Retrospective cohort study to assess the association between treatment with tocilizumab and mortality among mechanically ventilated patients with COVID-19.

OBJECTIVES: Assess the association between tocilizumab administration and clinical outcomes among mechanically ventilated patients with COVID-19 pneumonia. DESIGN: Retrospective cohort study. SETTING: Large integrated health system with 9 million members in California, USA. PARTICIPANTS: 4185 Kaiser Permanente members hospitalised with COVID-19 pneumonia requiring invasive mechanical ventilation (IMV). INTERVENTIONS: Receipt of tocilizumab within 10 days of initiation of IMV. OUTCOME MEASURES: Using a retrospective cohort of consecutive patients hospitalised with COVID-19 pneumonia who required IMV in a large integrated health system in California, USA, we assessed the association between tocilizumab administration and 28-day mortality, time to extubation from IMV and time to hospital discharge. RESULTS: Among 4185 patients, 184 received tocilizumab and 4001 patients did not receive tocilizumab within 10 days of initiation of IMV. After inverse probability weighting, baseline characteristics were well balanced between groups. Patients treated with tocilizumab had a similar risk of death in the 28 days after intubation compared with patients not treated with tocilizumab (adjusted HR (aHR), 1.21, 95% CI 0.98 to 1.50), but did have a significantly longer time-to-extubation (aHR 0.71; 95% CI 0.57 to 0.88) and time-to-hospital-discharge (aHR 0.66; 95% CI 0.50 to 0.88). However, patients treated with tocilizumab ≤2 days after initiation of IMV had a similar risk of mortality (aHR 1.47; 95% CI 0.96 to 2.26), but significantly shorter time-to-extubation (aHR 0.37; 95% CI 0.23 to 0.58) and time-to-hospital-discharge (aHR 0.31; 95% CI CI 0.17 to 0.56) compared with patients treated with tocilizumab 3-10 days after initiation of IMV. CONCLUSIONS: Among mechanically ventilated patients with COVID-19, the risk of death in the 28-day follow-up period was similar, but time-to-extubation and time-to-hospital-discharge were longer in patients who received tocilizumab within 10 days of initiation of IMV compared with patients who did not receive tocilizumab.

Association of Physician Adenoma Detection Rates With Postcolonoscopy Colorectal Cancer.

Importance: Although colonoscopy is frequently performed in the United States, there is limited evidence to support threshold values for physician adenoma detection rate as a quality metric. Objective: To evaluate the association between physician adenoma detection rate values and risks of postcolonoscopy colorectal cancer and related deaths. Design, Setting, and Participants: Retrospective cohort study in 3 large integrated health care systems (Kaiser Permanente Northern California, Kaiser Permanente Southern California, and Kaiser Permanente Washington) with 43 endoscopy centers, 383 eligible physicians, and 735 396 patients aged 50 to 75 years who received a colonoscopy that did not detect cancer (negative colonoscopy) between January 2011 and June 2017, with patient follow-up through December 2017. Exposures: The adenoma detection rate of each patient's physician based on screening examinations in the calendar year prior to the patient's negative colonoscopy. Adenoma detection rate was defined as a continuous variable in statistical analyses and was also dichotomized as at or above vs below the median for descriptive analyses. Main Outcomes and Measures: The primary outcome (postcolonoscopy colorectal cancer) was tumor registry-verified colorectal adenocarcinoma diagnosed at least 6 months after any negative colonoscopy (all indications). The secondary outcomes included death from postcolonoscopy colorectal cancer. Results: Among 735 396 patients who had 852 624 negative colonoscopies, 440 352 (51.6%) were performed on female patients, median patient age was 61.4 years (IQR, 55.5-67.2 years), median follow-up per patient was 3.25 years (IQR, 1.56-5.01 years), and there were 619 postcolonoscopy colorectal cancers and 36 related deaths during more than 2.4 million person-years of follow-up. The patients of physicians with higher adenoma detection rates had significantly lower risks for postcolonoscopy colorectal cancer (hazard ratio [HR], 0.97 per 1% absolute adenoma detection rate increase [95% CI, 0.96-0.98]) and death from postcolonoscopy colorectal cancer (HR, 0.95 per 1% absolute adenoma detection rate increase [95% CI, 0.92-0.99]) across a broad range of adenoma detection rate values, with no interaction by sex (P value for interaction = .18). Compared with adenoma detection rates below the median of 28.3%, detection rates at or above the median were significantly associated with a lower risk of postcolonoscopy colorectal cancer (1.79 vs 3.10 cases per 10 000 person-years; absolute difference in 7-year risk, -12.2 per 10 000 negative colonoscopies [95% CI, -10.3 to -13.4]; HR, 0.61 [95% CI, 0.52-0.73]) and related deaths (0.05 vs 0.22 cases per 10 000 person-years; absolute difference in 7-year risk, -1.2 per 10 000 negative colonoscopies [95%, CI, -0.80 to -1.69]; HR, 0.26 [95% CI, 0.11-0.65]). Conclusions and Relevance: Within 3 large community-based settings, colonoscopies by physicians with higher adenoma detection rates were significantly associated with lower risks of postcolonoscopy colorectal cancer across a broad range of adenoma detection rate values. These findings may help inform recommended targets for colonoscopy quality measures.

Proton Pump Inhibitor Use and Risk of Gastric, Colorectal, Liver, and Pancreatic Cancers in a Community-Based Population.

INTRODUCTION: Proton pump inhibitors (PPIs) are commonly used for gastrointestinal disorders; given they increase the systemic levels of gastrin, a trophic hormone, there is a concern about their carcinogenicity. This study evaluated the association between PPI use and gastrointestinal cancers. METHODS: We performed a nested case-control study in a large, community-based integrated healthcare setting. Cases were adults with gastric (n = 1,233), colorectal (n = 18,595), liver (n = 2,329), or pancreatic cancers (n = 567). Each case was matched with up to 10 controls by age, sex, race/ethnicity, medical facility, and enrollment duration. The primary exposure was defined as ≥2-year cumulative PPI supply. Data were obtained from pharmacy, cancer registry, and electronic medical record databases. Associations were evaluated using conditional logistic regression and adjusted for multiple confounders. We also evaluated the cancer risks separately by PPI dose, duration of use, and dose and duration. RESULTS: PPI use of ≥2-years was not associated with the risks of gastric (odds ratio [OR]: 1.07, 95% confidence interval [CI]: 0.81-1.42), colorectal (OR: 1.05, 95% CI: 0.99-1.12), liver (OR: 1.14, 95% CI: 0.91-1.43), or pancreatic cancers (OR: 1.22, 95% CI: 0.89-1.67), compared to non-users. In exploratory analyses, elevated cancer risks were primarily restricted to those with ≥10 years of PPI use, but no consistent associations were found for increasing PPI dose and/or duration of use. DISCUSSION: PPI use of ≥2 years was not associated with increased risks of gastrointestinal cancers. The cancer risks associated with PPI use of ≥10 years requires further study.

Long-term Risk of Colorectal Cancer and Related Death After Adenoma Removal in a Large, Community-based Population.

BACKGROUND & AIMS: The long-term risks of colorectal cancer (CRC) and CRC-related death following adenoma removal are uncertain. Data are needed to inform evidence-based surveillance guidelines, which vary in follow-up recommendations for some polyp types. Using data from a large, community-based integrated health care setting, we examined the risks of CRC and related death by baseline colonoscopy adenoma findings. METHODS: Participants at 21 medical centers underwent baseline colonoscopies from 2004 through 2010; findings were categorized as no-adenoma, low-risk adenoma, or high-risk adenoma. Participants were followed until the earliest of CRC diagnosis, death, health plan disenrollment, or December 31, 2017. Risks of CRC and related deaths among the high- and low-risk adenoma groups were compared with the no-adenoma group using Cox regression adjusting for confounders. RESULTS: Among 186,046 patients, 64,422 met eligibility criteria (54.3% female; mean age, 61.6 ± 7.1 years; median follow-up time, 8.1 years from the baseline colonoscopy). Compared with the no-adenoma group (45,881 patients), the high-risk adenoma group (7563 patients) had a higher risk of CRC (hazard ratio [HR] 2.61; 95% confidence interval [CI] 1.87-3.63) and related death (HR 3.94; 95% CI 1.90-6.56), whereas the low-risk adenoma group (10,978 patients) did not have a significant increase in risk of CRC (HR 1.29; 95% CI 0.89-1.88) or related death (HR 0.65; 95% CI 0.19-2.18). CONCLUSIONS: With up to 14 years of follow-up, high-risk adenomas were associated with an increased risk of CRC and related death, supporting early colonoscopy surveillance. Low-risk adenomas were not associated with a significantly increased risk of CRC or related deaths. These results can inform current surveillance guidelines for high- and low-risk adenomas.

Long-term Risk of Colorectal Cancer and Related Deaths After a Colonoscopy With Normal Findings.

Importance: Guidelines recommend a 10-year rescreening interval after a colonoscopy with normal findings (negative colonoscopy results), but evidence supporting this recommendation is limited. Objective: To examine the long-term risks of colorectal cancer and colorectal cancer deaths after a negative colonoscopy result, in comparison with individuals unscreened, in a large, community-based setting. Design, Setting, and Participants: A retrospective cohort study was conducted in an integrated health care delivery organization serving more than 4 million members across Northern California. A total of 1 251 318 average-risk screening-eligible patients (age 50-75 years) between January 1, 1998, and December 31, 2015, were included. The study was concluded on December 31, 2016. Exposures: Screening was examined as a time-varying exposure; all participants contributed person-time unscreened until they were either screened or censored. If the screening received was a negative colonoscopy result, the participants contributed person-time in the negative colonoscopy results group until they were censored. Main Outcomes and Measures: Using Cox proportional hazards regression models, the hazard ratios (HRs) for colorectal cancer and related deaths were calculated according to time since negative colonoscopy result (or since cohort entry for those unscreened). Hazard ratios were adjusted for age, sex, race/ethnicity, Charlson comorbidity score, and body mass index. Results: Of the 1 251 318 patients, 613 692 were men (49.0%); mean age was 55.6 (7.0) years. Compared with the unscreened participants, those with a negative colonoscopy result had a reduced risk of colorectal cancer and related deaths throughout the more than 12-year follow-up period, and although reductions in risk were attenuated with increasing years of follow-up, there was a 46% lower risk of colorectal cancer (hazard ratio, 0.54; 95% CI, 0.31-0.94) and 88% lower risk of related deaths (hazard ratio, 0.12; 95% CI, 0.02-0.82) at the current guideline-recommended 10-year rescreening interval. Conclusions and Relevance: A negative colonoscopy result in average-risk patients was associated with a lower risk of colorectal cancer and related deaths for more than 12 years after examination, compared with unscreened patients. Our study findings may be able to inform guidelines for rescreening after a negative colonoscopy result and future studies to evaluate the costs and benefits of earlier vs later rescreening intervals.

Vaccination Patterns in Children After Autism Spectrum Disorder Diagnosis and in Their Younger Siblings.

Importance: In recent years, rates of vaccination have been declining. Whether this phenomenon disproportionately affects children with autism spectrum disorder (ASD) or their younger siblings is unknown. Objectives: To investigate if children after receiving an ASD diagnosis obtain their remaining scheduled vaccines according to the Advisory Committee on Immunization Practices (ACIP) recommendations and to compare the vaccination patterns of younger siblings of children with ASD with the vaccination patterns of younger siblings of children without ASD. Design, Setting, and Participants: This investigation was a retrospective matched cohort study. The setting was 6 integrated health care delivery systems across the United States within the Vaccine Safety Datalink. Participants were children born between January 1, 1995, and September 30, 2010, and their younger siblings born between January 1, 1997, and September 30, 2014. The end of follow-up was September 30, 2015. Exposures: Recommended childhood vaccines between ages 1 month and 12 years. Main Outcome and Measure: The proportion of children who received all of their vaccine doses according to ACIP recommendations. Results: The study included 3729 children with ASD (676 [18.1%] female), 592 907 children without ASD, and their respective younger siblings. Among children without ASD, 250 193 (42.2%) were female. For vaccines recommended between ages 4 and 6 years, children with ASD were significantly less likely to be fully vaccinated compared with children without ASD (adjusted rate ratio, 0.87; 95% CI, 0.85-0.88). Within each age category, vaccination rates were significantly lower among younger siblings of children with ASD compared with younger siblings of children without ASD. The adjusted rate ratios varied from 0.86 for siblings younger than 1 year to 0.96 for those 11 to 12 years old. Parents who had a child with ASD were more likely to refuse at least 1 recommended vaccine for that child's younger sibling and to limit the number of vaccines administered during the younger sibling's first year of life. Conclusions and Relevance: Children with ASD and their younger siblings were undervaccinated compared with the general population. The results of this study suggest that children with ASD and their younger siblings are at increased risk of vaccine-preventable diseases.

Adenoma detection rate and risk of colorectal cancer and death.

BACKGROUND: The proportion of screening colonoscopic examinations performed by a physician that detect one or more adenomas (the adenoma detection rate) is a recommended quality measure. However, little is known about the association between this rate and patients' risks of a subsequent colorectal cancer (interval cancer) and death. METHODS: Using data from an integrated health care delivery organization, we evaluated the associations between the adenoma detection rate and the risks of colorectal cancer diagnosed 6 months to 10 years after colonoscopy and of cancer-related death. With the use of Cox regression, our estimates of attributable risk were adjusted for the demographic characteristics of the patients, indications for colonoscopy, and coexisting conditions. RESULTS: We evaluated 314,872 colonoscopies performed by 136 gastroenterologists; the adenoma detection rates ranged from 7.4 to 52.5%. During the follow-up period, we identified 712 interval colorectal adenocarcinomas, including 255 advanced-stage cancers, and 147 deaths from interval colorectal cancer. The unadjusted risks of interval cancer according to quintiles of adenoma detection rates, from lowest to highest, were 9.8, 8.6, 8.0, 7.0, and 4.8 cases per 10,000 person-years of follow-up, respectively. Among patients of physicians with adenoma detection rates in the highest quintile, as compared with patients of physicians with detection rates in the lowest quintile, the adjusted hazard ratio for any interval cancer was 0.52 (95% confidence interval [CI], 0.39 to 0.69), for advanced-stage interval cancer, 0.43 (95% CI, 0.29 to 0.64), and for fatal interval cancer, 0.38 (95% CI, 0.22 to 0.65). Each 1.0% increase in the adenoma detection rate was associated with a 3.0% decrease in the risk of cancer (hazard ratio, 0.97; 95% CI, 0.96 to 0.98). CONCLUSIONS: The adenoma detection rate was inversely associated with the risks of interval colorectal cancer, advanced-stage interval cancer, and fatal interval cancer. (Funded by the Kaiser Permanente Community Benefit program and the National Cancer Institute.).

Birthplace and mortality among insured Latinos: the paradox revisited.

OBJECTIVES: We investigated the Latino paradox in a managed care setting and examined the role of birthplace. METHODS: We evaluated 133,155 non-Latino Whites and 5,237 Latinos (36% born in the United States, 34% in Central and South America, 21% in Mexico, and 8% in the Caribbean Islands) who were enrolled in an integrated healthcare delivery system in northern California. Baseline data were from 1964-1973, and the median followup was 34 years. Main outcome measures were cause-specific and all-cause mortality. RESULTS: In fully-adjusted analyses, and compared with non-Latino Whites, the risk of death from circulatory causes was significantly lower among US-born Latinos (hazard ratio [HR] .79, 95% confidence interval [CI] .66-.93), among Central and South America-born Latinos (HR .76, 95% CI .63-.91), and Caribbean-born Latinos (HR .66, 95% CI .47-0.93). Risk of death by malignant neoplasms was significantly lower among US-born Latinos (HR .68, 95% CI .56-.83). Risk of respiratory death was significantly lower among Central and South America-born Latinos (HR .50, 95% CI .32-.80). All-cause mortality risk was significantly decreased in US-born Latinos (HR .79, 95% CI .71-.87), Central and South America-born Latinos (HR .81, 95% CI .73-.90), and Caribbean-born Latinos (HR .76, 95% CI .63-.93) but not in Mexico-born Latinos. CONCLUSIONS: In our managed care setting, the Latino paradox phenomenon varied by birthplace; it was more evident among US-born Latinos. This subgroup experienced lower circulatory, cancer, and all-cause mortality than did non-Latino Whites, despite higher prevalences of current smoking, obesity, and asymptomatic hyperglycemia.

Risk adjusting community-acquired pneumonia hospital outcomes using automated databases.

OBJECTIVE: To describe the development and assessment of the Abbreviated Fine Severity Score (AFSS), a simplified version of the Pneumonia Severity Index (PSI) suitable for providing risk-adjusted reports to clinicians caring for patients hospitalized with community-acquired pneumonia. STUDY DESIGN: Retrospective cohort study. METHODS: We defined the AFSS based on data available in administrative and laboratory databases. We downloaded and linked these hospitalization and laboratory data from 2 cohorts (11,030 patients and 6147 patients) hospitalized with community-acquired pneumonia in all Kaiser Permanente Medical Care Program hospitals in northern California. We then assessed the relationship between the AFSS and mortality, length of stay, intensive care unit admission, and the use of assisted ventilation. Using logistic regression analysis, we assessed the performance of the AFSS and determined the area under the receiver operating characteristic curve (c statistic). Using a combination of manual and electronic medical record review, we compared the AFSS with the full PSI in 2 subsets of patients in northern California and Denver, Colorado, whose medical records were manually reviewed. RESULTS: The AFSS compares favorably with the PSI with respect to predicting mortality. It has good discrimination with respect to inhospital (c = 0.74) and 30-day (c = 0.75) mortality. It also correlates strongly with the PSI (r = 0.87 and r = 0.93 in the 2 medical record review subsets). CONCLUSIONS: The AFSS can be used to provide clinically relevant risk-adjusted outcomes reports to clinicians in an integrated healthcare delivery system. It is possible to apply risk-adjustment methods from research settings to operational ones.

Case-control study of antibiotic use and subsequent Clostridium difficile-associated diarrhea in hospitalized patients.

OBJECTIVE: To determine which antibiotics increase or decrease the risk of Clostridium difficile-associated diarrhea (CDAD). DESIGN: Retrospective case-control study. SETTING: Nonprofit, integrated healthcare delivery system in Northern California. PATIENTS: Study participants included patients with cases of hospital-acquired CDAD that occurred during the period from 1999 through 2005 (n=1,142) and control patients (n= 3,351) matched for facility, calendar quarter during which hospitalization occurred, diagnosis related group for the index hospitalization, and length of hospital stay. All case and control patients had received antibiotics in the 60 days before the index date. For each antibiotic, the risk of CDAD was examined in relation to whether the patient received the antibiotic, after adjustment for use of other antibiotics, demographic characteristics, selected health conditions, and use of healthcare services. RESULTS: The following antibiotics were associated with a significantly increased risk of acquiring CDAD: imipenem-cilastin (odds ratio [OR], 2.77), clindamycin (OR, 2.31), cefuroxime (OR, 2.16), moxifloxacin (OR, 1.88), ceftazidime (OR, 1.82), cefpodoxime (OR, 1.58), ceftizoxime (OR, 1.57), and ceftriaxone (OR, 1.49). Metronidazole and doxycycline were associated with a significantly reduced risk of CDAD (OR for metronidazole, 0.67; OR for doxycycline, 0.41). Other factors associated with an increased risk of CDAD were older age, longer hospital stays, use of proton pump inhibitors, prior gastrointestinal disease, and prior infection (not including C. difficile infection.) CONCLUSIONS: Some antibiotics appear to increase the risk of acquiring CDAD, notably clindamycin, third-generation cephalosporins, and carbapenems, whereas metronidazole and doxycycline appear to be protective, compared with other antibiotics.

Traditional and novel risk factors for clinically diagnosed abdominal aortic aneurysm: the Kaiser multiphasic health checkup cohort study.

BACKGROUND: Identification of risk factors for and early diagnosis of clinically significant abdominal aortic aneurysm (AAA) before rupture is vital to optimize outcomes in these patients. Our aim was to examine traditional and three novel potential risk factors (abdominal obesity, white blood cell count, and kidney function) for abdominal aortic aneurysm (AAA, comprising discharge diagnosis or surgical repair) in a large multiethnic population. METHODS: Cohort study (N =104,813) conducted at an integrated health care delivery system in northern California. RESULTS: After a median of 13 years, 605 AAA events (490 in men and 115 in women; 91 [15%] fatal) were observed. In multivariable analysis, factors significantly associated with risk of clinically detected AAA included male gender, older age, black race (inversely), low educational attainment, cigarette smoking (with dose-response relation), height, treated and untreated hypertension, high total serum cholesterol, elevated white blood cell count, known coronary artery disease, history of intermittent claudication, and reduced kidney function. A significant Asian race by gender interaction was found such that Asian race had a (borderline significant) protective association with AAA in men but not in women. CONCLUSIONS: Our findings confirm that major atherosclerotic risk factors, except for diabetes and obesity, are also prospectively related to AAA and suggest that elevated white blood cell count and reduced kidney function may improve risk stratification for clinically relevant AAA.