Shared decision-making for postoperative opioid prescribing and preoperative pain management education decreases excess opioid burden.

INTRODUCTION: Managing postoperative pain requires an individualized approach in order to balance adequate pain control with risk of persistent opioid use and narcotic abuse associated with inappropriately outsized narcotic prescriptions. Shared decision-making has been proposed to address individual pain management needs. We report here the results of a quality improvement initiative instituting prescribing guidelines using shared decision-making and preoperative pain expectation and management education to decrease excess opioid pills after surgery and improve patient satisfaction. METHODS: Pre-intervention prescribing habits were obtained by retrospective review perioperative pharmacy records for patients undergoing general surgeries in the 24 months prior to initiation of intervention. Patients scheduled to undergo General Surgery procedures were given a survey at their preoperative visit. Preoperative education was performed by the surgical team as a part of the Informed Consent process using a standardized handout and patients were asked to choose the number of narcotic pills they wished to obtain within prescribing recommendations. Postoperative surveys were administered during or after their 2-week postoperative visit. RESULTS: 131 patients completed pre-intervention and post-intervention surveys. The average prescription size decreased from 12.29 oxycodone pills per surgery prior to institution of pathway to 6.80 pills per surgery after institution of pathway (p < 0.001). The percentage of unused pills after surgery decreased from an estimated 70.5% pre-intervention to 48.5% (p < 0.001) post-intervention. 61.1% of patients with excess pills returned or planned to return medication to the pharmacy with 16.8% of patients reporting alternative disposal of excess medication. Patient-reported satisfaction was higher with current surgery compared to prior surgeries (p < 0.001). CONCLUSION: Institution of procedure-specific prescribing recommendations and preoperative pain management education using shared decision-making between patient and provider decreases opioid excess burden, resulting in fewer unused narcotic pills entering the community. Furthermore, allowing patients to participate in decision-making with their provider results in increased patient satisfaction.

Practice patterns of hepatobiliary surgery within the military.

BACKGROUND: The purpose of this study is to evaluate the trends of hepatobiliary surgeries performed at military hospitals and to discuss potential implications on resident training and military readiness. While there is data to suggest centralization of surgical specialty services leads to improved patient outcomes, the military does not currently have a specific centralization policy. Implementation of such a policy could potentially impact resident training and readiness of military surgeons. Even in the absence of such a policy, there may still be a trend toward centralization of more complex surgeries like hepatobiliary surgeries. The present study evaluates the numbers and types of hepatobiliary procedures performed at military hospitals. METHODS: This study is a retrospective review of de-identified data from Military Health System Mart (M2) from 2014 to 2020. The M2 database contains patient data from all Defense Health Agency treatment facilities, encompassing all branches of the United States Military. Variables collected include number and types of hepatobiliary procedures performed and patient demographics. The primary endpoint was the number and type of surgery for each medical facility. Linear regression was used to evaluate significant trends in numbers of surgeries over time. RESULTS: Fifty-five military hospitals performed hepatobiliary surgeries from 2014 to 2020. A total of 1,087 hepatobiliary surgeries were performed during this time; cholecystectomies, percutaneous procedures, and endoscopic procedures were excluded. There was no significant decrease in overall case volume. The most commonly performed hepatobiliary surgery was "unlisted laparoscopic liver procedure." The military training facility with the most hepatobiliary cases was Brooke Army Medical Center. CONCLUSION: The number of hepatobiliary surgeries performed in military hospitals has not significantly decreased over the years 2014-2020, despite a national trend toward centralization. Centralization of hepatobiliary surgeries in the future may impact residency training as well as military medical readiness.

Practice Patterns of Pancreatic Surgery Within the Military.

INTRODUCTION: Pancreatic surgery is technically challenging, with mortality rates at high-volume centers ranging from 0% to 5%. An inverse relationship between surgeon volume and perioperative mortality has been reported suggesting that patients benefit from experienced surgeons at high-volume centers. There is little published on the volume of pancreatic surgeries performed in military treatment facilities (MTF) and there is no centralization policy regarding pancreatic surgery. This study evaluates pancreatic procedures at MTFs. We hypothesize that a small group of MTFs perform most pancreatic procedures, including more complex pancreatic surgeries. METHODS: This is a retrospective review of de-identified data from MHS Mart (M2) from 2014 to 2020. The database contains patient data from all Defense Health Agency treatment facilities. Variables collected include number and types of pancreatic procedures performed and patient demographics. The primary endpoint was the number and type of surgery for each MTF. RESULTS: Twenty-six MTFs performed pancreatic surgeries from 2014 to 2020. There was a significant decrease in the number of cases from 2014 to 2020. Nine hospitals performed one surgery over eight years. The most common surgery was a distal pancreatectomy, followed by a pancreaticoduodenectomy. There was a decrease in the number of pancreaticoduodenectomies and distal pancreatectomies performed over this period. CONCLUSIONS: Pancreatic surgery is being performed at few MTFs with a downward trajectory over time. Further studies would be needed to assess the impact on patient care regarding postoperative complications, barriers to timely patient care, and impact on readiness of military surgeons.

MKRN3 inhibits puberty onset via interaction with IGF2BP1 and regulation of hypothalamic plasticity.

Makorin ring finger protein 3 (MKRN3) was identified as an inhibitor of puberty initiation with the report of loss-of-function mutations in association with central precocious puberty. Consistent with this inhibitory role, a prepubertal decrease in Mkrn3 expression was observed in the mouse hypothalamus. Here, we investigated the mechanisms of action of MKRN3 in the central regulation of puberty onset. We showed that MKRN3 deletion in hypothalamic neurons derived from human induced pluripotent stem cells was associated with significant changes in expression of genes controlling hypothalamic development and plasticity. Mkrn3 deletion in a mouse model led to early puberty onset in female mice. We found that Mkrn3 deletion increased the number of dendritic spines in the arcuate nucleus but did not alter the morphology of GnRH neurons during postnatal development. In addition, we identified neurokinin B (NKB) as an Mkrn3 target. Using proteomics, we identified insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) as another target of MKRN3. Interactome analysis revealed that IGF2BP1 interacted with MKRN3, along with several members of the polyadenylate-binding protein family. Our data show that one of the mechanisms by which MKRN3 inhibits pubertal initiation is through regulation of prepubertal hypothalamic development and plasticity, as well as through effects on NKB and IGF2BP1.

Modulating redox homeostasis and cellular reprogramming through inhibited methylenetetrahydrofolate dehydrogenase 2 enzymatic activities in lung cancer.

Recent reports have indicated the role of highly expressed methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) enzyme in cancers, showing poor survival; however, detailed mechanistic insight of metabolic functions of MTHFD2 have not been well-defined. Therefore, we aimed to examine the metabolic functions and cellular reprograming potential of MTHFD2 in lung cancer (LCa). In this study, we initially confirmed the expression levels of MTHFD2 in LCa not only in tissue and OncomineTM database, but also at molecular levels. Further, we reprogrammed metabolic activities in these cells through MTHFD2 gene knockdown via lentiviral transduction, and assessed their viability, transformation and self-renewal ability. In vivo tumorigenicity was also evaluated in NOD/SCID mice. Results showed that MTHFD2 was highly expressed in stage-dependent LCa tissues as well in cell lines, A549, H1299 and H441. Cellular viability, transformation and self-renewal abilities were significantly inhibited in MTHFD2-knockdown LCa cell lines. These cells also showed suppressed tumor-initiating ability and reduced tumor size compared to vector controls. Under low oxygen tension, MTHFD2-knockdown groups showed no significant increase in sphere formation, and hence the stemness. Conclusively, the suppressed levels of MTHFD2 is essential for cellular metabolic reprogramming leading to inhibited LCa growth and tumor aggressiveness.

The Peripubertal Decline in Makorin Ring Finger Protein 3 Expression is Independent of Leptin Action.

A critical body weight is necessary for pubertal development, an effect mediated in part by leptin. The potential regulation by leptin of Makorin Ring Finger Protein 3 (MKRN3), in which loss-of-function mutations are the most common genetic cause of central precocious puberty, has not been previously explored. In mice, expression of Mkrn3 in the hypothalamic arcuate nucleus is high early in life and declines before the onset of puberty. Therefore, we aimed to explore if leptin contributes to the decrease in hypothalamic Mkrn3 mRNA levels observed in mice during pubertal development. We first used a leptin-deficient (ob/ob) mouse model. Mkrn3 mRNA levels in the mediobasal hypothalamus (MBH), which includes the arcuate nucleus, and in the preoptic area (POA), both showed a significant decrease with age from postnatal day (PND) 12 to PND30 in ob/ob mice in both males and females, similar to that observed in wild-type mice. To further explore the effects of leptin on Mkrn3 expression, we exposed prepubertal wild-type mice to high levels of leptin from age PND9-12, which did not result in any significant difference in Mkrn3 expression levels in either the MBH or POA. In summary, regulation of Mkrn3 expression by leptin was not observed in either the MBH or the POA, 2 hypothalamic sites important for pubertal maturation. These data suggest that the decline in Mkrn3 at the onset of puberty may occur independently of leptin and support our hypothesis that MKRN3 is a bona fide controller of puberty initiation.

MKRN3 inhibits the reproductive axis through actions in kisspeptin-expressing neurons.

The identification of loss-of-function mutations in MKRN3 in patients with central precocious puberty in association with the decrease in MKRN3 expression in the medial basal hypothalamus of mice before the initiation of reproductive maturation suggests that MKRN3 is acting as a brake on gonadotropin-releasing hormone (GnRH) secretion during childhood. In the current study, we investigated the mechanism by which MKRN3 prevents premature manifestation of the pubertal process. We showed that, as in mice, MKRN3 expression is high in the hypothalamus of rats and nonhuman primates early in life, decreases as puberty approaches, and is independent of sex steroid hormones. We demonstrated that Mkrn3 is expressed in Kiss1 neurons of the mouse hypothalamic arcuate nucleus and that MKRN3 repressed promoter activity of human KISS1 and TAC3, 2 key stimulators of GnRH secretion. We further showed that MKRN3 has ubiquitinase activity, that this activity is reduced by MKRN3 mutations affecting the RING finger domain, and that these mutations compromised the ability of MKRN3 to repress KISS1 and TAC3 promoter activity. These results indicate that MKRN3 acts to prevent puberty initiation, at least in part, by repressing KISS1 and TAC3 transcription and that this action may involve an MKRN3-directed ubiquitination-mediated mechanism.

Wheel running decreases palatable diet preference in Sprague-Dawley rats.

Physical activity has beneficial effects on not only improving some disease conditions but also by preventing the development of multiple disorders. Experiments in this study examined the effects of wheel running on intakes of chow and palatable diet e.g. high fat (HF) or high sucrose (HS) diet in male and female Sprague-Dawley rats. Experiment 1 demonstrated that acute wheel running results in robust HF or HS diet avoidance in male rats. Although female rats with running wheel access initially showed complete avoidance of the two palatable diets, the avoidance of the HS diet was transient. Experiment 2 demonstrated that male rats developed decreased HF diet preferences regardless of the order of diet and wheel running access presentation. Running associated changes in HF diet preference in females, on the other hand, depended on the testing schedule. In female rats, simultaneous presentation of the HF diet and running access resulted in transient complete HF diet avoidance whereas running experience prior to HF diet access did not affect the high preference for the HF diet. Ovariectomy in females resulted in HF diet preference patterns that were similar to those in male rats during simultaneous exposure of HF and wheel running access but similar to intact females when running occurred before HF exposure. Overall, the results demonstrated wheel running associated changes in palatable diet preferences that were in part sex dependent. Furthermore, ovarian hormones play a role in some of the sex differences. These data reveal complexity in the mechanisms underlying exercise associated changes in palatable diet preference.

Challenges in harmonizing integrated healthcare network laboratories: Multi-center evaluation of the AccuTnI+3 troponin assay.

BACKGROUND: Beckman Coulter has recently introduced a new troponin assay manufactured for the Access2 and DxI platforms, releasing it under the name AccuTnI+3. Clinical laboratories are required to validate method performance before testing and reporting patient results. METHODS: Beckman Coulter Access 2 instruments (n=42) across Kaiser Permanente Northern California were evaluated for their performance characteristics using the AccuTnI+3 reagent. Precision, linearity, and patient sample comparisons were performed on each instrument. Limit of the blank (LOB), limit of detection (LOD), limit of quantitation (LOQ), serum plasma comparisons, and specimen stability were evaluated using a single instrument. RESULTS: The assay was linear from 0-100,000ng/L. The LOB, LOD and LOQ were determined to be 5, 8 and 20ng/L, respectively. Interday precision on the low QC (mean concentration 41ng/L) ranged from 3.0% to 14.2%. The bias observed between the former assay (AccuTnI) and the AccuTnI+3 was comparable to the inter-instrument bias for either assay. Non-uniform distribution was observed in the precision and inter-instrument/inter-assay comparisons among the instruments evaluated. CONCLUSIONS: The AccuTnI and AccuTnI+3 troponin assays are equivalent across the analytical measuring range. There was no significant difference at the medical decision point. No changes in patient results are anticipated. However, the assay-independent inter-instrument bias observed is an important consideration for harmonization efforts.

Neonatal total bilirubin measurements: Still room for harmonization.

BACKGROUND: Universal screening of total bilirubin in neonates is endorsed by experts from the American Academy of Pediatrics and is increasingly common. Methodological differences between diazo-based quantitation ("wet" chemistry) and reflectance spectrophotometric quantitation ("dry" chemistry) can lead to unnecessary treatment. A recent recalibration of the only commercially available "dry" chemistry assay was issued to reduce these differences. This study evaluated the post-recalibration bias between the two assay types. METHODS: Method comparison of neonatal total bilirubin (Beckman AU680 vs Ortho-Clinical-Diagnostics Vitros) was achieved using freshly-drawn neonatal samples (n=239). RESULTS: The Vitros produced neonatal bilirubin results with a 12.4% average positive bias compared to the AU680 total bilirubin results. The AU680 direct bilirubin reaction had 5.6% cross reactivity with unconjugated bilirubin. CONCLUSIONS: Neonatal or total bilirubin quantitation remains unharmonized between platforms. Care should be taken to understand the bias of specific platforms.

Development of an equation to correct for hemolysis in direct bilirubin measurements.

BACKGROUND: Direct bilirubin is measured for the investigation of pediatric and adult jaundice. Package inserts suggest that hemolysis decreases direct bilirubin measurements, but no published studies have adequately described the extent of interference. METHODS: The influence of hemolysis on direct bilirubin quantification (Beckman AU680) was evaluated by titrating increasing amounts of hemoglobin into specimens with variable starting concentrations of direct bilirubin. An equation was derived to predict the nominal interference-free concentration of direct bilirubin as a function of measured concentration and hemolysis-index. RESULTS: Hemolysis decreased the direct bilirubin concentration reported by the AU680. The extent of interference is a function of both the interference-free concentration of direct bilirubin and the degree of hemolysis. CONCLUSIONS: The concentration of direct bilirubin in hemolyzed specimens can be predicted.