Tumor-intrinsic and Cancer-associated Fibroblast Subtypes Independently Predict Outcomes in Pancreatic Cancer.

OBJECTIVE: To assess the utility of tumor-intrinsic and cancer-associated fibroblast (CAF) subtypes of pancreatic ductal adenocarcinoma (PDAC) in predicting response to neoadjuvant therapy (NAT) and overall survival. BACKGROUND: PDAC remains a deadly disease with limited treatment options, and both the tumor as well as the microenvironment play an important role in pathogenesis. Gene expression-based tumor-intrinsic subtypes (classical and basal-like) have been shown to predict outcomes, but tumor microenvironment subtypes are still evolving. METHODS: RNA-sequencing was performed on 114 deidentified resected PDAC tumors. Clinical data were collected by retrospective chart review. Single sample classifiers (SSCs) were used to determine classical and basal-like subtypes as well as tumor-permissive permCAF and tumor-restraining restCAF subtypes. Survival was analyzed using log-rank test. RESULTS: Patients who received NAT had an increase in overall survival (OS), with median survival of 27.9 months compared to 20.1 months for those who did not receive NAT, but the difference did not reach statistical significance (HR 0.64, P=0.076). Either tumor-intrinsic or CAF subtypes alone were associated with OS regardless of NAT or no NAT, and patients with classical or restCAF subtype had the best outcomes. When evaluated together, patients with classical-restCAF subtype had the best OS and basal-permCAF the worst OS (P<0.0001). NAT patients with classical-restCAF subtype demonstrated the longest OS compared to the other groups (P=0.00041). CONCLUSIONS: CAF subtypes have an additive effect over tumor-intrinsic subtypes in predicting survival with or without neoadjuvant FOLFIRINOX in PDAC. Molecular subtyping of both tumor and CAF compartments of PDAC may be important steps in selecting first-line systemic therapy.

Determination of permissive and restraining cancer-associated fibroblast (DeCAF) subtypes.

Cancer-associated fibroblast (CAF) subpopulations in pancreatic ductal adenocarcinoma (PDAC) have been identified using single-cell RNA sequencing (scRNAseq) with divergent characteristics, but their clinical relevance remains unclear. We translate scRNAseq-derived CAF cell-subpopulation-specific marker genes to bulk RNAseq data, and develop a single- sample classifier, DeCAF, for the classification of clinically rest raining and perm issive CAF subtypes. We validate DeCAF in 19 independent bulk transcriptomic datasets across four tumor types (PDAC, mesothelioma, bladder and renal cell carcinoma). DeCAF subtypes have distinct histology features, immune landscapes, and are prognostic and predict response to therapy across cancer types. We demonstrate that DeCAF is clinically replicable and robust for the classification of CAF subtypes in patients for multiple tumor types, providing a better framework for the future development and translation of therapies against permissive CAF subtypes and preservation of restraining CAF subtypes. Significance: We introduce a replicable and robust classifier, DeCAF, that delineates the significance of the role of permissive and restraining CAF subtypes in cancer patients. DeCAF is clinically tractable, prognostic and predictive of treatment response in multiple cancer types and lays the translational groundwork for the preclinical and clinical development of CAF subtype specific therapies.

Targeting circadian transcriptional programs in triple negative breast cancer through a cis-regulatory mechanism.

Circadian clock genes are emerging targets in many types of cancer, but their mechanistic contributions to tumor progression are still largely unknown. This makes it challenging to stratify patient populations and develop corresponding treatments. In this work, we show that in breast cancer, the disrupted expression of circadian genes has the potential to serve as biomarkers. We also show that the master circadian transcription factors (TFs) BMAL1 and CLOCK are required for the proliferation of metastatic mesenchymal stem-like (mMSL) triple-negative breast cancer (TNBC) cells. Using currently available small molecule modulators, we found that a stabilizer of cryptochrome 2 (CRY2), the direct repressor of BMAL1 and CLOCK transcriptional activity, synergizes with inhibitors of proteasome, which is required for BMAL1 and CLOCK function, to repress a transcriptional program comprising circadian cycling genes in mMSL TNBC cells. Omics analyses on drug-treated cells implied that this repression of transcription is mediated by the transcription factor binding sites (TFBSs) features in the cis-regulatory elements (CRE) of clock-controlled genes. Through a massive parallel reporter assay, we defined a set of CRE features that are potentially repressed by the specific drug combination. The identification of cis -element enrichment may serve as a new way of defining and targeting tumor types through the modulation of cis -regulatory programs, and ultimately provide a new paradigm of therapy design for cancer types with unclear drivers like TNBC.

Myofibroblastic cancer-associated fibroblast subtype heterogeneity in pancreatic cancer.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) has a fibrotic stroma that has both tumor-promoting and tumor-restraining properties. Different types of cancer-associated fibroblasts (CAFs) have been described. Here, we investigated whether CAFs within the same subtype exhibit heterogeneous functions. METHODS: We evaluated the gene and protein expression differences in two myofibroblastic CAF (myCAF) lines using single-cell and bulk RNA-sequencing. We utilized proliferation and migration assays to determine the effect of different CAF lines on a tumor cell line. RESULTS: We found that myCAF lines express an activated stroma subtype gene signature, which is associated with a shorter survival in patients. Although both myCAF lines expressed α-smooth muscle actin (α-SMA), platelet-derived growth factor-α (PDGFR-α), fibroblast-activated protein (FAP), and vimentin, we observed heterogeneity between the two lines. Similarly, despite being consistent with myCAF gene expression overall, heterogeneity within specific genes was observed. We found that these differences extended to the functional level where the two myCAF lines had different effects on the same tumor cell line. The myCAF216 line, which had slightly increased inflammatory CAF-like gene expression and higher protein expression of α-SMA, PDGFR-α, and FAP was found to restrain migration of tumor cells. CONCLUSIONS: We found that two myCAF lines with globally similar expression characteristics had different effects on the same tumor cell line, one promoting and the other restraining migration. Our study highlights that there may be unappreciated heterogeneity within CAF subtypes. Further investigation and attention to specific genes or proteins that may drive this heterogeneity will be important.

Unipolar Hemiarthroplasty, Bipolar Hemiarthroplasty, or Total Hip Arthroplasty for Hip Fracture in Older Individuals.

BACKGROUND: Practice patterns regarding the use of unipolar hemiarthroplasty, bipolar hemiarthroplasty, and total hip arthroplasty (THA) for femoral neck fractures in older patients vary widely. This is due in part to limited data stipulating the specific circumstances under which each form of arthroplasty provides the most predictable outcome. The purpose of this study was to investigate the patient characteristics for which unipolar hemiarthroplasty, bipolar hemiarthroplasty, or THA might be preferable due to a lower risk of all-cause revision. METHODS: A U.S. health-care system's hip fracture registry was used to identify patients ≥60 years old who underwent unipolar hemiarthroplasty, bipolar hemiarthroplasty, or THA for hip fracture from 2009 through 2021. Unipolar and bipolar hemiarthroplasty were compared with THA within patient subgroups defined by age (60 to 79 versus ≥80 years) and American Society of Anesthesiologists (ASA) classification (I or II versus III); patients with an ASA classification of IV or higher were excluded. Multivariable Cox proportional hazard regression analysis was used to evaluate all-cause revision risk while adjusting for confounders, with mortality considered as a competing risk. RESULTS: There were 14,277 patients in the final sample (median age, 82 years; 70% female; 80% White; 69% with an ASA classification of III; median follow-up, 2.7 years), and the procedures included 7,587 unipolar hemiarthroplasties, 5,479 bipolar hemiarthroplasties, and 1,211 THAs. In the multivariable analysis of all patients, both unipolar (hazard ratio [HR] = 2.15, 95% confidence interval [CI] = 1.48 to 3.12; p < 0.001) and bipolar (HR = 1.92, 95% CI = 1.31 to 2.80; p < 0.001) hemiarthroplasty had higher revision risks than THA. In the age-stratified multivariable analysis of patients aged 60 to 79 years, both unipolar (HR = 2.17, 95% CI = 1.42 to 3.34; p = 0.004) and bipolar (HR = 1.69, 95% CI = 1.08 to 2.65; p = 0.022) hemiarthroplasty also had higher revision risks than THA. In the ASA-stratified multivariable analysis, patients with an ASA classification of I or II had a higher revision risk after either unipolar (HR = 3.52, 95% CI = 1.87 to 6.64; p < 0.001) or bipolar (HR = 2.31, 95% CI = 1.19 to 4.49; p = 0.013) hemiarthroplasty than after THA. No difference in revision risk between either of the hemiarthroplasties and THA was observed among patients with an age of ≥80 years or those with an ASA classification of III. CONCLUSIONS: In this study of hip fractures in older patients, THA was associated with a lower risk of all-cause revision compared with unipolar and bipolar hemiarthroplasty among patients who were 60 to 79 years old and those who had an ASA classification of I or II. LEVEL OF EVIDENCE: Therapeutic Level III . See Instructions for Authors for a complete description of levels of evidence.

Can Dual Mobility Cups Reduce Revision and Dislocation Risks? An Analysis of 107,528 Primary Total Hip Arthroplasties in the United States.

BACKGROUND: Dual mobility acetabular cups (DMC) were designed to increase the effective femoral head size and improve stability with the goal of reducing revision risk at the potential cost of polyethylene thickness. We sought to evaluate revision risk following primary elective total hip arthroplasty with DMC compared to highly cross-linked polyethylene (XLPE). METHODS: A cohort study was conducted using data from a Kaiser Permanente's total joint arthroplasty registry. Patients ≥18 years who underwent primary elective total hip arthroplasty using DMC, unipolar Metal-on-XLPE (MoXLPE), or unipolar Ceramic-on-XLPE (CoXLPE) were identified (2010 to 2021). The final sample comprised 2,219 DMC, 48,251 MoXLPE, and 57,058 CoXLPE. Multiple Cox proportional hazard regressions were used to evaluate aseptic revision and any dislocation regardless of revision within 6 years follow-up. RESULTS: In adjusted analyses, no differences in aseptic revision risk were observed for MoXLPE (hazard ratio [HR] = 1.04, 95% confidence interval [CI] = 0.72 to 1.51) or CoXLPE (HR = 0.98, 95% CI = 0.69 to 1.40) compared to DMC. No differences in dislocation risk were observed for MoXLPE (HR = 1.42, 95% CI = 0.93 to 2.15) or CoXLPE (HR = 1.25, 95% CI = 0.84 to 1.87) compared to DMC. CONCLUSIONS: In a US-based cohort, 6-year aseptic revision risk of DMC was similar to metal or ceramic femoral head unipolar constructs. Furthermore, no difference in dislocation risk was observed. Continued longer-term follow-up may reveal if there is a reduced risk of dislocation that comes at the cost of increased late revision. LEVEL OF EVIDENCE: Level III.

The Impact of Age on the Post-operative Outcomes in Patients Undergoing Resection for Oesophageal and Gastric Cancer.

BACKGROUND: Within our ageing population, there is an increasing number of elderly patients presenting with oesophagogastric cancer. Resection remains the mainstay of curative treatment however it has substantial morbidity. The aim of this study was to assess whether age was an independent predictor of resection related complications in our unit. METHODS: A retrospective cohort study of prospectively collated data from 2002 to 2020 of patients undergoing resection for oesophageal and gastric cancers was analysed. Patients aged over 75 and 75 and under were compared for peri-operative morbidity (via the Clavien-Dindo classification), length of stay (LOS), unplanned readmission, 30- and 90-day mortality, and use of neoadjuvant therapy. RESULTS: Data for 466 consecutive patients undergoing oesophagogastric resection (277 oesophagectomy and 189 gastrectomy) were available for analysis. 22% of patients were aged over 75 (14% (39/277) of the oesophagectomy cohort, 34% (65/189) of the gastrectomy cohort). Oesophagectomy patients over 75 were more likely to develop post-operative complications, particularly cardiac or thromboembolic, (69.2%) than those in the younger cohort (50.4%, p = 0.029). There was no difference in complication rates between the younger and older patients undergoing gastrectomy (29.0% vs. 33.9% p = 0.495). The 30- and 90-day mortality rates were 1.4% (n = 4) and 2.5% (n = 7), respectively, for the oesophagectomy cohort and 1.1% (n = 2) and 1.6% (n = 3) for the gastrectomy cohort, with no difference between age groups. CONCLUSION: In this series, we found that patients over the age of 75 were able to undergo oesophageal and gastric resection with curative intent with acceptable post-operative morbidity and mortality.

Initial experience with laparoscopic gastric bypass in an Australian general foregut surgery unit.

BACKGROUND: Laparoscopic gastric bypass (LGB) is an increasingly utilized approach to bariatric surgery in Australia. A high proportion of those procedures are revisional due to Australia's legacy of laparoscopic adjustable gastric banding (LAGB), which is not the case internationally. The aim of this study was to compare post-operative outcomes in an Australian general foregut surgery unit against benchmarks published in the literature. METHODS: This is retrospective cohort study of morbidly obese patients undergoing primary or revisional laparoscopic Roux-en-Y gastric bypass (RYGB) or laparoscopic one anastomosis gastric bypass (OAGB) with the two senior authors between 5 May 2015 and 27 June 2019. Perioperative data for the unit's first 100 cases were collected prospectively, stored on a unit database and analysed. Post-operative complications at 30 days, 90 days, mortality, length of hospital stay, and Defined Adverse Events were chosen as indicators of the perioperative outcome (as defined in the Monash Bariatric Surgery Registry). RESULTS: In this cohort, 35% of procedures were RYGB and 65% were OAGB. The majority (58%) were revisional procedures. Most patients (74%) were female. The median age was 50. The comorbidity profile of the population was similar to those published internationally. The median hospital stay was 4 days. There was no mortality. Early complications occurred in 9% of patients, with 3% occurring late. CONCLUSION: Outcomes of our first 100 cases are comparable with those recorded in the literature, notwithstanding a much higher proportion of revisional cases. LGB can be safely introduced in Australian general foregut surgery units by experienced laparoscopic surgeons.

Association Between Race/Ethnicity and 90-Day Emergency Department Visits in Patients Undergoing Elective Total Knee Arthroplasty or Total Hip Arthroplasty in a Universally Insured Population.

BACKGROUND: Research has identified disparities in returns to care by race/ethnicity following primary total joint arthroplasty. We sought to identify risk factors for 90-day emergency department (ED) returns following primary total knee arthroplasty (TKA) or total hip arthroplasty (THA) for these populations. METHODS: Black, Hispanic, and non-Hispanic White patients who underwent elective primary unilateral TKA and THA in an integrated US healthcare system were identified. Risk factors for 90-day postoperative ED visits including patient demographics, household income and education, comorbidities, preoperative healthcare utilization, and copay data were identified with multivariable logistic regression. RESULTS: Postoperative 90-day ED visits occurred in 13.3% of 79,565 TKA patients (17.2% Black; 14.9% Hispanic; 12.5% White) and 11.0% of THA patients (13.4% Black; 12.1% Hispanic; 10.7% White). Across racial/ethnic categories, patients who had an ED visit within 1 year of their TKA or THA date were more likely to have a 90-day ED return. Shared risk factors for TKA patients were chronic lung disease and outpatient utilization (25th and 75th percentile), while peripheral vascular disease was a shared risk factor for THA patients. Risk factors for multiple races of TKA and THA patients included depression, drug abuse, and psychosis. Prior copay for White (TKA) and Hispanic (TKA and THA) patients was protective, while preoperative primary care was protective for Black THA patients. CONCLUSION: Future strategies to reduce postoperative ED returns should include directed patient outreach for patients who had ED visits and mental health in the year prior to TKA and THA. LEVEL OF EVIDENCE: III.

Use of Preoperative CT Scans and Patient-Specific Instrumentation May Not Improve Short-Term Adverse Events After Shoulder Arthroplasty: Results from a Large Integrated Health-Care System.

Ongoing innovation leads to a continuous influx of new technologies related to shoulder arthroplasty. These are made available to surgeons and marketed to both health-care providers and patients with the hope of improving outcomes. We sought to evaluate how preoperative planning technologies for shoulder arthroplasty affect outcomes. Methods: This was a retrospective cohort study conducted using data from an integrated health-care system's shoulder arthroplasty registry. Adult patients who underwent primary elective anatomic or reverse total shoulder arthroplasty (2015 to 2020) were identified. Preoperative planning technologies were identified as (1) a computed tomography (CT) scan and (2) patient-specific instrumentation (PSI). Multivariable Cox regression and logistic regression were used to compare the risk of aseptic revision and 90-day adverse events, respectively, between procedures for which technologies were and were not used. Results: The study sample included 8,117 procedures (in 7,372 patients) with an average follow-up of 2.9 years (maximum, 6 years). No reduction in the risk of aseptic revision was observed for patients having either preoperative CT scans (hazard ratio [HR] = 1.22; 95% confidence interval [CI] = 0.87 to 1.72) or PSI (HR = 1.44; 95% CI = 0.71 to 2.92). Patients having CT scans had a lower likelihood of 90-day emergency department visits (odds ratio [OR] = 0.84; 95% CI = 0.73 to 0.97) but a higher likelihood of 90-day venous thromboembolic events (OR = 1.79; 95% CI = 1.18 to 2.74). Patients with PSI use had a higher likelihood of 90-day deep infection (OR = 7.74; 95% CI = 1.11 to 53.94). Conclusions: We found no reduction in the risk of aseptic revision with the use of these technologies. Patients having CT scans and PSI use had a higher likelihood of venous thromboembolism and deep infection, respectively. Ongoing research with extended follow-up is being conducted to further examine the effects of these technologies on patient outcomes. Level of Evidence: Diagnostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Watching the clock in glioblastoma.

Glioblastoma (GBM) is the most prevalent malignant primary brain tumor, accounting for 14.2% of all diagnosed tumors and 50.1% of all malignant tumors, and the median survival time is approximately 8 months irrespective of whether a patient receives treatment without significant improvement despite expansive research (Ostrom QT, Price M, Neff C, et al. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2015-2019. Neurooncology. 2022; 24(suppl 5):v1-v95.). Recently, important roles for the circadian clock in GBM tumorigenesis have been reported. Positive regulators of circadian-controlled transcription, brain and muscle ARNT-like 1 (BMAL1), and circadian locomotor output cycles kaput (CLOCK), are highly expressed also in GBM and correlated with poor patient prognosis. BMAL1 and CLOCK promote the maintenance of GBM stem cells (GSCs) and the establishment of a pro-tumorigenic tumor microenvironment (TME), suggesting that targeting the core clock proteins may augment GBM treatment. Here, we review findings that highlight the critical role the circadian clock plays in GBM biology and the strategies by which the circadian clock can be leveraged for GBM treatment in the clinic moving forward.

Preoperative Patient Optimization: Outcomes from Elective Total Joint Arthroplasty in a Large US Healthcare System.

INTRODUCTION: Patient factors are known to affect outcomes in arthroplasty surgery. A preoperative program to address modifiable factors may aid in more appropriate patient selection. We sought to assess patient selection and 90-day postoperative outcomes for total joint arthroplasty (TJA) candidates before and after implementation of a preoperative optimization protocol. METHODS: A retrospective time-trend study using data from an integrated healthcare system's total joint replacement registry was done. The study sample consisted of patients aged 18 years or older who underwent primary elective total hip arthroplasty (THA) and total knee arthroplasty (TKA) for osteoarthritis between 2009 and 2019. Patients were divided into two cohorts: procedures performed from 2009 to 2013 ("preoptimization protocol") and those from 2015 to 2019 ("postoptimization protocol"); 2014 was excluded because an evidence-based preoperative patient optimization protocol was progressively implemented throughout the year. Patient characteristics, optimization factors, and 90-day outcomes (including emergency department [ED] visits, readmission, all-cause revision, deep infection, venous thromboembolism, and mortality) were compared between the two cohorts using the Pearson chi-square test or Wilcoxon test. RESULTS: The study sample included 25,925 THA and 60,484 TKA. In the THA cohort, 10,364 (40.0%) and 15,561 (60.0%) were from the preoptimization and postoptimization cohorts, respectively. The postoptimization THA cohort saw lower rates of ED visits (12.1% vs. 9.4%, P < 0.001) and readmissions (5.6% vs. 3.8%, P < 0.001). In the TKA cohort, 24,054 (39.8%) and 36,430 (60.2%) were from the preoptimization and postoptimization cohorts, respectively. The postoptimization TKA cohort saw lower rates of ED visits (13.1% vs. 11.9%, P < 0.001), readmissions (5.6% vs. 3.0%, P < 0.001), all-cause revisions (0.5% vs. 0.3%, P = 0.003), venous thromboembolism (1.3% vs. 0.9%, P < 0.001), and mortality (0.3% vs. 0.2%, P = 0.011). DISCUSSION: An evidence-based protocol to improve patient selection based on modifiable patient factors was adopted by orthopaedic surgeons in the system and utilization of the protocol before TJA was associated with fewer postoperative complications over time. LEVEL OF EVIDENCE: Level IV.

N-Heterocyclic carbenes as privileged ligands for nickel-catalysed alkene functionalisation.

Alkene functionalisation is a powerful strategy that has enabled access to a wide array of compounds including valuable pharmaceuticals and agrochemicals. The reactivity of the alkene π-bond has allowed incorporation of a diverse range of atoms and functional groups through a wide variety of reaction pathways. N-Heterocyclic carbenes (NHCs) are a class of persistent carbenes that are widely employed as ancillary ligands due to their ability to act as strong σ-donors compared to widely-applied conventional phosphine-based ligands. NHCs are also unique as their molecular bulk provides steric influence for regio- and stereo-control in many alkene functionalisation reactions, illustrated by the examples covered in this review. A combination of the unique reactivity of NHC ligands and nickel's characteristics has facilitated the design of reaction pathways that show distinct selectivity and reactivity, including the activation of bonds previously considered "inert", such as C-H bonds, the C-O bond of ethers and esters, and the C-N bonds of amides. This review summarises the advancements in Ni(NHC) catalysed alkene functionalisation up to 2022, covering the following major reaction classes: Heck-type reactions, hydrofunctionalisation and dicarbofunctionalisation.

Evidence-based objective performance criteria for the evaluation of hip and knee replacement devices and technologies.

BACKGROUND: Objective performance criteria (OPC) is a novel method to provide minimum performance standards and improve the regulated introduction of original or incremental device innovations in order to prevent patients from being exposed to potentially inferior designs whilst allowing timely access to improvements. We developed 2-year safety and effectiveness OPC for total hip and knee replacement (THR and TKR). METHODS: Analyses of large databases were conducted using various data sources: a systematic literature review; a direct data analysis from The Functional Outcomes Research for Comparative Effectiveness in Total Joint Replacement and Quality Improvement Registry (FORCE-TJR) and the Kaiser Permanente Implant Registry (KPIR); and claims data analyses from longitudinal discharge data in New York and California states. The literature review included U.S. patients (≥18 years) who received THR or TKR for primary end-stage osteoarthritis and prospectively collected data on patient-reported outcome measures (PROMs) from at least 100 subjects and/or 2-year implant survival for at least 250 implants. Random effects models were used for meta-analysis. RESULTS: Data were available from a total of 951 100 patients. After screening of 7979 abstracts, 294 studies underwent full-text review and 31 studies contributed to the evidence synthesis (333 995 implants). Direct data analysis of FORCE-TJR contributed 9223 joint replacement patients to the construction of OPC for effectiveness; KPIR contributed 262 044 patients for the construction of OPC for safety. Claims database analysis contributed 345 838 patients to the construction of safety OPC. OPC for safety were constructed for cumulative incidences of 2-year all-cause and septic revision (THR/TKR 2.0%/1.6% and 0.6%/0.7%), and OPC for effectiveness were constructed based on four disease-specific and three general health-related quality of life PROMs (HOOS/KOOS 87.1/80.6; HSS/KSS function 94.4/90.6; SF-12/SF-36, PCS 46.5/41.9, EQ-5D 0.88/0.84). CONCLUSION: This study is the first to construct a 2-year OPC for the safety and effectiveness of THR and TKR based on U.S. real-world data. Based on these OPC, potential benchmarks for (single-arm study) evaluation of new device innovations are suggested for a regulated and safe introduction to the (commercial) market.

In person and virtual process mapping experiences to capture and explore variability in clinical practice: application to genetic referral pathways across seven Australian hospital networks.

Genetic referral for Lynch syndrome (LS) exemplifies complex clinical pathways. Identifying target behaviours (TBs) for change and associated barriers requires structured group consultation activities with busy clinicians - consolidating implementation activities whilst retaining rigour is crucial. This study aimed to: i) use process mapping to gain in-depth understandings of site-specific LS testing and referral practices in Australian hospitals and support identification of TBs for change, ii) explore if barriers to identified TBs could be identified through process mapping focus-group data, and iii) demonstrate pandemic-induced transition from in-person to virtual group interactive process mapping methods. LS clinical stakeholders attended interactive in-person or virtual focus groups to develop site-specific "process maps" visually representing referral pathways. Content analysis of transcriptions informed site-specific process maps, then clinical audit data was compared to highlight TBs for change. TBs were reviewed in follow-up focus groups. Secondary thematic analysis explored barriers to identified TBs, coded against the Theoretical Domains Framework (TDF). The transition from in-person to pandemic-induced virtual group interactive process mapping methods was documented. Process mapping highlighted six key areas of clinical practice variation across sites and site-specific TBs for change were identified. Key barriers to identified TBs emerged, categorised to seven TDF domains. Process mapping revealed variations in clinical practices surrounding LS referral between sites. Incorporating qualitative perspectives enhances process mapping by facilitating identification of TBs for change and barriers, providing a pathway to developing targeted interventions. Virtual process mapping activities produced detailed data and enabled comprehensive map development.

To achieve change in the health system using implementation approaches, time-poor clinicians must engage in information-gathering and idea-generation activities. This research revealed that qualitative process mapping focus groups held both in-person and virtually can be used to streamline these activities, by simultaneously identifying target behaviours for change, and barriers to change, while gaining information about site-specific clinical processes. Hospital process mapping shows that complex clinical processes vary significantly between sites, and that understanding local variation is crucial to developing targeted interventions. This study has informed new approaches to implementation research methods.

Similar rates of revision surgery following primary anatomic compared with reverse shoulder arthroplasty in patients aged 70 years or older with glenohumeral osteoarthritis: a cohort study of 3791 patients.

BACKGROUND: Reverse total shoulder arthroplasty (RTSA), initially indicated for cuff tear arthropathy, is increasingly used to treat elderly patients with primary glenohumeral osteoarthritis (GHOA) and an intact rotator cuff. This is often done to avoid revision surgery in elderly patients for rotator cuff failure with anatomic total shoulder arthroplasty (TSA) despite traditionally good outcomes of TSA. We sought to determine whether there was a difference in outcomes in patients aged ≥70 years who received RTSA vs. TSA for GHOA. METHODS: A retrospective cohort study was conducted using data from a US integrated health care system's shoulder arthroplasty registry. Patients aged ≥70 years who underwent primary shoulder arthroplasty for GHOA with an intact rotator cuff were included (2012-2021). RTSA was compared with TSA. Multivariable Cox proportional hazard regression was used to evaluate all-cause revision risk during follow-up, whereas multivariable logistic regression was used to evaluate 90-day emergency department (ED) visits and 90-day readmissions. RESULTS: The final study sample comprised 685 RTSA patients and 3106 TSA patients. The mean age was 75.8 years (standard deviation, 4.6 years), and 43.4% of patients were men. After accounting for confounders, we observed no significant difference in all-cause revision risk for RTSA vs. TSA (hazard ratio, 0.79; 95% confidence interval [CI], 0.39-1.58). The most common reason for revision following RTSA was glenoid component loosening (40.0%). Over half of revisions following TSA were for rotator cuff tear (54.0%). No difference based on procedure type was observed in the likelihood of 90-day ED visits (odds ratio, 0.94; 95% CI, 0.71-1.26) and 90-day readmissions (odds ratio, 1.32; 95% CI, 0.83-2.09). CONCLUSION: RTSA and TSA for GHOA with an intact rotator cuff in patients aged ≥70 years had a similar revision risk, as well as a similar likelihood of 90-day ED visits and readmissions. Although revision risk was similar, the most common causes of revision were different, with rotator cuff tears in TSA patients and glenoid component loosening in RTSA patients.

Prolonged Opioid Usage Following Hip Fracture Surgery in Opioid-Naïve Older Patients.

BACKGROUND: While the risk of long-term dependence following the opioid treatment of musculoskeletal injury is often studied in younger populations, studies in older patients have centered on short-term risks such as oversedation and delirium. This study investigated prolonged opioid usage after hip fracture in older individuals, focusing on prevalence, risk factors, and changes over time. METHODS: In this retrospective cohort study of 47,309 opioid-naïve patients aged ≥ 60 years who underwent hip fracture surgery (2009 to 2020), outpatient opioid use was evaluated in 3 postoperative time periods: P1 (day 0 to 30 postsurgery); P2 (day 31 to 90); and P3 (day 91 to 180). The primary outcome was prolonged outpatient opioid use, defined as having one or more opioid prescriptions dispensed in all 3 time periods. RESULTS: The incidence of prolonged opioid usage among patients surviving to P3 was 6.3% (2,834 of 44,850). Initial prescription quantities decreased over time, as did the risk of prolonged opioid usage (from 8.0% in 2009 to 3.9% in 2019). In the multivariable analyses, risk factors for prolonged opioid usage included younger age, women, current/former smoking, fracture fixation (as compared to hemiarthroplasty), and anxiety. Prolonged opioid usage was less common among patients who were Asian or had a history of dementia. CONCLUSIONS: While prior research on the hazards of opioids in the elderly has focused on short-term risks such as oversedation and delirium, these findings suggest that prolonged opioid usage may be a risk for this older population as well. As initial prescription amounts have decreased, declines in prolonged opioid medication usage have also been observed.

Does Aseptic Revision Risk Differ for Primary Total Knee Arthroplasty Patients Who Have and Do not Have a Prior Primary or Revision Arthroplasty?

BACKGROUND: We sought to evaluate the risk of aseptic revision in total knee arthroplasty (TKA) patients who have and do not have a history of primary or revision arthroplasty of a different major joint. METHODS: We conducted a matched cohort study using data from Kaiser Permanente's arthroplasty registries. Patients who underwent primary unilateral TKA (index knee) were identified (2009-2018). Two matches based on exposure history were performed: (1) 33,714 TKAs with a history of primary arthroplasty of a different joint (contralateral knee, either hip, and/or either shoulder) were matched to 67,121 TKAs without an arthroplasty history and (2) 597 TKAs with a history of aseptic revision in a different joint were matched to 1,190 TKAs with a history of a prior arthroplasty in a different joint, but without any revision. After the matches were performed, Cox regressions were used to evaluate aseptic revision risk of the index knee using the no history groups as the reference in regression models. RESULTS: No difference in aseptic revision risk for the index knee was observed when comparing patients who had a prior primary arthroplasty in a different joint to those who did not have an arthroplasty history (hazard ratio = 0.95, 95% CI = 0.86-1.06). Those patients who did not have any prior aseptic revision history in a different joint had higher risk of aseptic revision in the index knee (hazard ratio = 2.06, 95% CI = 1.17-3.63). CONCLUSION: Patients who had a prior revision history had over a 2-fold higher risk of aseptic revision in the index knee, warranting close surveillance of these patients. LEVEL OF EVIDENCE: Level III.

Tranexamic acid is not associated with decreased infection risk after primary shoulder arthroplasty: a cohort study of 9276 patients.

BACKGROUND: The use of tranexamic acid (TXA) is associated with less blood loss and reduced transfusion risk after shoulder arthroplasty surgery. Recent studies have shown lower odds of postoperative infection after hip or knee arthroplasty with its use. The purpose of this study was to determine whether TXA use reduces the risk of infection after primary elective shoulder arthroplasty. METHODS: A retrospective cohort study was conducted using data from a US integrated health care system's shoulder arthroplasty registry. Patients aged 18 years who underwent primary elective anatomic total shoulder arthroplasty for osteoarthritis or primary reverse shoulder arthroplasty for rotator cuff arthropathy were included (2013-2020). We compared patients who received preoperative intravenous TXA to those who did not receive TXA by assessing the risk for revision due to deep infection within 5 years' follow-up using multivariable Cox proportional hazard regression. Interaction between TXA and diabetes status was analyzed separately. RESULTS: The study sample included 9276 shoulder arthroplasties performed by 153 surgeons at 43 hospitals. The mean age was 70.0 years and 48% were male. The 5-year probability of revision for deep infection was 0.8% and 0.7% for patients with and without TXA, respectively. We failed to observe a difference in infection risk after adjustment for confounders and surgeon differences (hazard ratio [HR] 1.00, 95% confidence interval [CI] 0.56-1.80, P = .998). Further, no differences were observed in patients with (HR 1.64, 95% CI 0.42-6.44, P = .481) or without diabetes (HR 0.79, 95% CI 0.40-1.55, P = .488). CONCLUSION: In a multicenter cohort of more than 9000 primary shoulder arthroplasty procedures, the use of preoperative TXA was not associated with a decrease in the 5-year probability of revision for deep infection.

Barriers to family history collection among Spanish-speaking primary care patients: a BRIDGE qualitative study.

Objectives: Family history is an important tool for assessing disease risk, and tailoring recommendations for screening and genetic services referral. This study explored barriers to family history collection with Spanish-speaking patients. Methods: This qualitative study was conducted in two US healthcare systems. We conducted semi-structured interviews with medical assistants, physicians, and interpreters with experience collecting family history for Spanish-speaking patients. Results: The most common patient-level barrier was the perception that some Spanish-speaking patients had limited knowledge of family history. Interpersonal communication barriers related to dialectical differences and decisions about using formal interpreters vs. Spanish-speaking staff. Organizational barriers included time pressures related to using interpreters, and ad hoc workflow adaptations for Spanish-speaking patients that might leave gaps in family history collection. Conclusions: This study identified multi-level barriers to family history collection with Spanish-speaking patients in primary care. Findings suggest that a key priority to enhance communication would be to standardize processes for working with interpreters. Innovation: To improve communication with and care provided to Spanish-speaking patients, there is a need to increase healthcare provider awareness about implicit bias, to address ad hoc workflow adjustments within practice settings, to evaluate the need for professional interpreter services, and to improve digital tools to facilitate family history collection.