CRY2 isoform selectivity of a circadian clock modulator with antiglioblastoma efficacy.

The mammalian cryptochrome isoforms, CRY1 and CRY2, are core circadian clock regulators that work redundantly. Recent studies revealed distinct roles of these closely related homologs in clock output pathways. Isoform-selective control of CRY1 and CRY2 is critical for further understanding their redundant and distinct roles. KL001 was the first identified small-molecule CRY modulator that activates both CRY1 and CRY2. SHP656 is an orally available KL001 derivative and has shown efficacy in blood glucose control and inhibition of glioblastoma stem cell (GSC) growth in animal models. However, CRY isoform selectivity of SHP656 was uncharacterized, limiting understanding of the roles of CRY1 and CRY2. Here, we report the elucidation of CRY2 selectivity of SHP656. SHP656 lengthened cellular circadian period in a CRY2-dependent manner and selectively interacted with CRY2. By determining the X-ray crystal structure of CRY2 in complex with SHP656 and performing molecular dynamics simulations, we elucidated compound interaction mechanisms. SHP656 binding was compatible with the intrinsic CRY2 gatekeeper W417 "in" orientation and also a close "further in" conformation. Perturbation of W417 interaction with the lid loop resulted in a reduced effect of SHP656 on CRY2, supporting an important role of gatekeeper orientation in isoform selectivity. We also identified the R form of SHP656 (called SHP1703) as the active isomer. Treatment with SHP1703 effectively reduced GSC viability. Our results suggest a direct role of CRY2 in glioblastoma antitumorigenesis and provide a rationale for the selective modulation of CRY isoforms in the therapeutic treatment of glioblastoma and other circadian clock-related diseases.

Engagement and return of results preferences among a primarily African American genomic sequencing research cohort.

Genomics researchers are increasingly interested in what constitutes effective engagement of individuals from underrepresented groups. This is critical for longitudinal projects needed to inform the implementation of precision medicine. Return of results is one opportunity for engagement. The aims of this study were to determine participant perspectives on optimal engagement strategies and priorities for return of results and the extent to which focus groups were an effective modality for gathering input on these topics. We conducted six professionally moderated focus groups with 49 participants in a genomics research study. Transcripts from audio-recorded sessions were coded by two researchers and themes were discussed with the wider research team. All groups raised the issue of mistrust. Individuals participated nonetheless to contribute their perspectives and benefit their community. Many group members preferred engagement modalities that are offered to all participants and allow them to share the nuances of their perspectives over the use of participant representatives and surveys. All groups created a consensus ranking for result return priorities. Results for life-threatening conditions were the highest priority to return, followed by those related to treatable conditions that affect physical or mental health. We advocate for engagement strategies that reach as many participants as possible and allow them to share their perspectives in detail. Such strategies are valued by participants, can be effective for developing return of results policies, and may help institutions become more trustworthy.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Lynch syndrome testing of colorectal cancer patients in a high-income country with universal healthcare: a retrospective study of current practice and gaps in seven australian hospitals.

BACKGROUND: To inform effective genomic medicine strategies, it is important to examine current approaches and gaps in well-established applications. Lynch syndrome (LS) causes 3-5% of colorectal cancers (CRCs). While guidelines commonly recommend LS tumour testing of all CRC patients, implementation in health systems is known to be highly variable. To provide insights on the heterogeneity in practice and current bottlenecks in a high-income country with universal healthcare, we characterise the approaches and gaps in LS testing and referral in seven Australian hospitals across three states. METHODS: We obtained surgery, pathology, and genetics services data for 1,624 patients who underwent CRC resections from 01/01/2017 to 31/12/2018 in the included hospitals. RESULTS: Tumour testing approaches differed between hospitals, with 0-19% of patients missing mismatch repair deficiency test results (total 211/1,624 patients). Tumour tests to exclude somatic MLH1 loss were incomplete at five hospitals (42/187 patients). Of 74 patients with tumour tests completed appropriately and indicating high risk of LS, 36 (49%) were missing a record of referral to genetics services for diagnostic testing, with higher missingness for older patients (0% of patients aged ≤ 40 years, 76% of patients aged > 70 years). Of 38 patients with high-risk tumour test results and genetics services referral, diagnostic testing was carried out for 25 (89%) and identified a LS pathogenic/likely pathogenic variant for 11 patients (44% of 25; 0.7% of 1,624 patients). CONCLUSIONS: Given the LS testing and referral gaps, further work is needed to identify strategies for successful integration of LS testing into clinical care, and provide a model for hereditary cancers and broader genomic medicine. Standardised reporting may help clinicians interpret tumour test results and initiate further actions.

The association between critical shoulder angle and revision following anatomic total shoulder arthroplasty: a matched case-control study.

HYPOTHESIS: The concept of the critical shoulder angle (CSA) was introduced in 2013, with studies showing that larger CSA is associated with rotator cuff tears (RCTs) and smaller CSA with glenohumeral osteoarthritis. We hypothesized outcomes following total shoulder arthroplasty (TSA) would differ depending on CSA. METHODS: We conducted a matched case-control study using Kaiser Permanente's Shoulder Arthroplasty Registry to identify patients who underwent primary elective anatomic TSA for the diagnosis of osteoarthritis from 2009-2018. Seventy-eight adult patients who underwent revision following the primary TSA due to glenoid component failure or rotator cuff tear comprised the case group. A control group of nonrevised patients were identified from the same source population. Two controls were matched to each case by age, gender, body mass index, American Society of Anesthesiologists classification, surgeon who performed the index TSA, and post-TSA follow-up time. The relationship between revision and CSA as measured on radiographs were analyzed as a 1:2 matched-pairs case-control study with use of multiple conditional multivariable logistic regression. RESULTS: Revised cases had a higher likelihood of a CSA ≥35° (odds ratio [OR] = 2.41, 95% confidence interval [CI] = 1.27-4.59). A higher likelihood of CSA ≥35° was observed for those revised for glenoid loosening (OR = 4.58, 95% CI = 1.20-17.50) and revised for rotator cuff tear (OR = 2.41, 95% CI = 1.18-4.92) compared with nonrevised controls. Every 5° increase in CSA had higher odds of overall revision (OR = 1.62, 95% CI = 1.18-2.21), glenoid loosening (OR = 2.50, 95% CI = 1.27-4.92), and rotator cuff tear (OR = 1.51, 95% CI = 1.07-2.14). CONCLUSION: In a matched case-control study of primary anatomic TSA, individuals who were revised for aseptic glenoid loosening and superior cuff failure had a higher CSA compared with nonrevised individuals. These data suggest that surgeons may consider using reverse arthroplasty in cases of primary shoulder arthritis with a CSA of 35° or greater.

Cause-Specific Stem Revision Risk in Primary Total Hip Arthroplasty Using Cemented vs Cementless Femoral Stem Fixation in a US Cohort.

BACKGROUND: We sought to evaluate the cause-specific revision risk following hybrid (cemented stem mated to a cementless acetabular implant) vs cementless total hip arthroplasty (THA) in a US cohort. METHODS: Primary elective THA for osteoarthritis was identified using Kaiser Permanente's Total Joint Replacement Registry (2001-2018). Multivariable Cox regression was used to evaluate cause-specific revision, including aseptic loosening, infection, instability, and periprosthetic fracture (PPF), for hybrid vs cementless THA. Analysis was stratified by age (<65, 65-74, and ≥75 years) and gender. RESULTS: The study cohort comprised 88,830 THAs, including 4539 (5.1%) hybrid THAs. In stratified analysis, hybrid THA had a higher revision risk for loosening in females in all 3 age subgroups. A lower risk of revision for PPF was observed following hybrid THA in females aged ≥75 years. For females ≥75 years, cementless THA had an excess PPF risk of 0.9% while hybrid THA had an excess loosening risk of 0.2%, translating to a theoretical prevention of 10 PPF revisions but a price of 3 loosening revisions per 1000 hybrid THAs. No difference in revision risk was observed in males. CONCLUSION: We observed differences in cause-specific revision risks by method of stem fixation which depended upon patient age and gender. Although the trend toward all cementless fixation continue, there may be a role for hybrid fixation in females ≥75 years to mitigate risk for revision due to PPF at the potential cost of a slight increase in longer term aseptic loosening. LEVEL OF EVIDENCE: Level III.

Revision Risk in a Cohort of US Patients Younger Than 55 Undergoing Primary Elective Total Hip Arthroplasty.

BACKGROUND: As indications for elective total hip arthroplasty (THA) expand to younger patients, we sought to (1) compare revision risk following primary elective THA in patients <55 years at the time of their THA to patients aged ≥65 years and (2) identify specific risk factors for revision in patients <55 years. METHODS: A Kaiser Permanente's total joint replacement registry was used to conduct a cohort study including primary elective THA patients aged ≥18 (2001-2018). In total, 11,671 patients <55 years and 53,106 patients ≥65 years were included. Multiple Cox regression was used to evaluate cause-specific revision risk, including septic revision, aseptic loosening, instability, and periprosthetic fracture. Stepwise Cox regression was used to identify patient and surgical factors associated with cause-specific revision in patients <55 years. RESULTS: Patients <55 years had a higher risk of septic revision (hazard ratio [HR] = 1.30, 95% confidence interval [CI] = 1.02-1.66), aseptic loosening (HR = 2.60, 95% CI = 1.99-3.40), and instability (HR = 1.35, 95% CI = 1.09-1.68), but a lower risk of revision for periprosthetic fracture (HR = 0.36, 95% CI = 0.22-0.59) compared to patients aged ≥65 years. In the <55 age group, risk factors for septic revision included higher body mass index, drug abuse, and liver disease. Hypertension, anterior approach, and ceramic-on-ceramic were associated with aseptic loosening. White race, American Society of Anesthesiologists classification ≥3, smoker, paralysis, posterior approach, ceramic-on-ceramic, and smaller head diameter were associated with instability. CONCLUSION: Identified risk factors varied depending on the cause for revision. Although septic revisions were related to patient characteristics, more modifiable factors, such as implant or surgical approach, were associated with revision due to aseptic loosening and instability. LEVEL OF EVIDENCE: III.

The design, implementation, and effectiveness of intervention strategies aimed at improving genetic referral practices: a systematic review of the literature.

PURPOSE: Despite rapid advancements in genetics and genomics, referral practices remain suboptimal. This systematic review assesses the extent to which approaches from implementation science have been applied to address suboptimal genetic referral practices. METHODS: A search of MEDLINE, EMBASE, and PsycINFO generated 7,794 articles, of which 28 were included. Lay barriers were mapped to the Theoretical Domains Framework (TDF) and interventions mapped to behavior change techniques. Use of implementation and behavior change frameworks was assessed, and the Theory and Techniques Tool used to determine theoretical alignment. RESULTS: Knowledge was the most frequent retrospectively TDF-coded barrier, followed by environmental context and resources, and skills. Significant referral improvements occurred in 56% of studies. Among these, the most frequent interventions were clinical data review systems, family history collection and referral tools, and embedding genetics staff into nongenetic specialties. Few studies used implementation frameworks or reported implementation outcomes, though some deployed intuitive strategies that aligned with theory. CONCLUSION: Genetic referral interventions are rarely informed by implementation and/or behavior change theories, limiting opportunities for learning across contexts. Retrospective coding has provided a suite of theoretically linked strategies, which may be useful for informing future efforts. Incorporating these strategies into clinical guidelines may facilitate operationalization within the system.

Comparing models of delivery for cancer genetics services among patients receiving primary care who meet criteria for genetic evaluation in two healthcare systems: BRIDGE randomized controlled trial.

BACKGROUND: Advances in genetics and sequencing technologies are enabling the identification of more individuals with inherited cancer susceptibility who could benefit from tailored screening and prevention recommendations. While cancer family history information is used in primary care settings to identify unaffected patients who could benefit from a cancer genetics evaluation, this information is underutilized. System-level population health management strategies are needed to assist health care systems in identifying patients who may benefit from genetic services. In addition, because of the limited number of trained genetics specialists and increasing patient volume, the development of innovative and sustainable approaches to delivering cancer genetic services is essential. METHODS: We are conducting a randomized controlled trial, entitled Broadening the Reach, Impact, and Delivery of Genetic Services (BRIDGE), to address these needs. The trial is comparing uptake of genetic counseling, uptake of genetic testing, and patient adherence to management recommendations for automated, patient-directed versus enhanced standard of care cancer genetics services delivery models. An algorithm-based system that utilizes structured cancer family history data available in the electronic health record (EHR) is used to identify unaffected patients who receive primary care at the study sites and meet current guidelines for cancer genetic testing. We are enrolling eligible patients at two healthcare systems (University of Utah Health and New York University Langone Health) through outreach to a randomly selected sample of 2780 eligible patients in the two sites, with 1:1 randomization to the genetic services delivery arms within sites. Study outcomes are assessed through genetics clinic records, EHR, and two follow-up questionnaires at 4 weeks and 12 months after last genetic counseling contactpre-test genetic counseling. DISCUSSION: BRIDGE is being conducted in two healthcare systems with different clinical structures and patient populations. Innovative aspects of the trial include a randomized comparison of a chatbot-based genetic services delivery model to standard of care, as well as identification of at-risk individuals through a sustainable EHR-based system. The findings from the BRIDGE trial will advance the state of the science in identification of unaffected patients with inherited cancer susceptibility and delivery of genetic services to those patients. TRIAL REGISTRATION: BRIDGE is registered as NCT03985852 . The trial was registered on June 6, 2019 at clinicaltrials.gov .

Preferences for and acceptability of receiving pharmacogenomic results by mail: A focus group study with a primarily African-American cohort.

Although genetic counseling is traditionally done through in-person, one-on-one visits, workforce shortages call for efficient result return mechanisms. Studies have shown that telephone and in-person return of cancer genetic results are equivalent for patient outcomes. Few studies have been conducted with other modes, result types or racially diverse participants. This study explored participants' perspectives on receiving pharmacogenomic results by mail. Two experienced moderators facilitated six focus groups with 49 individuals who self-identified primarily as African-American and consented to participate in a genome sequencing cohort study. Participants were given a hypothetical pharmacogenomic result report (positive for c.521T>C in SLCO1B1). An accompanying letter explained that the result was associated with statin intolerance along with a recommendation to share it with one's doctor and immediate relatives. Participants reacted to the idea of receiving this type of result by mail, discussing whether the letter's information was sufficient and what they predicted they would do with the result. Two researchers coded the focus group transcripts and identified themes. Many participants thought that it was appropriate to receive the result through the mail, but some suggested a phone call alerting the recipient to the letter. Others emphasized that although a letter was acceptable for disclosing pharmacogenomic results, it would be insufficient for what they perceived as life-threatening results. Most participants found the content sufficient. Some participants suggested resources about statin intolerance and warning signs be added. Most claimed they would share the result with their doctor, yet few participants offered they would share the result with their relatives. This exploratory study advances the evidence that African-American research participants are receptive to return of certain genetic results by approaches that do not involve direct contact with a genetic counselor and intend to share results with providers. ClinSeq: A Large-Scale Medical Sequencing Clinical Research Pilot Study (NCT00410241).

Postoperative opioid utilization associated with revision risk following primary shoulder arthroplasty.

INTRODUCTION: With a substantial increase in utilization of primary shoulder arthroplasty, it is important to understand risk factors that may signal early failure and need for revision. Recent studies have reported that sustained postoperative opioid use is associated with a higher revision risk after total hip or knee arthroplasty. In this study, we evaluated postoperative opioid utilization as a risk factor for revision after primary shoulder arthroplasty. METHODS: We conducted a cohort study using data from a United States integrated health care system's Shoulder Arthroplasty Registry. Patients who had a primary elective shoulder arthroplasty were identified (2009-2017); those with cancer or who underwent other arthroplasty procedures (either shoulder, hip, or knee) within the preceding year were excluded. Cumulative daily opioid utilization during the first year postoperative, calculated as oral morphine equivalents (OME), was categorized into 3 exposure groups: high user (≥15 mg OME daily), moderate user (<15 mg OME daily), and no opioid use (reference group). The exposure window was stratified into 2 time periods: postoperative days 1-90 and postoperative days 91-360. Multivariable Cox proportional-hazards regression was used to evaluate the association between postoperative opioid use and aseptic revision risk. RESULTS: The final study sample included 8325 shoulder arthroplasty procedures. Of these individuals, 3707 (45%) received some opioid within the 1 year before the index procedure. We failed to observe a difference in aseptic revision risk between opioid utilization in the first 90 days postoperatively, regardless of dose. After the first 90 days, a higher revision risk was observed for high opioid users compared with nonusers (hazard ratio = 1.62, 95% confidence interval = 1.10-2.41), and no association was observed for moderate users (hazard ratio = 1.25, 95% confidence interval = 0.82-1.91). CONCLUSIONS: We found a positive association between opioid consumption and aseptic revision risk after primary shoulder arthroplasty. This study cannot determine if opioids have a direct physiological cause that increases the risk of revision; rather it is likely that opioid consumption is a marker of chronic pain, poor function, and/or poor coping mechanisms. Further study is needed to determine if programs designed to decrease opioid use may impact revision risk after shoulder arthroplasty.