Prospective Evaluation of the Kaiser Permanente Prostate Cancer Risk Calculator in Biopsy-Naïve Men with Mild PSA Elevations.

INTRODUCTION: Our goal was to assess the impact of providing prostate cancer risk estimates to patients and urologists among biopsy-naïve men with mild PSA elevations. METHODS: This prospective intervention study was conducted in urology departments in Kaiser Permanente Northern California among biopsy-naïve men with mild PSA elevations (<10 ng/mL) between March 2021 and March 2023. The intervention was providing prostate cancer risk estimates for intermediate-/high-grade cancer (Grade Groups 2-5) and any cancer to patients and urologists using our previously validated risk calculator. Biopsy outcomes were compared to a historical comparison group biopsied between January 2016 and December 2019. RESULTS: Over 24 months, the risk calculator was used to estimate risk for 1962 men, of whom 1455 (74%) accepted the biopsy. The men who accepted the biopsy had higher predicted intermediate-/high-grade cancer risks (median 24%, interquartile range [IQR] 17%-31%, vs 20%, IQR 14%-29%; P < .0001) and higher predicted risks for any cancer (median 48%, IQR 40%-56%, vs 45%, IQR 37%-53%, respectively; P < .0001) than those who declined the biopsy. Compared to the historical group, use of the risk calculator resulted in a biopsy population enriched with intermediate-/high-grade cancer: 29% vs 25%; similar rates of low-grade cancer: 24% vs 24%; and fewer negative biopsies: 47% vs 51%, respectively; overall P = .013. CONCLUSIONS: In biopsy-naïve men with mild PSA elevations, use of this risk calculator resulted in a biopsy population that had more intermediate-/high-grade cancer and fewer negative biopsies compared to a historical group.

Shifts in Diagnostic Testing for Headache in the Emergency Department, 2015 to 2021.

Importance: Subarachnoid hemorrhage is typically diagnosed by noncontrast head computed tomography (CT); lumbar puncture is recommended if computed tomography is nondiagnostic, although CT cerebral angiography has been promoted as an alternative to lumbar puncture in this diagnostic pathway. The outcomes of this debate in practice have not been studied. Objective: To determine whether CT cerebral angiography use has increased in lieu of lumbar puncture among emergency department (ED) patients with headache, with an increase in unruptured intracranial aneurysm detection. Design, Setting, and Participants: This retrospective cohort study took place in 21 community EDs of an integrated health care system in Northern California between 2015 and 2021. Participants were adult (aged >17 years) health plan members with a chief concern of headache. Exclusions were prior diagnoses of subarachnoid hemorrhage, unruptured intracranial aneurysm, cerebral arteriovenous malformation, or cerebrospinal fluid shunt. Data were analyzed from October to November 2023. Exposures: CT cerebral angiography and/or lumbar puncture during the ED encounter. Main Outcomes and Measures: Primary and secondary outcomes were 14-day and 90-day unruptured intracranial aneurysm detection, respectively. Safety outcomes were missed diagnoses of subarachnoid hemorrhage or bacterial meningitis. The annual incidence of unruptured intracranial aneurysm detection was normalized to the incidence of subarachnoid hemorrhage (UIA:SAH ratio). Average annualized percentage changes were quantified using joinpoint regression analysis. Results: Among 198 109 included ED encounters, the mean (SD) age was 47.5 (18.4) years; 140 001 patients (70.7%) were female; 29 035 (14.7%) were Black or African American, 59 896 (30.2%) were Hispanic or Latino, and 75 602 (38.2%) were White. Per year, CT cerebral angiography use increased (18.8%; 95% CI, 17.7% to 20.3%) and lumbar punctures decreased (-11.1%; 95% CI, -12.0% to -10.4%), with a corresponding increase in the 14-day UIA:SAH ratio (3.5%; 95% CI, 0.9% to 7.4%). Overall, computed tomography cerebral angiography use increased 6-fold relative to lumbar puncture, with a 33% increase in the detection of UIA. Results were similar at 90 days and robust to sensitivity analyses. Subarachnoid hemorrhage (1004 cases) and bacterial meningitis (118 cases) were misdiagnosed in 5% and 18% of cases, respectively, with no annual trends (P = .34; z1003 = .95 and P = .74; z117 = -.34, respectively). Conclusions and Relevance: In this cohort study of ED patients with headache, increases in CT cerebral angiography use were associated with fewer lumbar punctures and higher detection of unruptured intracranial aneurysms, with no significant change in missed diagnoses of subarachnoid hemorrhage or bacterial meningitis. While this shift in diagnostic strategy appeared safe in the short-term, the long-term consequences remain unclear.

A refined procedure for esophageal resection using a full minimally invasive approach.

OBJECTIVE: Newer minimally invasive approaches to esophagectomy have brought substantial benefits to esophageal-cancer patients and continue to improve. We report here our experience with a streamlined procedure as part of a comprehensive perioperative-care program that provides additional advances in the continued evolution of this procedure. METHODS: All patients with primary esophageal cancer referred for resection to the Oakland Medical Center of the Kaiser-Permanente Northern California health plan who underwent this approach between January 2013 and August 2018 were included. Operative and clinical outcome variables were extracted from the electronic medical record, operating-room files, and manual chart review. RESULTS: 142 patients underwent the new procedure and care program; 121 (85.2%) were men with mean age of 64.5 years. 127 (89.4%) were adenocarcinoma; 117 (82.4%) were clinical stage III or IVA. 115 (81.0%) required no jejunostomy. Median hospital length-of-stay was 3 days and 8 (5.6%) patients required admission to the intensive care unit. Postoperative complications occurred in 22 (15.5%) patients within 30 days of the procedure. There were no inpatient deaths; one patient (0.7%) died within 30 days following discharge and three additional deaths (2.1%) occurred through 90 days of follow-up. CONCLUSIONS: This approach resulted in excellent clinical outcomes, including short hospital stays with limited need for the intensive care unit, few perioperative complications, and relatively few patients requiring feeding tubes on discharge. This comprehensive approach to esophagectomy is feasible and provides another clinically meaningful advance in the progress of minimally invasive esophagectomy. Further development and dissemination of this method is warranted.

Spinal corticosteroid injections are not associated with increased influenza risk.

BACKGROUND CONTEXT: Spinal corticosteroid injections (CSI) are often used to treat radicular and axial pain arising from the spine. Systemic corticosteroids are well known to cause immunosuppression, and locally injected spinal CSI are known to have some systemic absorption. However, it is unknown whether spinal CSI increases the risk of systemic viral infections, such as influenza. PURPOSE: To determine whether spinal CSI causes an increased risk for influenza infection and whether they reduce the protective effect of vaccination STUDY DESIGN/SETTING: A retrospective cohort study was performed at Kaiser Permanente Northern California, a large healthcare system with a diverse population. PATIENT SAMPLE: Adults (n=60,880) who received a spinal CSI during influenza seasons from 2016 to 2019. A comparison was made with 121,760 case-matched individuals who did not receive a spinal CSI. OUTCOME MEASURES: The primary outcome was odds of influenza diagnosis following spinal CSI compared with case-matched controls. Secondary analysis examined odds of influenza diagnosis based on vaccination status, multiple same-day injections, and epidural versus non-epidural route of injection. METHODS: The electronic health record and associated research databases were analyzed to identify patients who received a spinal CSI during three consecutive flu seasons, 2016 through 2019. Injections were stratified into epidural versus non-epidural CSI and single injections versus multiple same-day injections. Additionally, the rate of influenza in vaccinated versus non-vaccinated individuals was examined. Inpatient flu diagnosis was used as a proxy for severe disease. After case matching was completed, odds ratios for flu diagnosis were calculated using a logistical regression model. RESULTS: The odds of flu diagnosis following spinal CSI were not increased compared with controls (OR 0.93 [0.87-1.01, 95% Wald CL]). For epidural CSI the OR was 0.91 (0.83-1.00, 95% Wald CL), and non-epidural it was 1.00 (0.89-1.13, 95% Wald CL). There were similar findings for multiple same-day injections and when looking at inpatient flu diagnosis. For vaccinated individuals, the OR for flu following spinal CSI was 0.86 (0.80-0.92, 95% Wald CL), which indicates a protective effect in these patients. CONCLUSIONS: Spinal CSI did not increase the odds of subsequently receiving a diagnosis of influenza, regardless of vaccination status, location of injection, single versus multiple same-day injection, or co-morbidity. Vaccination had a protective effect against influenza, and this was not adversely affected by receiving spinal CSI during the flu season.

Race-Specific Trends in Prostate Cancer Screening and Presentation before and after the 2012 United States Preventive Services Task Force Statement.

INTRODUCTION: Our goal was to assess temporal changes in the race-specific rates of prostate specific antigen (PSA) screening, prostate biopsy, overall prostate cancer detection and metastatic cancer at presentation among screen-eligible men in Kaiser Permanente Northern California before and after the 2012 United States Preventive Services Task Force Prostate Cancer Screening Statement. METHODS: This was a retrospective study spanning the years 2006 to 2017 in screen-eligible Kaiser Permanente Northern California members (Black men ages 45-69, all other men ages 50-69) with no history of prostate cancer. We compared the race-specific biennial rates of PSA testing, prostate biopsy, overall prostate cancer incidence and metastatic cancer at presentation. RESULTS: A total of 422,664 to 567,660 men per biennial period were evaluated (72% White, 8% Black, 20% Asian). Following the 2012 United States Preventive Services Task Force statement, all races experienced similar declines in screening (22%-25%), biopsy (47%-57%) and overall cancer detection (34%-48%) rates. We found an increase in metastatic rates (39%-105%). CONCLUSIONS: Following the 2012 United States Preventive Services Task Force Statement, in men under the age of 70, PSA screening, biopsy and overall prostate cancer detection rates significantly decreased in a similar fashion across all races, while rates of metastatic disease significantly increased in all races.

New and sex-specific migraine susceptibility loci identified from a multiethnic genome-wide meta-analysis.

Migraine is a common disabling primary headache disorder that is ranked as the most common neurological cause of disability worldwide. Women present with migraine much more frequently than men, but the reasons for this difference are unknown. Migraine heritability is estimated to up to 57%, yet much of the genetic risk remains unaccounted for, especially in non-European ancestry populations. To elucidate the etiology of this common disorder, we conduct a multiethnic genome-wide association meta-analysis of migraine, combining results from the GERA and UK Biobank cohorts, followed by a European-ancestry meta-analysis using public summary statistics. We report 79 loci associated with migraine, of which 45 were novel. Sex-stratified analyses identify three additional novel loci (CPS1, PBRM1, and SLC25A21) specific to women. This large multiethnic migraine study provides important information that may substantially improve our understanding of the etiology of migraine susceptibility.

Association of COA1 with Patellar Tendonitis: A Genome-wide Association Analysis.

PURPOSE: It is unknown why some athletes develop patellar tendinopathy and others do not, even when accounting for similar workloads between individuals. Genetic differences between these two populations may be a contributing factor. The purpose of this work was to screen the entire genome for genetic markers associated with patellar tendinopathy. METHODS: Genome-wide association (GWA) analyses were performed utilizing data from the Kaiser Permanente Research Board (KPRB) and the UK Biobank. Patellar tendinopathy cases were identified based on electronic health records from KPRB and UK Biobank. GWA analyses from both cohorts were tested for patellar tendinopathy using a logistic regression model adjusting for sex, height, weight, age, and race/ethnicity using allele counts for single nucleotide polymorphisms. The data from the two GWA studies (KPRB and UK Biobank) were combined in a meta-analysis. RESULTS: There were a total of 1670 cases of patellar tendinopathy and 293,866 controls within the two cohorts. Two single nucleotide polymorphisms located in the intron of the cytochrome c oxidase assembly factor 1 (COA1) gene showed a genome-wide significant association in the meta-analysis. CONCLUSIONS: Genetic markers in COA1 seem to be associated with patellar tendinopathy and are potential risk factors for patellar tendinopathy that deserve further validation regarding molecular mechanisms.

Prospective validation of the Kaiser Permanente prostate cancer risk calculator in a contemporary, racially diverse, referral population.

PURPOSE: To prospectively validate a new prostate cancer risk calculator in a racially diverse population. MATERIALS AND METHODS: We recently developed, internally validated and published the Kaiser Permanente Prostate Cancer Risk Calculator. This study is a prospective validation of the calculator in a separate, referral population over a 21-month period. All patients were tested with a uniform PSA assay and a standardized systematic, ultrasound-guided biopsy scheme. We report on 3 calculator models: Model 1 included age, race, PSA, prior biopsy status, body mass index, and family history of prostate cancer; Model 2 added digital rectal exam to Model 1 variables; Model 3 added prostate volume to Model 2 variables. We considered three outcomes: high-grade disease (Gleason score ≥7), low-grade disease (Gleason score=6), and no cancer. Predictive discrimination and calibration were calculated. How each model might alter biopsy frequency and outcomes at various thresholds of risk was assessed. We compared the performance of our calculator with two other calculators. RESULTS: In 4178 patients (16.2% Asian, 11.3% African American, 13.5% Hispanic), cancer was found in 53%; 62% were Gleason score ≥7. Using a high-grade risk threshold for biopsy of ≥10%, Model 2 predictions would result in 9% of men avoiding a biopsy, while only missing 2% of high-grade cancers. At the same threshold, Model 3 predictions would result in 26% of men avoiding a biopsy, while only missing 5% of high-grade cancers. The c-statistics for Models 1, 2, and 3 to predict high-grade disease vs. low-grade or no cancer were 0.76, 0.79 and 0.85, respectively. The c-statistics for Models 1, 2, and 3 to predict any prostate cancer vs. no cancer were 0.70, 0.72 and 0.80, respectively. All models were well calibrated for all outcomes. Our Model 3 calculator had superior discrimination for high grade disease (c-statistic=0.85, 0.84-0.86) and any cancer (0.80, 0.79-0.82) compared to the PBCG calculator [(0.79, 0.78-0.80); 0.72 (0.70-0.73)] and the PCPT calculator [(0.75, 0.74-0.77); 0.69 (0.67-0.70)], respectively. In the high-grade cancer predicted risk range of 0-30%, our Model 2 was better calibrated than the PCPT and PBCG calculators. CONCLUSIONS: This validation of our calculator showed excellent performance characteristics.

Closing the gap: Identification and management of familial hypercholesterolemia in an integrated healthcare delivery system.

BACKGROUND: Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder that causes markedly elevated risk for early onset coronary artery disease. Despite availability of effective therapy, only 5-10% of affected individuals worldwide are diagnosed. OBJECTIVE: To develop and evaluate a novel approach for identifying and managing patients with FH in a large integrated health system with a diverse patient population, using inexpensive methods. METHODS: Using Make Early Diagnosis/Prevent Early Death (MEDPED) criteria, we created a method for identifying patients at high risk for FH within the Kaiser Permanente Northern California electronic medical record. This led to a pragmatic workflow for contacting patients, establishing a diagnosis in a dedicated FH clinic, and initiating management. We prospectively collected data on the first 100 patients to assess implementation effectiveness. RESULTS: Ninety-three (93.0%, 95%CI: 86.1%-97.1%) of the first 100 evaluated patients were diagnosed with FH (median age = 38 years) of whom only 5% were previously recognized; 48% were taking no lipid-lowering therapy, and 7% had acute coronary symptoms. 82 underwent successful genetic testing of whom 55 (67.1%; 95%CI: 55.8%-77.1%) had a pathogenic mutation. Following clinic evaluation, 83 of 85 (97.6%) medication-eligible patients were prescribed combination lipid-lowering therapy. 20 family members in the healthcare system were diagnosed with FH through cascade testing. CONCLUSIONS: This novel approach was effective for identifying and managing patients with undiagnosed FH. Care gaps in providing appropriate lipid-lowering therapy were successfully addressed. Further development and dissemination of integrated approaches to FH care are warranted.

A Genome-wide Association Study for Concussion Risk.

PURPOSE: This study aimed to screen the entire genome for genetic markers associated with risk for concussion. METHODS: A genome-wide association analyses was performed using data from the Kaiser Permanente Research Bank and the UK Biobank. Concussion cases were identified based on electronic health records from the Kaiser Permanente Research Bank and the UK Biobank from individuals of European ancestry. Genome-wide association analyses from both cohorts were tested for concussion using a logistic regression model adjusting for sex, height, weight, and race/ethnicity using allele counts for single nucleotide polymorphisms. Previously identified genes within the literature were also tested for association with concussion. RESULTS: There were a total of 4064 cases of concussion and 291,472 controls within the databases, with two single nucleotide polymorphisms demonstrating a genome-wide significant association with concussion. The first polymorphism, rs144663795 (P = 9.7 × 10-11; OR = 2.91 per allele copy), is located within the intron of SPATA5. Strong, deleterious mutations in SPATA5 cause intellectual disability, hearing loss, and vision loss. The second polymorphism, rs117985931 (P = 3.97 × 10-9; OR = 3.59 per allele copy), is located within PLXNA4. PLXNA4 plays a key role is axon outgrowth during neural development, and DNA variants in PLXNA4 are associated with risk for Alzheimer's disease. Previous investigations have identified five candidate genes that may be associated with concussion, but none showed a significant association in the current model (P < 0.05). CONCLUSION: Two genetic markers were identified as potential risk factors for concussion and deserve further validation and investigation of molecular mechanisms.

Risk Factors for Conversion of Hip Arthroscopy to Total Hip Arthroplasty: A Large Closed-Cohort Study.

PURPOSE: To evaluate risk factors for conversion of hip arthroscopy to total hip arthroplasty (THA) within 2 years in a closed patient cohort. METHODS: This study was a case series of consecutive hip arthroscopy procedures from September 2008 to November 2018 in the electronic medical record of Kaiser Permanente Northern California. Patients were included with minimum 2-year follow-up or if they had conversion to THA within 2 years (the primary outcome) regardless of follow-up time. Patient characteristics at the time of the index arthroscopy were extracted; characteristics of patients who experienced the outcome event versus those who did not were compared by use of multivariable logistic regression models and receiver operating characteristic (ROC) curves. RESULTS: The mean follow-up time was 4.9 years (median 4.6, range 0.6 to 11.6). The mean age was 37.2 years (range 10 to 88), and 57% were female. During the follow-up period, 82 patients underwent a THA within 2 years of their arthroscopies (5.3%, 95% confidence interval 4.3% to 6.5%) after a median time of 9 months (interquartile range 5.9 to 14.4) after the initial arthroscopy. Increasing age was highly predictive of early THA conversion (area under the ROC curve = 0.78, P < .001). Although other predictors showed significant bivariable associations with early failure, body mass index (BMI), race, sex, and prior arthroscopy did not add meaningful independent predictive information. CONCLUSIONS: The risk of conversion to THA within 2 years after hip arthroscopy increased substantially with patient age at the time of the procedure. BMI, race, sex, and prior arthroscopy were not important independent predictors of conversion beyond the information contained in patient age. LEVEL OF EVIDENCE: Level IV, therapeutic case series.

Changing Provider PSA Screening Behavior Using Best Practice Advisories: Interventional Study in a Multispecialty Group Practice.

BACKGROUND: Most guidelines recommend against PSA-based screening for prostate cancer in men ≥ 70 years of age. Adherence to these guidelines is variable. OBJECTIVE: To determine whether the use of a "Best Practice Advisory" (BPA) intervention within the electronic medical record (EMR) system can alter the rate of PSA screening in men ≥ 70 years of age. DESIGN: This is an interventional study spanning the years 2013 through 2017, in men ≥ 70 years of age in Kaiser Permanente Northern California with no prior history of prostate cancer. The BPA intervention was activated in the EMR system on October 15, 2015, with no prior notice or education. SETTING: Integrated healthcare system including all Kaiser Permanente Northern California facilities. PARTICIPANTS: A population-based sample that included all male members ≥ 70 years of age without a history of prostate cancer. MAIN MEASURES: The main outcome was the rate of PSA testing in men ≥ 70 years of age. We compared the rates of PSA testing between the pre-BPA period (January 1, 2013-October 14, 2015) and the post-BPA period (October 15, 2015-December 31, 2017). An interrupted time series analysis of PSA ordering rates was performed. KEY RESULTS: Following the 2015 BPA intervention, screening rates substantially declined from 36.0 per 100 person-years to 14.9 per 100 person-years (rate ratio = 0.415; 95% CI: 0.410-0.419). The effect of the BPA was comparable among all patient races and ordering provider specialties. The interrupted time series analysis showed a rapid, large, and sustained drop in the rate of PSA ordering, and much less temporal variation in test ordering after activation of the BPA. CONCLUSION: Following activation of a BPA within the EMR, the rates of inappropriate PSA testing significantly declined by 58.5% in men ≥ 70 years of age and temporal variation was reduced.

Prospective development of a prostate cancer risk calculator in a racially diverse population: The Kaiser Permanente Prostate Cancer Risk Calculator.

PURPOSE: To prospectively develop a prostate cancer (CaP) risk calculator in a racially diverse population. MATERIALS AND METHODS: All patients referred for prostate biopsy due to an elevated prostate-specific antigen or abnormal digital rectal exam in a 19-months period at Kaiser Permanente Northern California underwent a standardized systematic, ultrasound-guided biopsy scheme (14-cores for initial biopsy, 18-20 cores for repeat biopsy). All pertinent clinical variables were prospectively collected. The highest Gleason score for each patient was recorded for all positive biopsies. We used a split sample design to develop and validate 3 multivariable prediction models using multinomial logistic regression with the least absolute shrinkage and selection operator. All models included these core variables: age, race, prostate-specific antigen, prior biopsy status, body mass index, and family history of CaP. Model 1 included only the core variables, Model 2 added digital rectal exam, and Model 3 added digital rectal exam and prostate volume. We considered 3 outcomes: high-grade disease (Gleason score ≥7), low-grade disease (Gleason score = 6), and no cancer. Predictive discrimination was quantified using the c-statistic. RESULTS: Complete data were available for 2,967 patients. Cancer was found in 50% of patients: of these, 58% were Gleason score ≥7 and 42% were low grade. Compared to Caucasians, African Americans were at a higher risk while Asians and Hispanics were at a lower risk for overall and high-grade cancer detection. The number of prior negative biopsies was also protective for these outcomes. The c-statistics for Model 1, 2, and 3 to predict high-grade disease vs. low-grade or no cancer were 0.76, 0.79, and 0.85, respectively. The c-statistics for Model 1, 2, and 3 to predict any CaP vs. no cancer were 0.69, 0.70, and 0.79, respectively. All models were well calibrated for all outcomes. CONCLUSIONS: In men with elevated PSA levels, our calculator provides useful information that may enhance the shared decision-making process regarding the need for biopsy.

Changes in Prostate Cancer Presentation Following the 2012 USPSTF Screening Statement: Observational Study in a Multispecialty Group Practice.

BACKGROUND: In 2012, the US Preventive Services Task Force (USPSTF) recommended against PSA-based screening for prostate cancer in men of all ages. Following this change, screening declined yet the complete impact on clinical presentation is not well defined in the screen-eligible population. OBJECTIVE: To determine if the rates of PSA screening, prostate biopsy, incident prostate cancer detection, and stage IV at presentation in screen-eligible men in Kaiser Permanente Northern California changed following the 2012 USPSTF Prostate Cancer Screening recommendations. DESIGN: Retrospective study spanning the years 2010 to 2015, in screen-eligible Kaiser Permanente Northern California members (African American men ages 45-69 and all other men ages 50-69) with no prior history of prostate cancer. Participants All screen-eligible, male members during 2010 (n = 403,931) to 2015 (n = 483,286) without a history of prostate cancer within all Kaiser Permanente Northern California facilities. MAIN MEASURES: Annual rates of PSA testing, prostate biopsy, incident prostate cancer detection, and stage IV cancer at presentation were compared between the pre-guideline period, 2010 and 2011, and the post-guideline period, 2014 and 2015, in men under the age of 70. KEY RESULTS: Following the 2012 USPSTF guideline change, screening rates declined 23.4% (95% CI 23.0-23.8%), biopsy rates declined 64.3% (95% CI 62.9-65.6%), and incident prostate cancer detection rates declined 53.5% (95% CI 50.1-56.7%) resulting in 1871 fewer incident cancers detected, and metastatic cancer rates increased 36.9% (95% CI 9.5-71.0%) resulting in 75 more stage IV cancers detected. CONCLUSION: Less screening resulted in a large decrease in cancer detection, some of which may be beneficial as many cancers may be indolent, yet this decrease occurred at the expense of an increase in metastatic cancer rates. For every 25 fewer cancers detected, one metastatic cancer was diagnosed. This information may be valuable in the shared decision-making process around prostate cancer screening.