Ocrelizumab treatment for relapsing-remitting multiple sclerosis after a suboptimal response to previous disease-modifying therapy: A nonrandomized controlled trial.

BACKGROUND: Many patients with multiple sclerosis (MS) experience suboptimal disease control despite the use of disease-modifying therapy (DMT). OBJECTIVE: To assess the efficacy and safety of ocrelizumab (OCR) in patients with relapsing-remitting MS (RRMS) and suboptimal response to prior DMTs. METHODS: Patients with RRMS and suboptimal responses (one clinically reported relapse and/or lesion activity) after ⩾ 6 months on another DMT were enrolled. OCR 600 mg was given intravenously every 24 weeks. The primary outcome was no evidence of disease activity (NEDA), defined as the absence of protocol-defined relapse, confirmed disability progression (CDP), T1 Gd-enhancing lesions, and new/enlarging T2 lesions. RESULTS: The intention-to-treat (ITT) population included 608 patients; NEDA was analyzed in a modified ITT (mITT) population (n = 576 (94.7%)). Over 96 weeks, 48.1% of mITT patients achieved NEDA, and most were free from protocol-defined relapse (89.6%), CDP (89.6%), and T1 Gd-enhancing lesions (95.5%); 59.5% had no new/enlarging T2 lesions. Safety observations were consistent with findings in the pivotal trials. CONCLUSION: Consistent efficacy of OCR on clinical and magnetic resonance imaging (MRI) disease activity measures and progression was shown in patients with RRMS and a suboptimal response to prior DMTs; no new safety signals were observed.

One- and Two-Year Analysis of a Five-Year Prospective Multicenter Study Assessing Radiographic and Patient-Reported Outcomes Following Triplanar First Tarsometatarsal Arthrodesis With Early Weightbearing for Symptomatic Hallux Valgus.

We report one- and 2-year results of a prospective, 5-year, multicenter study of radiographic, clinical, and patient-reported outcomes following triplanar first tarsometatarsal arthrodesis with early weightbearing. One-hundred and seventeen patients were included with a mean (95% confidence interval [CI]) follow-up time of 16.6 (15.5, 17.7) months. Mean (95% CI) time to weightbearing in a boot walker was 7.8 (6.6, 9.1) days, mean time to return to athletic shoes was 45.0 (43.5, 46.6) days, and mean time to return to unrestricted activity was 121.0 (114.5, 127.5) days. There was a significant improvement in radiographic measures with a mean corrective change of -18.0° (-19.6, -16.4) for hallux valgus angle, -8.3° (-8.9, -7.8) for intermetatarsal angle and -2.9 (-3.2, -2.7) for tibial sesamoid position at 12 months (n = 108). Additionally, there was a significant improvement in patient-reported outcomes (Visual Analog Scale, Manchester-Oxford Foot Questionnaire, and Patient-Reported Outcomes Measurement Information System) and changes were maintained at 12 and 24 months postoperatively. There was 1/117 (0.9%) reported recurrence of hallux valgus at 12 months. There were 16/117 (13.7%) subjects who experienced clinical complications of which 10/117 (8.5%) were related to hardware. Of the 7/117 (6.0%) who underwent reoperation, only 1/117 (0.9%) underwent surgery for a nonunion. The results of the interim report of this prospective, multicenter study demonstrate favorable clinical and radiographic improvement of the HV deformity, early return to weightbearing, low recurrence, and low rate of complications.

Serum Acetaminophen Protein Adduct Concentrations in Pediatric Emergency Department Patients.

OBJECTIVES: Acetaminophen toxicity is a common cause of pediatric liver failure. The diagnosis may be limited by the short window of detection of acetaminophen in serum. Recently acetaminophen protein adducts (APAP-CYS) have been used as a biomarker with a longer duration of detection. The objective of this study was to describe the serum concentrations of APAP-CYS in pediatric patients with and without reported therapeutic acetaminophen exposure. METHODS: A cross-sectional study of children age 1 to <12 years presenting to a pediatric emergency department. Subjects were stratified by recent acetaminophen use and had serum APAP-CYS measured using LC/MS. RESULTS: One hundred patients were enrolled. All of the patients whose caregivers denied acetaminophen exposure had nondetectable APAP-CYS. Fifty-two percent of subjects who were reported to have taken acetaminophen in the preceding 2 weeks had detectable serum APAP-CYS. The APAP-CYS concentrations were positively correlated with higher overall dose and more recent ingestion. CONCLUSIONS: APAP-CYS is detectable in the majority of children taking acetaminophen and not detected in the majority of children who are not exposed to acetaminophen.

Effectiveness of primary care-public health collaborations in the delivery of influenza vaccine: a cluster-randomized pragmatic trial.

OBJECTIVE: To assess effectiveness and feasibility of public-private collaboration in delivering influenza immunization to children. METHODS: Four pediatric and four family medicine (FM) practices in Colorado with a common public health department (PHD) were randomized at the beginning of baseline year (10/2009) to Intervention (joint community clinics and PHD nurses aiding in delivery at practices); or control involving usual care without PHD. Generalized estimating equations compared changes in rates over baseline between intervention and control practices at end of 2nd intervention year (Y2=5/2011). Barriers to collaboration were examined using qualitative methods. RESULTS: Overall, rates increased from baseline to Y2 by 9.2% in intervention and 3.2% in control (p<.0001), with significant increases in both pediatric and FM practices. The largest increases were seen among school-aged and adolescent children (p<.0001 for both), with differences for 6-month-old to 5-year-old children and for children with high-risk conditions not reaching significance. Barriers to collaboration included uncertainty regarding the delivery of vaccine supplies, concerns about using up all purchased vaccine by practices, and concerns about documentation of vaccination if collaboration occurred. CONCLUSIONS: In spite of barriers, public-private collaboration resulted in significantly higher influenza immunization rates, particularly for older, healthy children who visit providers less frequently.

The risk of major elective vascular surgical procedures in patients with end-stage renal disease.

OBJECTIVE: To examine the postoperative complications and death rate of major elective vascular surgery procedures in patients with end-stage renal disease (ESRD). BACKGROUND DATA: Patients with ESRD undergoing elective major vascular surgical procedures are thought to have a high rate of postoperative complications and death. METHODS: The American College of Surgeons-National Surgical Quality Improvement Program database was used to select ESRD and non-ESRD patients who had elective major vascular surgical procedures between 2004 and 2008. Multivariable logistic regression analysis was used to examine the impact of ESRD on 30-day surgical outcomes adjusted for age, race, sex, work relative value units, American Society of Anesthesiology class, and recent operations (within the past 30 days). RESULTS: ESRD patients undergoing elective major vascular surgery were significantly more likely than non-ESRD patients to develop surgical site infection, unplanned intubation, ventilator dependence, combined pulmonary outcome, and a need for reoperation within 30 days of surgery. Importantly, ESRD patients undergoing elective major vascular surgery were also at higher risk for composite outcome and death within 30 days from surgery. ESRD patients above age 65 years undergoing elective major vascular surgery had far worse 30-day outcomes when compared with the younger ESRD cohort. Examining these data by their anatomic site (carotid, aortic, and peripheral) demonstrated elevated rates of postoperative complications and death in patients with ESRD undergoing open abdominal aortic aneurysm repair, carotid endarterectomies, and peripheral vascular operations compared with the non-ESRD cohort. Endovascular abdominal aortic aneurysm repair in ESRD patients had complications and death rates comparable with non-ESRD patients. CONCLUSIONS: Patients with ESRD undergoing elective vascular surgery have a significantly elevated risk of postoperative complications and death after major vascular surgical operations--particularly in patients over age 65. These data, in combination with well-established reduced survival for the older ESRD population, call into question the utility of most carotid and aortic operations in these patients in the absence of symptoms or a rapidly enlarging aneurysm.

Safety evaluation of shorter infusion for ocrelizumab in a substudy of the Phase IIIb CHORDS trial.

The CHORDS trial evaluated ocrelizumab (OCR) in patients with relapsing-remitting multiple sclerosis who had a suboptimal response to previous disease-modifying treatment. The objective of the present study was to assess the safety of shorter OCR infusions in a substudy of CHORDS. After completing four doses of OCR per initial US prescribing recommendations in the main study, participants in the substudy (N = 129) received a fifth dose over a 2-h duration (vs. 3.5 h). Infusion-related reactions occurred in 12.4% of patients. None were severe, life-threatening or led to treatment discontinuation. Shorter infusion time did not change the safety profile of OCR. Clinicaltrials.gov (NCT0237856).

School-Based Health Centers as Medical Homes: Parents' and Adolescents' Perspectives.

OBJECTIVE: Preventive health services are underutilized by US adolescents, especially those from low-income populations. School-based health centers (SBHCs) have been endorsed as primary medical homes for adolescents. This study was undertaken to determine how adolescent SBHC users and their parents perceive SBHCs, particularly whether SBHCs fulfill each of the elements of a medical home as defined by the American Academy of Pediatrics. METHODS: Middle and high school adolescents who had been enrolled in a SBHC in a major metropolitan school district for a minimum of 1 year were interviewed about their perceptions of and experiences with SBHCs. English- and Spanish-speaking parents of SBHC-enrolled adolescents also participated in focus groups on this topic. RESULTS: Four focus groups with parents (n = 30) and 62 interviews with adolescents were completed. Both adolescents and parents indicated satisfaction with the quality and utilization of SBHC services, reporting that SBHCs were highly accessible and family centered. Many students preferred to access care at their SBHC instead of their primary care practice because of the convenience, perceived trustworthiness, compassion, and high quality of care at the SBHC. A few parents reported unmet medical needs from their adolescent's SBHC, and some differences emerged between English- and Spanish-speaking parents. CONCLUSIONS: Adolescents' and parents' perceptions of care received at these SBHCs are consistent with features of the medical home model. These findings suggest that SBHCs can provide coordinated, compassionate care to students in a large, urban school system and may be perceived as more accessible than traditional primary care settings.

The significance of preoperative impaired sensorium on surgical outcomes in nonemergent general surgical operations.

IMPORTANCE: With an aging population, preoperative assessment of the frail older adult requires evaluation beyond simply accounting for chronic diseases. Impaired cognition is a recognized characteristic of the frail older adult. OBJECTIVE: To examine the effect of preoperative impaired sensorium (IS) on general surgical outcomes. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study using data between January 2005 and December 2010 at academic and community hospitals participating in the American College of Surgeons National Surgical Quality Improvement Program. Patients undergoing nonemergent general surgical operations were studied. Multivariable logistic regression involving 45 preoperative patient-level risk factors and comorbidities was used to calculate the conditional probability of having IS. Patients having and not having preoperative IS were matched on their propensity scores using a 1:1 greedy matching technique. Propensity score matching resulted in almost all (n = 1765) patients with IS uniquely matching to a patient without IS, resulting in a cohort size of 3530. Complication rates between patients with and without IS were compared. MAIN OUTCOMES AND MEASURES: Rates of postoperative complications and death following nonemergent general surgical operations. RESULTS: In total, 294 037 patients were studied, of whom 1771 (0.6%) had preoperative IS. Patients with IS were older and had more significant preoperative risk factors and comorbidities. As a result, unadjusted analysis found that 22 of 23 postoperative complications were significantly more likely to occur in patients with IS. Within the matched cohort, rates of postoperative pneumonia, ventilator dependence, progressive renal insufficiency, urinary tract infection, stroke, venous thromboembolism, and postoperative death continued to be significantly (P < .05) elevated in patients with IS. CONCLUSIONS AND RELEVANCE: Impaired sensorium significantly increases postoperative morbidity and mortality independent of other preoperative risk factors and comorbidities following nonemergent general surgical operations. Incorporation of impaired cognitive function into routine preoperative risk assessment and decision making could be an important addition to traditional risk assessment strategies.

Urban and Rural Differences in Parental Attitudes About Influenza Vaccination and Vaccine Delivery Models.

OBJECTIVES: To assess and compare among parents of healthy children in urban and rural areas: (1) reported influenza vaccination status; (2) attitudes regarding influenza vaccination; and (3) attitudes about collaborative models for influenza vaccination delivery involving practices and public health departments. METHODS: A mail survey to random samples of parents from 2 urban and 2 rural private practices in Colorado from April 2012 to June 2012. RESULTS: The response rate was 58% (288/500). In the prior season, 63% of urban and 41% of rural parents reported their child received influenza vaccination (P < .001). No differences in attitudes about influenza infection or vaccination between urban and rural parents were found, with 75% of urban and 73% of rural parents agreeing their child should receive an influenza vaccine every year (P = .71). High proportions reported willingness to participate in a collaborative clinic in a community setting (59% urban, 70% rural, P = .05) or at their child's provider (73% urban, 73% rural, P = .99) with public health department assisting. Fewer (36% urban, 53% rural, P < .01) were likely to go to the public health department if referred by their provider. Rural parents were more willing for their child to receive vaccination outside of their provider's office (70% vs. 55%, P = .01). CONCLUSIONS: While attitudes regarding influenza vaccination were similar, rural children were much less likely to have received vaccination. Most parents were amenable to collaborative models of influenza vaccination delivery, but rural parents were more comfortable with influenza vaccination outside their provider's office, suggesting that other venues for influenza vaccination in rural settings should be promoted.

School-located vaccination of adolescents with insurance billing: cost, reimbursement, and vaccination outcomes.

PURPOSE: To assess, in a school-located adolescent vaccination program that billed health insurance, the program costs, the proportion of costs reimbursed, and the likelihood of vaccination. METHODS: During the 2010-2011 school year, vaccination clinics were held for sixth- to eighth-grade students at seven Denver public schools. Vaccine administration and purchase costs were compared with reimbursement by insurers. Multivariate analyses were used to compare the likelihood of vaccination among students in intervention schools with students in control schools who did not participate in the program, with analyses stratified by grade (sixth grade vs. seventh-eighth grades). RESULTS: Fifteen percent (466 of 3,144) of students attending intervention schools were vaccinated at school-located vaccination clinics. Among students vaccinated at school, 41% were uninsured, 37% publicly insured, and 22% privately insured. Estimated vaccine administration costs were $23.98 per vaccine dose. Seventy-eight percent of vaccine purchase costs and 14% of vaccine administration costs were reimbursed by insurers; 41% of total program costs were reimbursed. Sixth-grade students in intervention schools were more likely than those in control schools to receive tetanus-diphtheria-acellular pertussis (risk ratio [RR], 1.30; 95% confidence interval [CI], 1.08, 1.57), meningococcal conjugate (RR, 1.42; CI, 1.18, 1.70), and human papillomavirus (for females only, RR, 1.69; CI, 1.21, 2.36) vaccines during the 2010-2011 school year, with similar results for seventh- to eighth-grade students. CONCLUSIONS: Although school-located adolescent vaccination with billing appears feasible and likely to improve vaccination rates, improvements in insurance coverage and reimbursement rates may be needed for the long-term financial sustainability of such programs.

School-located influenza vaccination with third-party billing: outcomes, cost, and reimbursement.

OBJECTIVE: To assess rates of immunization; costs of conducting clinics; and reimbursements for a school-located influenza vaccination (SLIV) program that billed third-party payers. METHODS: SLIV clinics were conducted in 19 elementary schools in the Denver Public School district (September 2010 to February 2011). School personnel obtained parental consent, and a community vaccinator conducted clinics and performed billing. Vaccines For Children vaccine was available for eligible students. Parents were not billed for any fees. Data were collected regarding implementation costs and vaccine cost was calculated using published private sector prices. Reimbursement amounts were compared to costs. RESULTS: Overall, 30% of students (2784 of 9295) received ≥1 influenza vaccine; 39% (1079 of 2784) needed 2 doses and 80% received both. Excluding vaccine costs, implementation costs were $24.69 per vaccination. The percentage of vaccine costs reimbursed was 62% overall (82% from State Child Health Insurance Program (SCHIP), 50% from private insurance). The percentage of implementation costs reimbursed was 19% overall (23% from private, 27% from Medicaid, 29% from SCHIP and 0% among uninsured). Overall, 25% of total costs (implementation plus vaccine) were reimbursed. CONCLUSIONS: A SLIV program resulted in vaccination of nearly one third of elementary students. Reimbursement rates were limited by 1) school restrictions on charging parents fees, 2) low payments for vaccine administration from public payers and 3) high rates of denials from private insurers. Some of these problems might be reduced by provisions in the Affordable Care Act.

Risk of major nonemergent inpatient general surgical procedures in patients on long-term dialysis.

HYPOTHESIS: Patients on long-term dialysis undergoing major nonemergent general surgical procedures are thought to have high rates of postoperative complications and death. DESIGN: Retrospective cohort study. SETTING: Academic and private hospitals. PATIENTS: The American College of Surgeons National Surgical Quality Improvement Program database was used to select dialysis and nondialysis patients who had undergone nonemergent major general surgical procedures between 2005 and 2008. Multivariable logistic regression analysis was used to examine the effect of dialysis on 30-day surgical outcomes adjusted for age, race, sex, work relative value units, American Society of Anesthesiologists class, and recent operations (within the past 30 days). MAIN OUTCOME MEASURES: Patient morbidity, mortality, and failure-to-rescue rates. RESULTS: Dialysis patients undergoing major nonemergent general surgical procedures were significantly more likely to develop pneumonia, unplanned intubation, ventilator dependence, and need for a reoperation within 30 days from the index procedure. Dialysis patients also had a higher risk of vascular complications and postoperative death. Older dialysis patients (aged ≥ 65 years) had a significantly higher postoperative mortality rate compared with their younger counterparts. Dialysis patients were significantly more likely to die after any complication occurred, and mortality rates were especially high following stroke, myocardial infarction, and reintubation. Abnormalities in potentially modifiable preoperative variables (blood urea nitrogen level, albumin level, and hematocrit) did not increase the risk of postoperative complications or death in dialysis patients compared with nondialysis patients. CONCLUSIONS: Dialysis patients undergoing nonemergent general surgery have significantly elevated risks of postoperative complications and death, particularly if they are aged 65 years or older.

Advancing age and 30-day adverse outcomes after nonemergent general surgeries.

OBJECTIVES: To determine whether 30-day postoperative mortality, complications, failure-to-rescue (FTR) rates, and postoperative length of stay increase with advancing age. DESIGN: Retrospective cohort study. SETTING: Hospitals participating in the American College of Surgeons National Surgical Quality Improvement Program. PARTICIPANTS: Individuals undergoing nonemergent major general surgeries between 2005 and 2008 were studied (N = 165,600). MEASUREMENTS: Postoperative outcomes of interest were complications occurring within 30 days of the index operation, return to the operating room within 30 days, FTR after a postoperative complication, postsurgical length of stay, and 30-day mortality. RESULTS: Postoperative mortality, overall morbidity, and each type of postoperative complication increased with increasing age. Rates of FTR after each type of postoperative complication also increased with age. Mortality in individuals aged 80 and older after renal insufficiency (43.3%), stroke (36.5%), myocardial infarction (MI) (35.6%), and pulmonary complications (25-39%) were particularly high. Median postoperative length of stay increased with age after surgical site infection, urinary tract infection, pneumonia, return to the operating room, and overall morbidity but not after venous thromboembolism, stroke, MI, renal insufficiency, failure to wean from the ventilator, or reintubation. CONCLUSION: Thirty-day mortality and complication and FTR rates increase with age after nonemergent general surgeries. Individuals aged 80 and older have especially high mortality after renal, cardiovascular, and pulmonary complications. Surgeons need to be more selective with advancing age regarding who will benefit from the surgical intervention.

Relationship between asking an older adult about falls and surgical outcomes.

IMPORTANCE: More than one-third of all US inpatient operations are performed on patients aged 65 years and older. Existing preoperative risk assessment strategies are not adequate to meet the needs of the aging population. OBJECTIVES: To evaluate the relationship of a history of falls (a geriatric syndrome) to postoperative outcomes in older adults undergoing major elective operations. DESIGN, SETTING, AND PARTICIPANTS: This prospective, cohort study was conducted at a referral medical center. Persons aged 65 years and older undergoing elective colorectal and cardiac operations were enrolled. The predictor variable was having fallen in the 6 months prior to the operation. MAIN OUTCOMES AND MEASURES: Postoperative outcomes measured included 30-day complications, the need for discharge institutionalization, and 30-day readmission. RESULTS: There were 235 subjects with a mean (SD) age of 74 (6) years. Preoperative falls occurred in 33%. One or more postoperative complications occurred more frequently in the group with prior falls compared with the nonfallers following both colorectal (59% vs 25%; P = .004) and cardiac (39% vs 15%; P = .002) operations. These findings were independent of advancing chronologic age. The need for discharge to an institutional care facility occurred more frequently in the group that had fallen in comparison with the nonfallers in both the colorectal (52% vs 6%; P < .001) and cardiac (62% vs 32%; P = .001) groups. Similarly, 30-day readmission was higher in the group with prior falls following both colorectal (P = .04) and cardiac (P = .02) operations. CONCLUSIONS AND RELEVANCE: A history of 1 or more falls in the 6 months prior to an operation forecasts increased postoperative complications, the need for discharge institutionalization, and 30-day readmission across surgical specialties. Using a history of prior falls in preoperative risk assessment for an older adult represents a shift from current preoperative assessment strategies.

A population pharmacokinetic-pharmacogenetic analysis of atazanavir.

Atazanavir is a first-line HIV protease inhibitor commonly co-dosed with ritonavir. Ritonavir inhibits atazanavir metabolism, decreasing variability and increasing plasma concentrations. However, ritonavir use results in higher costs and increased drug-related adverse events. Elucidating atazanavir pharmacokinetics might allow for individualized ritonavir boosting. We previously demonstrated that genetically determined CYP3A5 nonexpression was associated with slower atazanavir clearance CL/F and higher trough concentrations. This effect was prominent in non-African-American men but absent in African-Americans. The present study considers additional genetic predictors of atazanavir CL/F with a focus on race differences. Nine polymorphisms in CYP3A4, ABCG2, NR1I2 (PXR), and SLCO1B1 were evaluated; 330 plasma samples from 30 HIV-negative volunteers, balanced by sex, race, and CYP3A5 expressor status, were available. Analyses were performed using nonlinear mixed-effects modeling (NONMEM). The following factors were univariately associated with atazanavir CL/F (% effect) : African-American race (decreased 35%), female sex (decreased 25%), older age (decreased 1.7%/year), CYP3A5 nonexpressors (decreased 26%), ABCB1 CGC haplotype carriers (1236C/2677G/3435C) (decreased 33%), and CYP3A4*1B carriers (decreased 31%). However, an independent genetic explanation for the differential race effect could not be identified. An interaction was observed with PXR 63396 C>T and CYP3A5 expressor status (p=0.0002). CYP3A5 nonexpressors with a PXR 63396 CC genotype had 37% slower CL/F versus those with CT or TT genotypes. For CYP3A5 expressors, those with a PXR 63396 CC genotype had 63% faster CL/F versus those with CT or TT genotypes. Although this study has as its main limitation a small overall sample size, these results nonetheless provide new leads and impetus to evaluate ways to individualize the need for ritonavir boosting using demographic and genetic predictors of atazanavir pharmacokinetics.