Marginal donor liver versus standard donor liver: A single-center observational study.

BACKGROUND: The effectiveness and safety of marginal donor livers remain controversial. This study aimed to investigate the clinical efficacy of marginal donor livers in patients with liver transplantation (LT). METHODS: This study included 199 liver donors (including 16 split donors) and 206 liver recipients from January 1, 2018 to January 27, 2020, with case follow-up until July 31, 2021. Clinical data of donors and recipients were retrospectively analyzed and were divided into the marginal donor and standard donor groups according to the criteria of marginal donor livers. Indices of liver and kidney functions, complications, and survival curves of the two groups were compared. RESULTS: Compared with the standard donor group, the blood creatinine levels were significantly higher in the marginal donor group in the first week after operation (P < 0.05); there were no significant differences in alanine aminotransferase, aspartate aminotransferase, and total bilirubin levels after LT (all P > 0.05); there was no significant difference in the incidence of complications after LT (P > 0.05); there was also no significant difference in the survival curve (P = 0.335). CONCLUSIONS: There were no significant differences in liver and kidney function and survival curve between the standard donor and marginal donor groups. The marginal donor liver appears safe and reliable for LT and may be an important strategy to expand the donor pool and solve the shortage of organs.

The effects of Kctd12, an auxiliary subunit of GABAB receptor in dentate gyrus on behavioral response to chronic social defeat stress in mice.

Adaptive responses to stress are critical to enhance physical and mental well-being, but excessive or prolonged stress may cause inadaptability and increase the risks of psychiatric disorders, such as depression. GABABR signaling is fundamental to brain function and has been identified in neuropsychiatric disorders. KCTD12 is a critical auxiliary subunit in GABABR signaling, but its role in mental disorders, such as depression is unclear. In the present study, we used a well-validated mice model, chronic social defeat stress (CSDS) to investigate behavioral responses to stress and explore the role of Kctd12 in stress response, as well as the relevant mechanisms. We found that CSDS increased the expression of Kctd12 in the dentate gyrus (DG), a subregion of hippocampus. Overexpression of Kctd12 in DG induced higher responsiveness to acute stress and increased vulnerability to social stress in mice, whereas knock-down of Kctd12 in DG prevented the social avoidance. Furthermore, an increased expression of GABAB receptor 2 (GB2) in the DG of CSDS-treated mice was observed, and CGP35348, an antagonist of GABABR, improved the stress-induced behavior responses along with suppressing the excess expression of Kctd12. In addition, Kctd12 regulated the excitability of granule cell in DG, and the stimulation of neuronal activity by silencing Kctd12 contributed to the antidepressant-like effect of fluoxetine. These findings identify that the Kctd12 in DG works as a critical mediator of stress responses, providing a promising therapeutic target in stress-related psychiatric disorders, including depression.

Coding mutations in NUS1 contribute to Parkinson's disease.

Whole-exome sequencing has been successful in identifying genetic factors contributing to familial or sporadic Parkinson's disease (PD). However, this approach has not been applied to explore the impact of de novo mutations on PD pathogenesis. Here, we sequenced the exomes of 39 early onset patients, their parents, and 20 unaffected siblings to investigate the effects of de novo mutations on PD. We identified 12 genes with de novo mutations (MAD1L1, NUP98, PPP2CB, PKMYT1, TRIM24, CEP131, CTTNBP2, NUS1, SMPD3, MGRN1, IFI35, and RUSC2), which could be functionally relevant to PD pathogenesis. Further analyses of two independent case-control cohorts (1,852 patients and 1,565 controls in one cohort and 3,237 patients and 2,858 controls in the other) revealed that NUS1 harbors significantly more rare nonsynonymous variants (P = 1.01E-5, odds ratio = 11.3) in PD patients than in controls. Functional studies in Drosophila demonstrated that the loss of NUS1 could reduce the climbing ability, dopamine level, and number of dopaminergic neurons in 30-day-old flies and could induce apoptosis in fly brain. Together, our data suggest that de novo mutations could contribute to early onset PD pathogenesis and identify NUS1 as a candidate gene for PD.

Activation of AMPK-dependent autophagy in the nucleus accumbens opposes cocaine-induced behaviors of mice.

Cocaine is a strong central nervous system stimulant, which can induce drug addiction. Previous studies have reported that cocaine-induced autophagy is involved in neuroinflammation and cell death. However, the role of autophagy in psychomotor sensitivity to cocaine has not been explored. Here, we reported that D1 receptor -CaMKII-AMPK-FoxO3a signaling pathway was involved in acute cocaine application-induced autophagy in the nucleus accumbens (NAc) both in vitro and in vivo. Furthermore, we found that knockdown of the ATG5 gene in the NAc augmented behavioral response to cocaine, and induction of autophagy in the NAc with rapamycin attenuated cocaine-induced behavioral response, which was coincident with the alterations of dendritic spine density in neurons of NAc. These results suggest that cocaine exposure leads to the induction of autophagy, which is a protective mechanism against behavioral response to cocaine of male mice.

The Value of 99mTc-PSMA SPECT/CT-Guided Surgery for Identifying and Locating Lymph Node Metastasis in Prostate Cancer Patients.

BACKGROUND: This study evaluated the effect of technetium-99m (99mTc)-labeled prostate-specific membrane antigen (PSMA)-based image-guided surgery on the oncologic outcomes for patients with primary or recurrent prostate cancer (PCa). METHODS: This study retrospectively analyzed 54 consecutive patients with PCa who underwent 99mTc-labeled PSMA-based image-guided surgery between January 2016 and September 2017. These patients received a radical prostatectomy (RP) with pelvic lymph node dissection (PLND) or salvage lymph node dissection (sLND). The resected specimens were compared with findings of postoperative histologic analysis. The responses to the treatment were recorded during the follow-up period. RESULTS: In 31 patients, PSMA single-photon emission computerized tomography (SPECT) and computed tomography (CT) could find 52 suspicious lymph node metastases (LNMs). With the help of PSMA SPECT/CT, 12 patients with recurrence received sLND, 19 primary PCa patients received RP with extended PLND, and 23 primary PCa patients received RP with standard PLND. The findings showed that PSMA SPECT/CT could detect LNMs with high sensitivity and specificity. In six patients, PSMA SPECT/CT could find more LNMs that were not found by MRI and help to modify the extent of lymphadenectomy. At the latest follow-up evaluation, 39 patients showed a biochemical response (BR), 9 patients showed a biochemical recurrence (BCR) after BR, and 6 patients never exhibited BR. The patients who received RP with standard PLND or extended PLND had a better prostate-specific antigen (PSA) response than the patients who received sLND. The patients with pelvic LNMs also had a better PSA response than the patients with retroperitoneal LNMs. CONCLUSIONS: This study showed that 99mTc-PSMA SPECT/CT-guided surgery can remove more LNMs than conventional imaging with high sensitivity and specificity and delay disease progression in PCa patients.

Copper-Catalyzed Redox-Neutral Cyanoalkylarylation of Activated Alkenes with Cyclobutanone Oxime Esters.

The copper-catalyzed cyclization of activated alkenes with cyclobutanone O-acyl oximes under redox-neutral conditions has been reported. This facile protocol provided an efficient approach to a variety of cyanoalkylated oxindoles and dihydroquinolin-2(1H)-ones with a broad substrate scope and excellent functional group tolerance. In this reaction, sequential C-C bond cleavage, radical addition, and cyclization processes were involved, wherein multiple bonds were constructed in a one-pot reaction. Mechanistic studies suggest that the reaction probably proceeded via a radical pathway.

Oxyresveratrol, a Stilbene Compound from Morus alba L. Twig Extract Active Against Trichophyton rubrum.

Morus alba L. (mulberry) twig is known to have an inhibitory effect on pathogens in traditional Chinese medicine. In the present study, the dermophytic fungus, Trichophyton rubrum, was used to evaluate the inhibitory effect of total M. alba twig extract and extracts obtained using solvents with different polarities by the method of 96-well MTT colorimetry. The main active substance was isolated and identified by tracking its activity. In addition, the inhibitory effects of active extracts and a single active substance were investigated in combination with miconazole nitrate. Our data indicated that ethyl acetate extracts of mulberry twig (TEE) exhibited a desired inhibitory activity on T. rubrum with the minimum inhibitory concentration (MIC) of 1.000 mg/mL. With activity tracking, the main substance showing antimicrobial activity was oxyresveratrol (OXY), which was isolated from TEE. Its MIC for inhibiting the growth of T. rubrum was 0.500 mg/mL. The combined use of miconazole nitrate and OXY showed a synergistic inhibitory effect, as shown by a significant decrease in the MIC of both components. Based on the OXY content in TEE, the contribution rate of OXY to the inhibitory effect of TEE on T. rubrum was 80.52%, so it was determined to be the main antimicrobial substance in M. alba twig. Copyright © 2017 John Wiley & Sons, Ltd.

Synthesis and In Vitro Anti-Influenza Virus Evaluation of Novel Sialic Acid (C-5 and C-9)-Pentacyclic Triterpene Derivatives.

The emergence of drug resistant variants of the influenza virus has led to a great need to identify novel and effective antiviral agents. In our previous study, a series of sialic acid (C-2 and C-4)-pentacyclic triterpene conjugates have been synthesized, and a five-fold more potent antiviral activity was observed when sialic acid was conjugated with pentacyclic triterpene via C-4 than C-2. It was here that we further reported the synthesis and anti-influenza activity of novel sialic acid (C-5 and C-9)-pentacyclic triterpene conjugates. Their structures were confirmed by ESI-HRMS, ¹H-NMR, and 13C-NMR spectroscopic analyses. Two conjugates (26 and 42) showed strong cytotoxicity to MDCK cells in the CellTiter-Glo assay at a concentration of 100 µM. However, they showed no significant cytotoxicity to HL-60, Hela, and A549 cell lines in MTT assay under the concentration of 10 µM (except compound 42 showed weak cytotoxicity to HL-60 cell line (10 µM, ~53%)). Compounds 20, 28, 36, and 44 displayed weak potency to influenza A/WSN/33 (H1N1) virus (100 µM, ~20-30%), and no significant anti-influenza activity was found for the other conjugates. The data suggested that both the C-5 acetylamide and C-9 hydroxy of sialic acid were important for its binding with hemagglutinin during viral entry into host cells, while C-4 and C-2 hydroxy were not critical for the binding process and could be replaced with hydrophobic moieties. The research presented herein had significant implications for the design of novel antiviral inhibitors based on a sialic acid scaffold.

MIC16 gene represents a potential novel genetic marker for population genetic studies of Toxoplasma gondii.

BACKGROUND: The zoonotic agent Toxoplasma gondii is distributed world-wide, and can infect a broad range of hosts including humans. Microneme protein 16 of T. gondii (TgMIC16) is responsible for binding to aldolase, and is associated with rhomboid cleavage and presence of trafficking signals during invasion. However, little is known of the TgMIC16 sequence diversity among T. gondii isolates from different hosts and geographical locations. RESULTS: In this study, we examined sequence variation in MIC16 gene among T. gondii isolates from different hosts and geographical regions. The entire genomic region of the MIC16 gene was amplified and sequenced, and phylogenetic relationship was reconstructed using Bayesian inference (BI) and maximum parsimony (MP) based on the MIC16 gene sequences. The results of sequence alignments showed two lengths of the sequence of MIC16 gene among all the examined 12 T. gondii strains: 4391 bp for strains TgCatBr5 and MAS, and 4394 bp for strains RH, TgPLH, GT1, PRU, QHO, PTG, PYS, GJS, CTG and TgToucan. Their A+T content ranged from 50.30 to 50.59 %. A total of 107 variable nucleotide positions (0.1-0.9 %) were identified, including 29 variations in 10 exons and 78 variations in 9 introns. Phylogenetic analysis of MIC16 sequences showed that typical genotypes (Type I, II and III) were able to be grouped into their respective genotypes. Moreover, the three major clonal lineages (Type I, II and III) can be differentiated by PCR-RFLP using restriction enzyme Pst I. CONCLUSIONS: Phylogenetic analysis and PCR-RFLP of the MIC16 locus among T. gondii isolates from different hosts and geographical regions allowed the differentiation of three major clonal lineages (Type I, II and III) into their respective genotypes, suggesting that MIC16 gene may provide a novel potential genetic marker for population genetic studies of T. gondii isolates.

A broadleaf species enhances an autotoxic conifers growth through belowground chemical interactions.

Plants may affect the performance of neighboring plants either positively or negatively through interspecific and intraspecific interactions. Productivity of mixed-species systems is ultimately the net result of positive and negative interactions among the component species. Despite increasing knowledge of positive interactions occurring in mixed-species tree systems, relatively little is known about the mechanisms underlying such interactions. Based on data from 25-year-old experimental stands in situ and a series of controlled experiments, we test the hypothesis that a broadleaf, non-N fixing species, Michelia macclurei, facilitates the performance of an autotoxic conifer Chinese fir (Cunninghamia lanceolata) through belowground chemical interactions. Chinese fir roots released the allelochemical cyclic dipeptide (6-hydroxy-1,3-dimethyl-8-nonadecyl-[1,4]-diazocane- 2,5-diketone) into the soil environment, resulting in self-growth inhibition, and deterioration of soil microorganisms that improve P availability. However, when grown with M. macclurei the growth of Chinese fir was consistently enhanced. In particular, Chinese fir enhanced root growth and distribution in deep soil layers. When compared with monocultures of Chinese fir, the presence of M. macclurei reduced release and increased degradation of cyclic dipeptide in the soil, resulting in a shift from self-inhibition to chemical facilitation. This association also improved the soil microbial community by increasing arbuscular mycorrhizal fungi, and induced the production of Chinese fir roots. We conclude that interspecific interactions are less negative than intraspecific ones between non-N fixing broadleaf and autotoxic conifer species. The impacts are generated by reducing allelochemical levels, enhancing belowground mutualisms, improving soil properties, and changing root distributions as well as the net effects of all the processes within the soil. In particular, allelochemical context alters the consequences of the belowground ecological interactions with a novel mechanism: reduction of self-inhibition through reduced release and increased degradation of an autotoxic compound in the mixed-species plantations. Such a mechanism would be useful in reforestation programs undertaken to rehabilitate forest plantations that suffer from problems associated with autotoxicity.

A Model-Based Temperature-Prediction Method by Temperature-Induced Spectral Variation and Correction of the Temperature Effect.

In the present paper, a new model-based method was proposed for temperature prediction and correction. First, a temperature prediction model was obtained from training samples; then, the temperature of test samples were predicted; and finally, the correction model was used to reduce the nonlinear effects of spectra from temperature variations. Two experiments were used to verify the proposed method, including a water-ethanol mixture experiment and a ternary mixture experiment. The results show that, compared with classic method such as continuous piecewise direct standardization (CPDS), our method is efficient for temperature correction. Furthermore, the temperatures of test samples are not necessary in the proposed method, making it easier to use in real applications.

Structural basis for the distinct core-antenna assembly of cryptophyte photosystem II.

Photosystem II (PSII) catalyzes the light-driven charge separation and water oxidation reactions of photosynthesis. Eukaryotic PSII core is usually associated with membrane-embedded light-harvesting antennae, which greatly increase the absorbance cross-section of the core. The peripheral antennae in different phototrophs vary considerably in protein composition and arrangement. Photosynthetic cryptophytes possess chlorophyll a/c binding proteins (CACs) that serve as their antennae. How these CACs assemble with the PSII core remains unclear. Here, we report the 2.57-Å resolution structure of cryptophyte PSII-CAC purified from cells at nitrogen-limited stationary growth phase. We show that each monomer of the PSII homodimer contains a core complex, six chlorophyll a/c binding proteins (CACs) and a previously unseen chlorophyll-binding protein (termed CAL-II). Six CACs are arranged as a double-layered arc-shaped non-parallel belt, and two such belts attach to the dimeric core from opposite sides. The CAL-II simultaneously interacts with a number of core subunits and five CACs. The distinct organization of CACs and the presence of CAL-II may play a critical role in stabilizing the dimeric PSII-CAC complex under stress conditions. Our study provides mechanistic insights into the assembly and function of the PSII-CAC complex as well as the possible adaptation of cryptophytes in response to environmental stresses.

Growth phase-dependent reorganization of cryptophyte photosystem I antennae.

Photosynthetic cryptophytes are eukaryotic algae that utilize membrane-embedded chlorophyll a/c binding proteins (CACs) and lumen-localized phycobiliproteins (PBPs) as their light-harvesting antennae. Cryptophytes go through logarithmic and stationary growth phases, and may adjust their light-harvesting capability according to their particular growth state. How cryptophytes change the type/arrangement of the photosynthetic antenna proteins to regulate their light-harvesting remains unknown. Here we solve four structures of cryptophyte photosystem I (PSI) bound with CACs that show the rearrangement of CACs at different growth phases. We identify a cryptophyte-unique protein, PsaQ, which harbors two chlorophyll molecules. PsaQ specifically binds to the lumenal region of PSI during logarithmic growth phase and may assist the association of PBPs with photosystems and energy transfer from PBPs to photosystems.

Architecture of the ATP-driven motor for protein import into chloroplasts.

Thousands of nuclear-encoded proteins are transported into chloroplasts through the TOC-TIC translocon spanning the chloroplast envelope membranes. A motor complex pulls the translocated proteins out of the TOC-TIC complex into the chloroplast stroma by hydrolyzing ATP. The Orf2971-FtsHi complex was suggested to serve as the ATP-hydrolyzing motor in Chlamydomonas reinhardtii, but little is known about its architecture and assembly. Here, we report the 3.2-Å resolution structure of the Chlamydomonas Orf2971-FtsHi complex. The 20-subunit complex spans the chloroplast inner envelope with two bulky modules protruding into the intermembrane space and stromal matrix. Six subunits form a hetero-hexamer potentially providing the pulling force through ATP hydrolysis. The remaining subunits, including potential enzymes/chaperones, likely facilitate the complex assembly and regulate its proper function. Our results provide the structural foundation for mechanistic understanding of chloroplast protein translocation.

Regulatory mechanism of the six-method massage antipyretic process on lipopolysaccharide-induced fever in juvenile rabbits: A targeted metabolomics approach.

Objective: To investigate the mechanism of the six-method massage antipyretic process (SMAP) and its influence on the body's metabolic state. Methods: The random number table method was used to divide 24 New Zealand 2-month-old rabbits with qualified basal body temperature into a control group, model group and massage group (n = 8 per group). The model group and massage groups were injected with 0.5 µg/ml lipopolysaccharide (1 ml/kg) into the auricular vein, and the control group was injected with the same amount of normal saline at the same temperature. One hour after modelling, the massage group was given SMAP (opening Tianmen, pushing Kangong, rubbing Taiyang, rubbing Erhougaogu, clearing the Tianheshui and pushing the spine). The change of anal temperature 5 h after moulding was recorded to clarify the antipyretic effect. Results: After modelling, the rectal temperature of the juvenile rabbits in the three groups increased. The rectal temperature of the model group was higher than that of the control group 5 h after modelling, and the rectal temperature of the massage group was lower than that of the model group (P < 0.05). The antipyretic mechanism is related to the regulation of the synthesis of phenylalanine, tyrosine and tryptophan, as well as the pentose phosphate pathway. Compared with the model group, the plasma interleukin (IL)-1, IL-6, interferon-gamma, toll-like receptor 4, nuclear factor κB, the mechanistic target of rapamycin complex 1, indoleamine 2,3-dioxygenase 1, aryl hydrocarbon receptor, liver aspartate transaminase (AST), alanine transaminase (ALT) and l-glutamate dehydrogenase (L-GLDH) expression in the massage group were significantly decreased (P < 0.05). Compared with the model group, the massage group had significantly reduced AST, ALT and L-GLDH expression in plasma (P < 0.05). Conclusion: The mechanism of SMAP therapy is related to regulating the expression of peripheral inflammatory factors and metabolic pathways.

Correlation between cancer-related cognitive impairment and resting cerebral glucose metabolism in patients with ovarian cancer.

Background: An increasing number of research have applied neuroimaging techniques to explore the potential neurobiological mechanism of Cancer-related cognitive impairment (CRCI). Purpose: To explore the correlation between resting brain glucose metabolism and CRCI using 18F-FDG PET/CT in ovarian cancer (OC) patients. Methods: From December 2021 to March 2022, 38 patients with OC were selected as the study group, and 38 healthy women of the same age (±1 year) who underwent routine physical examination using PET/CT were selected as the control group. Patients received further assessment with the Montreal Cognitive Assessment Scale (MoCA) and Perceived Deficit Questionnaire (PDQ). Independent sample t-test and Spearman correlation were conducted for data analysis. Results: The resting brain glucose metabolism in the OC group was significantly lower than in the healthy controls. 60.52 % patients had neuropsychological impairment and retrospective memory were the most serious perceived cognitive impairments. The resting brain glucose metabolism in OC patients did not significantly correlate with neuropsychological performance but had significant positive correlation with subjective cognitive evaluation. Discussion: Resting glucose metabolism was low in OC patients and associated with subjective cognitive impairment but not objective neuropsychological test results. 18F-FDG PET/CT can be used to evaluate brain function in OC patients and provide reliable imaging indicators for early recognition of and intervention for changes in cognitive function.

The effect of adding real-time postural feedback in balance and mobility training in older adults: A systematic review and meta-analysis.

OBJECTIVES: This study aimed to systematically review the additional value of providing real-time postural feedback during balance and mobility training in older people. METHODS: PubMed, Embase, CINAHL, and Web-of-Science were searched from inception to August 2023. Studies comparing the effectiveness of feedback-based versus non-feedback-based postural balance or mobility training on balance or mobility outcomes were selected. Similar outcomes were pooled in meta-analyses using a random-effect model. The quality of evidence for available outcomes was rated by Grading of Recommendations Assessment, Development and Evaluation (GRADE). RESULTS: Eight studies were identified with 203 subjects. Two studies showed that providing postural feedback immediately improved stability in static balance and gait. For the post-training effect, however, no significant change was found in trunk movement during single-leg standing (i.e., pitch angle, MD=0.65, 95 %CI=-0.77 to 2.07, low-quality; roll angle, MD=0.96, 95 %CI=-0.87 to 2.80, moderate-quality), in the Mini-BESTest (MD=1.88, 95 %CI=-0.05 to 3.80, moderate-quality), and in balance confidence (MD=0.29, 95 %CI=-3.43 to 4.2, moderate-quality). A worsened functional reach distance was associated with providing feedback during balance training (MD=-3.26, 95 %CI=-6.31 to -0.21, high-quality). Meta-analyses on mobility outcomes were mostly insignificant, except for the trunk-roll angle of walking (MD=0.87, 95 %CI=0.05 to 1.70, low-quality) and trunk-pitch angle of walking with head-turning (MD=1.87, 95 %CI=0.95 to 2.79, moderate-quality). CONCLUSION: Adding real-time postural feedback to balance and mobility training might immediately improve stability in balance and mobility in older people. However, mixed results were reported for its post-training effect.

Individualized Electrode Subset Improves the Calibration Accuracy of an EEG P300-design Brain-Computer Interface for People with Severe Cerebral Palsy.

Objective: This study examined the effect of individualized electroencephalogram (EEG) electrode location selection for non-invasive P300-design brain-computer interfaces (BCIs) in people with varying severity of cerebral palsy (CP). Approach: A forward selection algorithm was used to select the best performing 8 electrodes (of an available 32) to construct an individualized electrode subset for each participant. BCI accuracy of the individualized subset was compared to accuracy of a widely used default subset. Main Results: Electrode selection significantly improved BCI calibration accuracy for the group with severe CP. Significant group effect was not found for the group of typically developing controls and the group with mild CP. However, several individuals with mild CP showed improved performance. Using the individualized electrode subsets, there was no significant difference in accuracy between calibration and evaluation data in the mild CP group, but there was a reduction in accuracy from calibration to evaluation in controls. Significance: The findings suggested that electrode selection can accommodate developmental neurological impairments in people with severe CP, while the default electrode locations are sufficient for many people with milder impairments from CP and typically developing individuals.

Research Progress on the Pathogenesis of Knee Osteoarthritis.

Knee osteoarthritis (KOA) is a chronic joint bone disease characterized by inflammatory destruction and hyperplasia of bone. Its main clinical symptoms are joint mobility difficulties and pain, severe cases can lead to limb paralysis, which poses major pressure to the quality of life and mental health of patients, but also brings serious economic burden to society. The occurrence and development of KOA is influenced by many factors, including systemic factors and local factors. The joint biomechanical changes caused by aging, trauma and obesity, abnormal bone metabolism caused by metabolic syndrome, the effects of cytokines and related enzymes, genetic and biochemical abnormalities caused by plasma adiponectin, etc. all directly or indirectly lead to the occurrence of KOA. However, there is little literature that systematically and comprehensively integrates macro- and microscopic KOA pathogenesis. Therefore, it is necessary to comprehensively and systematically summarize the pathogenesis of KOA in order to provide a better theoretical basis for clinical treatment.

Association of Intraoperative Opioid Administration With Postoperative Pain and Opioid Use.

Importance: Opioids administered to treat postsurgical pain are a major contributor to the opioid crisis, leading to chronic use in a considerable proportion of patients. Initiatives promoting opioid-free or opioid-sparing modalities of perioperative pain management have led to reduced opioid administration in the operating room, but this reduction could have unforeseen detrimental effects in terms of postoperative pain outcomes, as the relationship between intraoperative opioid usage and later opioid requirements is not well understood. Objective: To characterize the association between intraoperative opioid usage and postoperative pain and opioid requirements. Design, Setting, and Participants: This retrospective cohort study evaluated electronic health record data from a quaternary care academic medical center (Massachusetts General Hospital) for adult patients who underwent noncardiac surgery with general anesthesia from April 2016 to March 2020. Patients who underwent cesarean surgery, received regional anesthesia, received opioids other than fentanyl or hydromorphone, were admitted to the intensive care unit, or who died intraoperatively were excluded. Statistical models were fitted on the propensity weighted data set to characterize the effect of intraoperative opioid exposures on primary and secondary outcomes. Data were analyzed from December 2021 to October 2022. Exposures: Intraoperative fentanyl and intraoperative hydromorphone average effect site concentration estimated using pharmacokinetic/pharmacodynamic models. Main Outcomes and Measures: The primary study outcomes were the maximal pain score during the postanesthesia care unit (PACU) stay and the cumulative opioid dose, quantified in morphine milligram equivalents (MME), administered during the PACU stay. Medium- and long-term outcomes associated with pain and opioid dependence were also evaluated. Results: The study cohort included a total of 61 249 individuals undergoing surgery (mean [SD] age, 55.44 [17.08] years; 32 778 [53.5%] female). Increased intraoperative fentanyl and intraoperative hydromorphone were both associated with reduced maximum pain scores in the PACU. Both exposures were also associated with a reduced probability and reduced total dosage of opioid administration in the PACU. In particular, increased fentanyl administration was associated with lower frequency of uncontrolled pain; a decrease in new chronic pain diagnoses reported at 3 months; fewer opioid prescriptions at 30, 90, and 180 days; and decreased new persistent opioid use, without significant increases in adverse effects. Conclusions and Relevance: Contrary to prevailing trends, reduced opioid administration during surgery may have the unintended outcome of increasing postoperative pain and opioid consumption. Conversely, improvements in long-term outcomes might be achieved by optimizing opioid administration during surgery.