prediction error of 1.1 cm. Although nulliparous women had slower active labor, they did not differ from multiparous women in their rate of latent labor or the cervical dilation at which they transitioned to active labor. In addition, nulliparous women began laboring with a more effaced cervix (45 vs. 31%) and lower fetal station (-2.8 vs. -3.2). CONCLUSION: We validated a biexponential model for labor progress using a large mixed parity cohort. We demonstrated that parity and initial fetal station add important clinical information that can be used to make a labor model more accurate. As such, parity and fetal station can be utilized in such structural models to predict normal labor progress and potentially identify abnormalities in labor progress.

HCN1 channels as targets for anesthetic and nonanesthetic propofol analogs in the amelioration of mechanical and thermal hyperalgesia in a mouse model of neuropathic pain.

Chronic pain after peripheral nerve injury is associated with afferent hyperexcitability and upregulation of hyperpolarization-activated, cyclic nucleotide-regulated (HCN)-mediated IH pacemaker currents in sensory neurons. HCN channels thus constitute an attractive target for treating chronic pain. HCN channels are ubiquitously expressed; analgesics targeting HCN1-rich cells in the peripheral nervous system must spare the cardiac pacemaker current (carried mostly by HCN2 and HCN4) and the central nervous system (where all four isoforms are expressed). The alkylphenol general anesthetic propofol (2,6-di-iso-propylphenol) selectively inhibits HCN1 channels versus HCN2-HCN4 and exhibits a modest pharmacokinetic preference for the periphery. Consequently, we hypothesized that propofol, and congeners, should be antihyperalgesic. Alkyl-substituted propofol analogs have different rank-order potencies with respect to HCN1 inhibition, GABA(A) receptor (GABA(A)-R) potentiation, and general anesthesia. Thus, 2,6- and 2,4-di-tertbutylphenol (2,6- and 2,4-DTBP, respectively) are more potent HCN1 antagonists than propofol, whereas 2,6- and 2,4-di-sec-butylphenol (2,6- and 2,4-DSBP, respectively) are less potent. In contrast, DSBPs, but not DTBPs, enhance GABA(A)-R function and are general anesthetics. 2,6-DTBP retained propofol's selectivity for HCN1 over HCN2-HCN4. In a peripheral nerve ligation model of neuropathic pain, 2,6-DTBP and subhypnotic propofol are antihyperalgesic. The findings are consistent with these alkylphenols exerting analgesia via non-GABA(A)-R targets and suggest that antagonism of central HCN1 channels may be of limited importance to general anesthesia. Alkylphenols are hydrophobic, and thus potential modifiers of lipid bilayers, but their effects on HCN channels are due to direct drug-channel interactions because they have little bilayer-modifying effect at therapeutic concentrations. The alkylphenol antihyperalgesic target may be HCN1 channels in the damaged peripheral nervous system.

Role of capsaicin in a murine model of labor and delivery.

BACKGROUND: The objectives of this study were to develop a murine model of labor and delivery and to use this model to examine whether capsaicin diminishes labor pain and expedites delivery. METHODS: To develop a murine model of labor pain, the authors identified and compared the incidence of four proposed pain behaviors in 46 mice: (1) No analgesia in labor and the postpartum period, and (2) increasing doses of an analgesic, morphine. The model was then used to examine the impact of topical cervical capsaicin on: (1) labor pain behaviors and (2) labor progress by examining its impact on the time from treatment to delivery of the first pup and on the duration of delivery per pup. The treatment was randomly allocated and the behavioral observation was blinded. RESULTS: In the absence of analgesia, there was a statistically significant decrease in all four proposed pain behaviors in the postpartum period compared with labor (cumulative 55.0 ± 16.1/h vs. 16.1 ± 8.7/h; P < 0.0001). Additionally, morphine reduced their incidence during labor in a dose-dependent manner (cumulative 55.0 ± 16.1.7/h control, 46.4 ± 15.8 morphine 0.1 mg/kg/h, 34.6 ± 5.6/h, morphine 0.5 mg/kg/h; P = 0.1988, 0.0014). In addition, the incidence of identified pain behaviors was reduced by pericervical capsaicin (cumulative 55.0 ± 16.1.7/h control, 38.9 ± 15.4 capsaicin, P = 0.02). CONCLUSIONS: In this pilot study, the authors developed a novel mouse model of labor and delivery. Pericervical capsaicin applied days before delivery reduces labor pain behaviors.

Cesarean hysterectomy requiring emergent thoracotomy: a case report of a complication of placenta percreta requiring a multidisciplinary effort.

BACKGROUND: Currently a leading indication for cesarean hysterectomy among multiparous women, placenta accreta is associated with significant maternal morbidity and mortality. CASE: A 34-year-old woman with a pregnancy complicated by placenta previa and previous cesarean deliveries was transferred to our institution following late diagnosis of placenta percreta. She underwent cesarean hysterectomy complicated by substantial hemorrhage. Massive blood product replacement precipitated severe hyperkaIemia and hypocalcemia with resultant asystole. Cardiac bypass with concomitant obligate anticoagulation was temporarily required while normalizing the patient's electrolytes. Numerous surgical and medical interventions were required to achieve hemostasis, and the patient survived to hospital discharge with moderate residual morbidity. CONCLUSION: Optimal management of placenta accreta requires a multidisciplinary approach within a tertiary center possessing extensive resources necessary for managing the most severe complications.

Beta-2 adrenoceptor genotype and progress in term and late preterm active labor.

OBJECTIVE: We sought to evaluate whether beta-2 adrenoceptor (ß2AR) genotype at a functional polymorphic site encoding for amino acid residue 16 influences rate of cervical dilatation in term and late preterm active labor. STUDY DESIGN: Subjects who underwent vaginal delivery at ≥34 weeks' gestational age from May 2006 through August 2007 were identified. Each subject had provided venous blood from which DNA was extracted for ß2AR genotyping. Digital cervical examinations with paired examination times were collected from intrapartum records. Rate of cervical dilatation in active labor was determined using linear regression. Rates were compared between genotype groups. RESULTS: Among 401 subjects with satisfactory genotype and intrapartum data, overall rate of active labor was 0.76±0.01 cm/h. When labor was compared by genotype, homozygous Arg/Arg16 subjects progressed at a slower rate (0.64±0.03 cm/h) than all other pooled genotypes (0.8±0.02 cm/h, P<.001). CONCLUSION: Homozygous ß2AR genotype encoding for Arg/Arg16 was associated with slower progress in active labor.

Aerobic exercise attenuates inducible TNF production in humans.

Aerobic exercise reduces coronary heart disease risk, but the mechanisms of this protection are not fully understood. Atherosclerosis is an inflammatory disease mediated by monocyte-derived macrophages, which accumulate in arterial plaques and become activated to release factors, including cytokines, that cause damage. Here we studied the effects of aerobic training on monocyte production of tumor necrosis factor (TNF) in whole blood ex vivo. Healthy young sedentary adults (n = 61, age 20-45 yr) were randomized to a moderate- (M) or a high- (H) intensity 12-wk training program. Whole blood was extracted before and after training, and then it was stimulated by addition of lipopolysaccharide (LPS); inducible TNF was measured in the plasma. Data were analyzed according to intention to treat principles using a random-effect model to determine the impact of training group on maximal aerobic capacity and LPS-stimulated TNF after correcting for covariates. Analyses revealed improvement in aerobic capacity in both the H (9%) and the M (7%) groups. However, aerobic training led to significant (P < 0.001) decreases in TNF release only in the H group. These data suggest that in healthy young adults, a 12-wk high-intensity aerobic training program downregulates blood monocyte production of stimulated cytokine release.