Long-term Health Outcomes of New Persistent Opioid Use After Surgery Among Medicare Beneficiaries.

OBJECTIVE: We examined long-term health outcomes associated with new persistent opioid use after surgery and hypothesized that patients with new persistent opioid use would have poorer overall health outcomes compared with those who did not develop new persistent opioid use after surgery. BACKGROUND: New persistent opioid use is a common surgical complication. Long-term opioid use increases risk of mortality, fractures, and falls; however, less is known about health care utilization among older adults with new persistent opioid use after surgical care. METHODS: We analyzed claims from a 20% national sample of Medicare beneficiaries ≥65 years undergoing surgery between January 1, 2009, and June 30, 2019. We estimated associations between new persistent use and subsequent health events between 6 and 12 months after surgery, including mortality, serious fall/fall-related injury, and respiratory or opioid/pain-related readmission/emergency department (ED) visits using a Cox proportional hazards model to estimate mortality and multivariable logistic regression for the remaining outcomes, adjusting for demographic/clinical characteristics. Our primary outcome was mortality within 6 to 12 months after surgery. Secondary outcomes included falls and readmissions or ED visits (respiratory, pain related/opioid related) within 6 to 12 months after surgery. RESULTS: Of 229,898 patients, 6874 (3.0%) developed new persistent opioid use. Compared with patients who did not develop new persistent opioid use, patients with new persistent opioid use had a higher risk of mortality (hazard ratio 3.44, CI, 2.99-3.96), falls [adjusted odds ratio (aOR): 1.21, 95% CI, 1.05-1.39], and respiratory-related (aOR: 1.67, 95% CI, 1.49-1.86) or pain-related/opioid-related (aOR: 1.68, 95% CI, 1.55-1.82) readmissions/ED visits. CONCLUSIONS: New persistent opioid use after surgery is associated with increased mortality and poorer health outcomes after surgery. Although the mechanisms that underlie this risk are not clear, persistent opioid use may also be a marker for greater morbidity requiring more care in the late postoperative period. Increased awareness of individuals at risk for new persistent use after surgery and close follow-up in the late postoperative period is critical to mitigate the harms associated with new persistent use.

Coordinating Tissue Regeneration Through Transforming Growth Factor-ß Activated Kinase 1 Inactivation and Reactivation.

Aberrant wound healing presents as inappropriate or insufficient tissue formation. Using a model of musculoskeletal injury, we demonstrate that loss of transforming growth factor-ß activated kinase 1 (TAK1) signaling reduces inappropriate tissue formation (heterotopic ossification) through reduced cellular differentiation. Upon identifying increased proliferation with loss of TAK1 signaling, we considered a regenerative approach to address insufficient tissue production through coordinated inactivation of TAK1 to promote cellular proliferation, followed by reactivation to elicit differentiation and extracellular matrix production. Although the current regenerative medicine paradigm is centered on the effects of drug treatment ("drug on"), the impact of drug withdrawal ("drug off") implicit in these regimens is unknown. Because current TAK1 inhibitors are unable to phenocopy genetic Tak1 loss, we introduce the dual-inducible COmbinational Sequential Inversion ENgineering (COSIEN) mouse model. The COSIEN mouse model, which allows us to study the response to targeted drug treatment ("drug on") and subsequent withdrawal ("drug off") through genetic modification, was used here to inactivate and reactivate Tak1 with the purpose of augmenting tissue regeneration in a calvarial defect model. Our study reveals the importance of both the "drug on" (Cre-mediated inactivation) and "drug off" (Flp-mediated reactivation) states during regenerative therapy using a mouse model with broad utility to study targeted therapies for disease. Stem Cells 2019;37:766-778.

Surgical Adjuncts to Rhinoplasty: An Algorithmic Approach.

BACKGROUND: Nasal aesthetics can be significantly affected by the interdependence of the surrounding bone and soft tissues of the face. These include the maxilla, septum, frontal bone, mandible, and the soft tissues and cartilage surrounding the nose. Therefore, it is pertinent to analyze and address these critical relationships of the nose in order to achieve a successful rhinoplasty. This work seeks to describe the battery of adjunct procedures available to supplement a rhinoplasty. Furthermore, each preoperative finding or indication for the adjunct is described in an algorithmic fashion. METHODS: A literature search using PubMed, Google Scholar, and a university library database was performed to locate papers describing adjunctive procedures to rhinoplasty. Indications and preoperative analysis were extracted from each paper. If the indication or finding was unclear, supplementary literature describing rhinoplasty and adjunctive analysis were sought in order to supplement our findings. RESULTS: Sixteen papers in total described adjunctive procedures for rhinoplasty. Each work highlighted a procedure or set of procedures on a surrounding facial feature including the forehead, brow, cheeks, lips, and chin, and neck. In total, 13 adjunct procedures for rhinoplasty are described with their respective indications. Additional literature and techniques were researched to clarify indicated procedures. CONCLUSION: The ability to correctly understand the critical relationships of the nose can help the surgeon correctly recognize the indication for a rhinoplasty adjunct procedure, leading to better aesthetic balance and surgical outcomes. LEVEL OF EVIDENCE II: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Characterizing the Circulating Cell Populations in Traumatic Heterotopic Ossification.

Heterotopic ossification (HO) occurs secondary to trauma, causing pain and functional limitations. Identification of the cells that contribute to HO is critical to the development of therapies. Given that innate immune cells and mesenchymal stem cells are known contributors to HO, we sought to define the contribution of these populations to HO and to identify what, if any, contribution circulating populations have to HO. A shared circulation was obtained using a parabiosis model, established between an enhanced green fluorescent protein-positive/luciferase+ donor and a same-strain nonreporter recipient mouse. The nonreporter mouse received Achilles tendon transection and dorsal burn injury to induce HO formation. Bioluminescence imaging and immunostaining were performed to define the circulatory contribution of immune and mesenchymal cell populations. Histologic analysis showed circulating cells present throughout each stage of the developing HO anlagen. Circulating cells were present at the injury site during the inflammatory phase and proliferative period, with diminished contribution in mature HO. Immunostaining demonstrated that most early circulatory cells were from the innate immune system; only a small population of mesenchymal cells were present in the HO. We demonstrate the time course of the participation of circulatory cells in trauma-induced HO and identify populations of circulating cells present in different stages of HO. These findings further elucidate the relative contribution of local and systemic cell populations to HO.

Comparison of Opioids Prescribed by Advanced Practice Clinicians vs Surgeons After Surgical Procedures in the US.

Importance: Advanced practice clinicians (APCs), defined as nurse practitioners and physician assistants, are increasingly being incorporated into surgical teams. Despite this inclusion, there are no recent national data on the role of these clinicians in surgical opioid prescribing or the dosing of such prescriptions. Objective: To calculate the proportion of surgical opioid prescriptions written by APCs and to compare the total and daily dosages of these prescriptions with those written by surgeons. Design, Setting, and Participants: This cross-sectional study used the Optum's De-Identified Clinformatics Data Mart, which contains deidentified claims from patients with private insurance and Medicare Advantage plans across the US. Adults and children who underwent 1 of 31 inpatient and outpatient surgical procedures from January 1, 2017, through November 30, 2019, were identified. The analysis was limited to procedures with 1 or more perioperative opioid prescriptions, defined as an opioid prescription dispensed within 3 days of the index date of surgery. Data were analyzed from April 1, 2021, to July 31, 2022. Exposures: Prescriber specialty. Main Outcomes and Measures: The outcome was the proportion of perioperative opioid prescriptions and refill prescriptions written by APCs. Linear regression was used to compare the total dosage of perioperative opioid prescriptions written by APCs vs surgeons measured in morphine milligram equivalents (MMEs). Models were adjusted for demographic characteristics, comorbidities, opioid-naive status, year of index date, hospitalization or observation status, surgical complications, and surgeon specialty. Analyses were conducted at the procedure level, and patients with multiple procedures were included. Results: Analyses included 628 197 procedures for 581 387 patients (358 541 females [57.1%]; mean [SD] age, 56 [18] years). Overall, APCs wrote 119 266 (19.0%) of the 628 197 perioperative opioid prescriptions and 59 679 (25.1%) of the 237 740 refill prescriptions. Perioperative opioid prescriptions written by APCs had higher total dosages compared with those written by surgeons (adjusted difference, 40.0 MMEs; 95% CI, 31.3-48.7 MMEs). This difference persisted in a subgroup analysis limited to opioid-naïve patients (adjusted difference, 15.7 MMEs; 95% CI, 13.9-17.5 MMEs). Conclusions and Relevance: In this cross-sectional analysis, one-fifth of perioperative opioid prescriptions and one-quarter of refill prescriptions were written by APCs. While surgeons wrote most perioperative opioid prescriptions that were intended for perioperative analgesia, higher total dosages from APCs suggest that opioid stewardship initiatives that support the role of APCs may be warranted.

Influence of faculty diversity on resident diversity across surgical subspecialties.

BACKGROUND: Disparities among women and individuals from racial/ethnic minority groups persist in surgical specialties at all training levels. We hypothesized that these populations are underrepresented in surgical specialties, and that diversity in faculty is correlated with diversity in trainees. METHODS: Linking aggregate data from the Association of American Medical Colleges (AAMC) Faculty Roster and the Graduate Medical Education (GME) Track databases, we evaluated self-reported gender and racial/ethnic composition of faculty and residents across six surgical specialties. RESULTS: Programs with more women faculty had significantly greater numbers of women residents. Programs with more faculty from racial/ethnic minority groups were significantly associated with greater numbers of residents from racial/ethnic minority groups. From 2001 to 2017, the proportion of women residents, women faculty, and faculty from racial/ethnic minority groups increased across all specialties; however, the proportion of residents from racial/ethnic minority groups remained unchanged. CONCLUSIONS: In surgical specialties, diversity among faculty and trainees are correlated. However, the proportion of residents from racial/ethnic minority groups has remained unchanged, even among programs with the highest proportion of faculty from racial/ethnic minority groups.

The effect of pregnancy intention on important maternal behaviors and satisfaction with care in a socially and economically at-risk population.

This study examined the association of pregnancy intention with maternal behaviors and the woman's perceived satisfaction with her prenatal and delivery care. Face-to-face interviews with 478 primarily Medicaid eligible women in Indianapolis, Indiana during their postpartum hospital stay were conducted to assess their degree of satisfaction with prenatal care and pregnancy intention, stratified into wanting to be pregnant now, later or never. Behaviors and characteristics influencing utilization of prenatal care were obtained from linked birth certificate data. A greater proportion of younger women (15-29) wanted to be pregnant later, a greater proportion of African-Americans never wanted to be pregnant, a greater proportion of divorced and never married women wanted to be pregnant later or never, and as parity increased the percentage of women never wanting to be pregnant increased. Multivariate analyses found that women never wanting to be pregnant were twice as likely to underutilize prenatal care, twice as likely to smoke while pregnant, half as likely to utilize WIC services and half as likely to recommend their providers to pregnant friends or relatives compared to women with a planned pregnancy, controlling for confounding variables. Finally, women wanting to be pregnant later were half as likely to rate their overall hospital care and prenatal care provider as high. Providers assessing their patients' pregnancy intention could better identify those women needing additional support services to adopt healthier behaviors and improve satisfaction with care. This study also demonstrated the value of more specific definitions of pregnancy intention.

Increased opioid prescription fills after dental procedures performed before weekends and holidays.

BACKGROUND: Excess opioid prescriptions place patients and communities at risk of experiencing opioid-related morbidity. The authors designed a study to test the hypothesis that opioid prescription fills would be more common after dental procedures performed the day before a weekend or holiday than other weekdays. METHODS: The authors performed a retrospective cohort study of 2,060,317 people, integrating Truven Health MarketScan insurance claims to evaluate variation in opioid fills for dental procedures performed the day before a weekend or holiday compared with other weekdays. Opioid-naïve people, aged 13 through 64 years, with eligible procedures from 2013 through 2017 were included. The primary outcome measure was a prescription opioid fill on the same date as the dental procedure. RESULTS: Multivariable logistic regression results showed significantly higher odds of filling an opioid prescription for patients with procedures the day before weekends and holidays (adjusted odds ratio, 1.27; 95% confidence interval, 1.26 to 1.28) than for patients with procedures on other weekdays. In addition, the youngest age category, 13 through 29 years, had the highest odds of filling an opioid prescription compared with other age categories (reference category: patients aged 50-64 years, adjusted odds ratio, 1.43; 95% confidence interval, 1.41 to 1.44). CONCLUSIONS: Outpatient dental procedures performed the day before a weekend or holiday were associated with a 27% increased adjusted odds of filling a prescription for an opioid. PRACTICAL IMPLICATIONS: Although patients and dentists might be concerned about the challenges of unmanaged pain on weekends and holidays, opioids are not warranted for most dental procedures and should be replaced with patient education and nonopioid analgesics. Oral health care professionals concerned about postprocedural pain control should consider scheduling complex procedures earlier in the week, when emergency care is available to reduce unwarranted preemptive prescribing of opioids, which might be driving increased opioid fills before weekends and holidays.

High-frequency spectral ultrasound imaging (SUSI) visualizes early post-traumatic heterotopic ossification (HO) in a mouse model.

PURPOSE: Early treatment of heterotopic ossification (HO) is currently limited by delayed diagnosis due to limited visualization at early time points. In this study, we validate the use of spectral ultrasound imaging (SUSI) in an animal model to detect HO as early as one week after burn tenotomy. METHODS: Concurrent SUSI, micro CT, and histology at 1, 2, 4, and 9weeks post-injury were used to follow the progression of HO after an Achilles tenotomy and 30% total body surface area burn (n=3-5 limbs per time point). To compare the use of SUSI in different types of injury models, mice (n=5 per group) underwent either burn/tenotomy or skin incision injury and were imaged using a 55MHz probe on VisualSonics VEVO 770 system at one week post injury to evaluate the ability of SUSI to distinguish between edema and HO. Average acoustic concentration (AAC) and average scatterer diameter (ASD) were calculated for each ultrasound image frame. Micro CT was used to calculate the total volume of HO. Histology was used to confirm bone formation. RESULTS: Using SUSI, HO was visualized as early as 1week after injury. HO was visualized earliest by 4weeks after injury by micro CT. The average acoustic concentration of HO was 33% more than that of the control limb (n=5). Spectroscopic foci of HO present at 1week that persisted throughout all time points correlated with the HO present at 9weeks on micro CT imaging. CONCLUSION: SUSI visualizes HO as early as one week after injury in an animal model. SUSI represents a new imaging modality with promise for early diagnosis of HO.

Evaluation of Salivary Cytokines for Diagnosis of both Trauma-Induced and Genetic Heterotopic Ossification.

PURPOSE: Heterotopic ossification (HO) occurs in the setting of persistent systemic inflammation. The identification of reliable biomarkers can serve as an early diagnostic tool for HO, especially given the current lack of effective treatment strategies. Although serum biomarkers have great utility, they can be inappropriate or ineffective in traumatic acute injuries and in patients with fibrodysplasia ossificans progressiva (FOP). Therefore, the goal of this study is to profile the cytokines associated with HO using a different non-invasive source of biomarkers. METHODS: Serum and saliva were collected from a model of trauma-induced HO (tHO) with hind limb Achilles' tenotomy and dorsal burn injury at indicated time points (pre-injury, 48 h, 1 week, and 3 weeks post-injury) and a genetic non-trauma HO model (Nfatc1-Cre/caAcvr1fl/wt ). Samples were analyzed for 27 cytokines using the Bio-Plex assay. Histologic evaluation was performed in Nfatc1-Cre/caAcvr1fl/wt mice and at 48 h and 1 week post-injury in burn tenotomy mice. The mRNA expression levels of these cytokines at the tenotomy site were also quantified with quantitative real-time PCR. Pearson correlation coefficient was assessed between saliva and serum. RESULTS: Levels of TNF-α and IL-1ß peaked at 48 h and 1 week post-injury in the burn/tenotomy cohort, and these values were significantly higher when compared with both uninjured (p < 0.01, p < 0.03) and burn-only mice (p < 0.01, p < 0.01). Immunofluorescence staining confirmed enhanced expression of IL-1ß, TNF-α, and MCP-1 at the tenotomy site 48 h after injury. Monocyte chemoattractant protein-1 (MCP-1) and VEGF was detected in saliva showing elevated levels at 1 week post-injury in our tHO model when compared with both uninjured (p < 0.001, p < 0.01) and burn-only mice (p < 0.005, p < 0.01). The Pearson correlation between serum MCP-1 and salivary MCP-1 was statistically significant (r = 0.9686, p < 0.001) Similarly, the Pearson correlation between serum VEGF and salivary VEGF was statistically significant (r = 0.9709, p < 0.05). CONCLUSION: In this preliminary study, we characterized the diagnostic potential of specific salivary cytokines that may serve as biomarkers for an early-stage diagnosis of HO. This study identified two candidate biomarkers for further study and suggests a novel method for diagnosis in the context of current difficult diagnosis and risks of current diagnostic methods in certain patients.

mTOR inhibition and BMP signaling act synergistically to reduce muscle fibrosis and improve myofiber regeneration.

Muscle trauma is highly morbid due to intramuscular scarring, or fibrosis, and muscle atrophy. Studies have shown that bone morphogenetic proteins (BMPs) reduce muscle atrophy. However, increased BMP signaling at muscle injury sites causes heterotopic ossification, as seen in patients with fibrodysplasia ossificans progressiva (FOP), or patients with surgically placed BMP implants for bone healing. We use a genetic mouse model of hyperactive BMP signaling to show the development of intramuscular fibrosis surrounding areas of ectopic bone following muscle injury. Rapamycin, which we have previously shown to eliminate ectopic ossification in this model, also eliminates fibrosis without reducing osteogenic differentiation, suggesting clinical value for patients with FOP and with BMP implants. Finally, we use reporter mice to show that BMP signaling is positively associated with myofiber cross-sectional area. These findings underscore an approach in which 2 therapeutics (rapamycin and BMP ligand) can offset each other, leading to an improved outcome.