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Objective: To provide comprehensive population-level estimates of the burden of healthcare-associated influenza. Design: Retrospective cross-sectional study. Setting: US Influenza Hospitalization Surveillance Network (FluSurv-NET) during 2012–2013 through 2018–2019 influenza seasons. Patients: Laboratory-confirmed influenza-related hospitalizations in an 8-county catchment area in Tennessee. Methods: The incidence of healthcare-associated influenza was determined using the traditional definition (ie, positive influenza test after hospital day 3) in addition to often underrecognized cases associated with recent post-acute care facility admission or a recent acute care hospitalization for a noninfluenza illness in the preceding 7 days. Results: Among the 5,904 laboratory-confirmed influenza-related hospitalizations, 147 (2.5%) had traditionally defined healthcare-associated influenza. When we included patients with a positive influenza test obtained in the first 3 days of hospitalization and who were either transferred to the hospital directly from a post-acute care facility or who were recently discharged from an acute care facility for a noninfluenza illness in the preceding 7 days, we identified an additional 1,031 cases (17.5% of all influenza-related hospitalizations). Conclusions: Including influenza cases associated with preadmission healthcare exposures with traditionally defined cases resulted in an 8-fold higher incidence of healthcare-associated influenza. These results emphasize the importance of capturing other healthcare exposures that may serve as the initial site of viral transmission to provide more comprehensive estimates of the burden of healthcare-associated influenza and to inform improved infection prevention strategies.

BackgroundAcute myocardial infarction (AMI) events have been reported among patients with certain viral and bacterial infections. Whether invasive pneumococcal disease (IPD) increases the risk of AMI remains unclear. We examined whether laboratory-confirmed IPD was associated with the risk of AMI.MethodsWe conducted a self-controlled case series analysis among adult Tennessee residents with evidence of an AMI hospitalization (2003–2019). Patient follow-up started 1 year before the earliest AMI and continued through the date of death, 1 year after AMI, or study end (December 2019). Periods for AMI assessment included the 7 to 1 days before IPD specimen collection (pre-IPD detection), day 0 through day 7 after IPD specimen collection (current IPD), day 8 to 28 after IPD specimen collection (post-IPD), and a control period (all other follow-up). We used conditional Poisson regression to calculate incidence rate ratios (IRRs) and 95% confidence intervals (CIs) for each risk period compared with control periods using within-person comparisons.ResultsWe studied 324 patients hospitalized for AMI with laboratory-confirmed IPD within 1 year before or after the AMI hospitalization. The incidence of AMI was significantly higher during the pre-IPD detection (IRR, 10.29; 95% CI: 6.33–16.73) and the current IPD (IRR, 92.95; 95% CI: 72.17–119.71) periods but nonsignificantly elevated in the post-IPD risk period (IRR, 1.83; 95% CI: .86–3.91) compared with control periods. The AMI incidence was higher in the post-IPD control period (29 to 365 days after IPD; IRR, 2.95; 95% CI: 2.01–4.32).ConclusionsHospitalizations with AMI were strongly associated with laboratory-confirmed IPD.

Background Candidemia is a common healthcare-associated infection with high mortality. Estimates of recurrence range from 1% to 17%. Few studies have focused on those with recurrent candidemia, who often experience more severe illness and greater treatment failure. We describe recurrent candidemia trends and risk factors. Methods We analyzed population-based candidemia surveillance data collected during 2011–2018. Persons with >1 episode (defined as the 30-day period after a positive Candida species) were classified as having recurrent candidemia. We compared factors during the initial episode between those who developed recurrent candidemia and those who did not. Results Of the 5428 persons identified with candidemia, 326 (6%) had recurrent infection. Recurrent episodes occurred 1.0 month to 7.6 years after any previous episode. In multivariable logistic regression controlling for surveillance site and year, recurrent candidemia was associated with being 19–44 years old (vs ≥65 years; adjusted odds ratio [aOR], 3.05 [95% confidence interval {CI}, 2.10–4.44]), being discharged to a private residence (vs medical facility; aOR, 1.53 [95% CI, 1.12–2.08]), hospitalization in the 90 days prior to initial episode (aOR, 1.66 [95% CI, 1.27–2.18]), receipt of total parenteral nutrition (aOR, 2.08 [95% CI, 1.58–2.73]), and hepatitis C infection (aOR, 1.65 [95% CI, 1.12–2.43]). Conclusions Candidemia recurrence >30 days after initial infection occurred in >1 in 20 persons with candidemia. Associations with younger age and hepatitis C suggest injection drug use may play a modifiable role. Prevention efforts targeting central line care and total parenteral nutrition use may help reduce the risk of recurrent candidemia.

Background The COVID-19 pandemic has resulted in unprecedented healthcare challenges, and COVID-19 has been linked to secondary infections. Candidemia, a fungal healthcare-associated infection, has been described in patients hospitalized with severe COVID-19. However, studies of candidemia and COVID-19 coinfection have been limited in sample size and geographic scope. We assessed differences in patients with candidemia with and without a COVID-19 diagnosis. Methods We conducted a case-level analysis using population-based candidemia surveillance data collected through the Centers for Disease Control and Prevention’s Emerging Infections Program during April–August 2020 to compare characteristics of candidemia patients with and without a positive test for COVID-19 in the 30 days before their Candida culture using chi-square or Fisher’s exact tests. Results Of the 251 candidemia patients included, 64 (25.5%) were positive for SARS-CoV-2. Liver disease, solid-organ malignancies, and prior surgeries were each >3 times more common in patients without COVID-19 coinfection, whereas intensive care unit–level care, mechanical ventilation, having a central venous catheter, and receipt of corticosteroids and immunosuppressants were each >1.3 times more common in patients with COVID-19. All-cause in-hospital fatality was 2 times higher among those with COVID-19 (62.5%) than without (32.1%). Conclusions One-quarter of candidemia patients had COVID-19. These patients were less likely to have certain underlying conditions and recent surgery commonly associated with candidemia and more likely to have acute risk factors linked to COVID-19 care, including immunosuppressive medications. Given the high mortality, it is important for clinicians to remain vigilant and take proactive measures to prevent candidemia in patients with COVID-19.

We characterized common exposures reported by a convenience sample of 202 US patients with coronavirus disease during January–April 2020 and identified factors associated with presumed household transmission. The most commonly reported settings of known exposure were households and healthcare facilities; among case-patients who had known contact with a confirmed case-patient compared with those who did not, healthcare occupations were more common. Among case-patients without known contact, use of public transportation was more common. Within the household, presumed transmission was highest from older (>65 years) index case-patients and from children to parents, independent of index case-patient age. These findings may inform guidance for limiting transmission and emphasize the value of testing to identify community-acquired infections.

Background The prioritization of U.S. health care personnel for early receipt of messenger RNA (mRNA) vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (Covid-19), allowed for the evaluation of the effectiveness of these new vaccines in a real-world setting. Methods We conducted a test-negative case–control study involving health care personnel across 25 U.S. states. Cases were defined on the basis of a positive polymerase-chain-reaction (PCR) or antigen-based test for SARS-CoV-2 and at least one Covid-19–like symptom. Controls were defined on the basis of a negative PCR test for SARS-CoV-2, regardless of symptoms, and were matched to cases according to the week of the test date and site. Using conditional logistic regression with adjustment for age, race and ethnic group, underlying conditions, and exposures to persons with Covid-19, we estimated vaccine effectiveness for partial vaccination (assessed 14 days after receipt of the first dose through 6 days after receipt of the second dose) and complete vaccination (assessed ≥7 days after receipt of the second dose). Results The study included 1482 case participants and 3449 control participants. Vaccine effectiveness for partial vaccination was 77.6% (95% confidence interval [CI], 70.9 to 82.7) with the BNT162b2 vaccine (Pfizer–BioNTech) and 88.9% (95% CI, 78.7 to 94.2) with the mRNA-1273 vaccine (Moderna); for complete vaccination, vaccine effectiveness was 88.8% (95% CI, 84.6 to 91.8) and 96.3% (95% CI, 91.3 to 98.4), respectively. Vaccine effectiveness was similar in subgroups defined according to age (

Throughout the COVID-19 pandemic, health care personnel (HCP) have been at high risk for exposure to SARS-CoV-2, the virus that causes COVID-19, through patient interactions and community exposure (1). The Advisory Committee on Immunization Practices recommended prioritization of HCP for COVID-19 vaccination to maintain provision of critical services and reduce spread of infection in health care settings (2). Early distribution of two mRNA COVID-19 vaccines (Pfizer-BioNTech and Moderna) to HCP allowed assessment of the effectiveness of these vaccines in a real-world setting. A test-negative case-control study is underway to evaluate mRNA COVID-19 vaccine effectiveness (VE) against symptomatic illness among HCP at 33 U.S. sites across 25 U.S. states. Interim analyses indicated that the VE of a single dose (measured 14 days after the first dose through 6 days after the second dose) was 82% (95% confidence interval [CI] = 74%-87%), adjusted for age, race/ethnicity, and underlying medical conditions. The adjusted VE of 2 doses (measured ≥7 days after the second dose) was 94% (95% CI = 87%-97%). VE of partial (1-dose) and complete (2-dose) vaccination in this population is comparable to that reported from clinical trials and recent observational studies, supporting the effectiveness of mRNA COVID-19 vaccines against symptomatic disease in adults, with strong 2-dose protection.

Background: Despite significant morbidity and mortality, estimates of the burden of healthcare-associated viral respiratory infections (HA-VRI) for noninfluenza infections are limited. Of the studies assessing the burden of respiratory syncytial virus (RSV), cases are typically classified as healthcare associated if a positive test result occurred after the first 3 days following admission, which may miss healthcare exposures prior to admission. Utilizing an expanded definition of healthcare-associated RSV, we assessed the estimates of disease prevalence. Methods: This study included laboratory-confirmed cases of RSV in adult and pediatric patients admitted to acute-care hospitals in a catchment area of 8 counties in Tennessee identified between October 1, 2016, and April 30, 2019. Surveillance information was abstracted from hospital and state laboratory databases, hospital infection control databases, reportable condition databases, and electronic health records as a part of the Influenza Hospitalization Surveillance Network by the Emerging Infections Program. Cases were defined as healthcare-associated RSV if laboratory confirmation of infection occurred (1) on or after hospital day 4 (ie, “traditional definition”) or (2) between hospital day 0 and 3 in patients transferred from a chronic care facility or with a recent discharge from another acute-care facility in the 7 days preceding the current index admission (ie, “enhanced definition”). The proportion of laboratory-confirmed RSV designated as HA-VRI using both the traditional definition as well as with the added enhanced definition were compared. Results: We identified 900 cases of RSV in hospitalized patients over the study period. Using the traditional definition for HA-VRI, only 41 (4.6%) were deemed healthcare associated. Adding the cases identified using the enhanced definition, an additional 12 cases (1.3%) were noted in patients transferred from a chronic care facility for the current acute-care admission and 17 cases (1.9%) were noted in patients with a prior acute-care admission in the preceding 7 days. Using our expanded definition, the total proportion of healthcare-associated RSV in this cohort was 69 (7.7%) of 900 compared to 13.1% of cases for influenza (Figure 1). Although the burden of HA-VRI due to RSV was less than that of influenza, when stratified by age, the rate increased to 11.7% for those aged 50–64 years and to 10.1% for those aged ≥65 years (Figure 2). Conclusions: RSV infections are often not included in estimates of HA-VRI, but the proportion of cases that are healthcare associated are substantial. Typical surveillance methods likely underestimate the burden of disease related to RSV, especially for those aged ≥50 years.Funding: NoDisclosures: None

Background: Healthcare-associated transmission of influenza leads to significant morbidity, mortality, and cost. Most studies classify healthcare-associated viral respiratory infections (HA-VRI) as those with a positive test result after the first 3 days following admission, which does not account for healthcare exposures prior to admission. Utilizing an expanded definition of healthcare-associated influenza, we aimed to improve the estimates of disease prevalence on a population level. Methods: This study included laboratory-confirmed cases of influenza in adult and pediatric patients admitted to any acute-care hospital in a catchment area of 8 counties Tennessee identified between October 1, 2012, and April 30, 2019. Surveillance information was abstracted from hospital and state laboratory databases, hospital infection control practitioner databases, reportable condition databases, and electronic health records as a part of the Influenza Hospitalization Surveillance Network (FluSurv-NET) by the Centers for Disease Control and Prevention (CDC) Emerging Infections Program (EIP). Cases were defined as healthcare-associated influenza laboratory confirmation of infection occurred (1) on or after hospital day 4 (“traditional definition”), or (2) between hospital days 0 and 3 in patients transferred from a chronic care facility or with a recent discharge from another acute-care facility in the 7 days preceding the current index admission (ie, enhanced definition). The proportion of laboratory-confirmed influenza designated as HA-VRI using both the traditional definition as well as with the added enhanced definition were compared. Data were imported into Stata software for analysis. Results: We identified 5,904 cases of laboratory-confirmed influenza in hospitalized patients over the study period. Using the traditional definition for HA-VRI, only 147 (2.5%, seasonal range 1.3%–3.4%) were deemed healthcare associated (Figure 1). Adding the cases identified using the enhanced definition, an additional 317 (5.4%, range 2.3%–6.7%) cases were noted in patients transferred from a chronic care facility for the current acute-care admission and 336 cases (5.7%; range, 4.1%–7.4%) were noted in patients with a prior acute-care facility admission in the preceding 7 days. Using our expanded definition, the total proportion of healthcare-associated influenza in this cohort was 772 of 5,904 (13.1%; range, 10.6%–14.8%). Conclusion: HA-VRI due to influenza is an underrecognized infection in hospitalized patients. Limiting surveillance assessment of this important outcome to just those patients with a positive influenza test after hospital day 3 captured only 19% of possible healthcare-associated influenza infections across 7 influenza seasons. These results suggest that the traditionally used definitions of healthcare-associated influenza underestimate the true burden of cases.Funding: NoDisclosures: None

Background Influenza hospitalizations result in substantial morbidity and mortality each year. Little is known about the association between influenza hospitalization and census tract‐based socioeconomic determinants beyond the effect of individual factors. Objective To evaluate whether census tract‐based determinants such as poverty and household crowding would contribute significantly to the risk of influenza hospitalization above and beyond individual‐level determinants. Methods We analyzed 33 515 laboratory‐confirmed influenza‐associated hospitalizations that occurred during the 2009‐2010 through 2013‐2014 influenza seasons using a population‐based surveillance system at 14 sites across the United States. Results Using a multilevel regression model, we found that individual factors were associated with influenza hospitalization with the highest adjusted odds ratio (AOR) of 9.20 (95% CI 8.72‐9.70) for those ≥65 vs 5‐17 years old. African Americans had an AOR of 1.67 (95% CI 1.60‐1.73) compared to Whites, and Hispanics had an AOR of 1.21 (95% CI 1.16‐1.26) compared to non‐Hispanics. Among census tract‐based determinants, those living in a tract with ≥20% vs

Background Further understanding of hospital readmissions after influenza illness could reduce readmissions. The aim of our study was to characterize the morbidity associated with laboratory confirmed influenza hospitalizations. Methods This was a retrospective study using data from 2006 to 2016 from the Tennessee (TN) Emerging Infections Program Influenza Surveillance Network, which prospectively identifies laboratory-confirmed influenza hospitalizations in Nashville, TN and surrounding counties. Using the TN Hospital Discharge Data System, which collects information on all hospitalizations and discharges in TN, cases were linked to subsequent hospitalizations up to 1 year. The International Classification of Diseases was used to define the primary diagnosis associated with each hospitalization. Demographic characteristics and outcomes were compared by using χ2 tests for categorical variables. Multivariable logistic regression was used to compare study outcomes. Results Of the 2,897 patients with a laboratory-confirmed influenza hospitalization, 1,364 (47%) had a hospital readmission during the subsequent year (figure). Multiple readmissions occurred in 740 patients (54%). The readmission group was older, female predominant, and had more comorbidities than patients not re-hospitalized. Acute COPD/asthma exacerbation, pneumonia, septicemia, and acute renal failure were the most common causes for readmission. Underlying cardiovascular disease (OR 1.6), lung disease (OR 1.6), kidney disease (OR 1.7), diabetes (OR 1.3), immunosuppression (OR 1.6), and liver disease (OR 2.1) were associated with increased risk of readmission (table). Conclusion An influenza hospitalization is associated with increased hospital readmissions. Approximately 47% of patients hospitalized with influenza are readmitted within 1 year. Patient comorbidities could be an important link to influenza readmissions. Disclosures W. Schaffner, Merck: Member, Data Safety Monitoring Board, Consulting fee. Pfizer: Member, Data Safety Monitoring Board, Consulting fee. Dynavax: Consultant, Consulting fee. Seqirus: Consultant, Consulting fee. SutroVax: Consultant, Consulting fee. Shionogi: Consultant, Consulting fee. H. K. Talbot, sanofi pasteur: Investigator, Research grant. Gilead: Investigator, Research grant. MedImmune: Investigator, Research grant. Vaxinnate: Safety Board, none. Seqirus: Safety Board, none.

BACKGROUND: The authors evaluated the feasibility, toxicity, and efficacy of gefitinib added to first-line combined-modality therapy for patients with locally advanced squamous carcinoma of the head and neck. METHODS: Patients with biopsy-proven locally advanced squamous carcinoma of the head and neck who had low expected cure rates with local treatment modalities alone were eligible for this treatment. All patients received a 6-week induction course of docetaxel, carboplatin, infusional 5-fluorouracil, and gefitinib (250 mg daily). Gefitinib was continued while patients received concurrent weekly docetaxel and radiation therapy. After the completion of radiation therapy, gefitinib was continued until patients developed disease progression or for a maximum of 24 months. RESULTS: Sixty-two patients (53% with stage IV disease) received protocol treatment, and 50 patients (81%) were able to complete the regimen. The addition of gefitinib increased the incidence of grade 3/4 mucositis (27%) and diarrhea (16%) during induction therapy but did not appear to add substantially to toxicity during concurrent chemoradiation. The estimated 3-year progression-free and overall survival rates for the entire group were 41% and 54%, respectively. CONCLUSIONS: The addition of gefitinib was associated with a moderate increase in toxicity with this combined modality regimen, particularly during induction therapy. Although this regimen was efficacious, the survival results overlap with results reported with chemoradiation alone. The role of epidermal growth factor receptor inhibitors in first-line, combined-modality therapy for patients with head and neck cancer remains undefined.

Stroke is a prevalent and devastating disorder, and no treatment is currently available to restore lost neuronal function after stroke. One unique therapy that improves recovery after stroke is neutralization of the neurite inhibitory protein Nogo-A. Here, we show, in a clinically relevant model, improved functional recovery and brain reorganization in the aged and adult rat when delayed anti-Nogo-A therapy is given after ischemic injury. These results support the efficacy of Nogo-A neutralization as treatment for ischemic stroke, even in the aged animal and after a 1-week delay, and implicate neuronal plasticity from unlesioned areas of the central nervous system as a mechanism for recovery.

Background Molecular testing for respiratory viruses in clinical practice is common, often with multiple viruses detected. Viral load has been correlated with illness severity, but correlation of co-detection of viruses and viral load is less clear. We sought to compare cycle threshold (Ct) values, a marker inversely related to viral load, between single vs. co-detection of common respiratory viruses. Methods Children Results From 11/15/15-7/15/16, 1255 children were enrolled, with median age of 26.5 months, 53.4% male, 54.3% White, 38.7% Black, 6.4% other, and 23.5% Hispanic. The median days of illness were 3 days. Of the total cohort, 904 (72%) tested positive for at least one viral pathogen. Table 1compares Ct values of single vs. co-detection for each individual virus. Conclusion Single detection with RSV, HRV, AdV, and PIV had lower Ct values, indicating higher viral loads, compared with co-detection with other viruses. Additional research is needed to understand the reason for lower viral loads for co-detection vs. single detection in select respiratory viruses. Disclosures W. Schaffner, Pfizer: Scientific Advisor, Consulting fee. Merck: Scientific Advisor, Consulting fee. Novavax: Consultant, Consulting fee. Dynavax: Consultant, Consulting fee. Sanofi-pasteur: Consultant, Consulting fee. GSK: Consultant, Consulting fee. Seqirus: Consultant, Consulting fee. N. B. Halasa, sanofi pasteur: Research Contractor, Research support. Astra Zeneca: Research Contractor, Grant recipient.

Background Inhibition of the platelet-derived growth factor receptor (PDGFR) might improve the efficacy of chemotherapy by lowering interstitial tumor pressure and allowing increased tumor penetration by cytotoxic agents. In this phase II trial, we added imatinib, a PDGFR inhibitor, to docetaxel in the first-line treatment of women with metastatic breast cancer (MBC). Patients and Methods Women with MBC who had received a maximum of 1 previous chemotherapy regimen were eligible for this trial. Initially, patients received oral imatinib 600 mg daily and docetaxel 30 mg/m 2 on days 1, 8, and 15 of a 28-day cycle. The imatinib dose was lowered from 600 mg to 400 mg daily because of toxicity (primarily gastrointestinal) observed in the first 15 patients. Patients were evaluated for response (Response Evaluation Criteria in Solid Tumors) after 8 weeks of therapy; treatment continued in responding/stable patients until tumor progression or unacceptable toxicity. The primary endpoint was the overall response rate. Results Thirty-seven patients entered this trial between May 2005 and March 2008. This regimen was relatively poorly tolerated, even after reduction of the imatinib dose, primarily because of gastrointestinal toxicity (nausea, vomiting, and diarrhea). Eight patients (22%) stopped therapy because of toxicity before the 8-week initial evaluation. Six of 37 enrolled patients (16%; 95% CI, 4.3%-28.1%) had partial responses; an additional 4 patients had stable disease for > 6 months. The median progression-free and overall survivals were 9.3 months and 15.4 months, respectively. Conclusion When compared with previous results with single-agent docetaxel, the combination of weekly docetaxel plus imatinib was tolerated relatively poorly and produced a low objective response rate. The efficacy of weekly docetaxel is not improved by concurrent administration of imatinib as a PDGFR inhibitor.

Purpose To evaluate the efficacy and safety of treatment with Yttrium-90 (90Y) ibritumomab tiuxetan following completion of short-course rituximab/chemotherapy in patients with previously untreated follicular non-Hodgkin lymphoma. Patients and Methods Forty-one patients with previously untreated follicular lymphoma received rituximab for 4 consecutive weeks, followed by 3 cycles of rituximab combined with either CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone; 88%) or CVP (cyclophosphamide/ vincristine/prednisone; 12%). To complete treatment, all patients received 90Y ibritumomab tiuxetan 4-6 weeks after the final dose of chemotherapy. The primary efficacy endpoint was the clinical complete response (CR) rate after completion of therapy; all patients were followed for progression-free survival (PFS) and overall survival (OS). Results After completion of shortcourse rituximab/chemotherapy, 95% had objective responses, with a 30% clinical CR rate. The clinical CR rate increased to 72% following 90Y ibritumomab tiuxetan. After a median follow-up of 67 months, the estimated 5-year PFS and OS rates are 64% and 96%, respectively. Reversible grade 3/4 neutropenia and thrombocytopenia occurred in 39% and 36% of the patients, respectively, following 90Y ibritumomab tiuxetan; nonhematologic toxicity was uncommon. Conclusion 90Y ibritumomab tiuxetan was well tolerated after short-course rituximab/chemotherapy and resulted in a high CR rate and a long PFS. Definitive demonstration of improved efficacy versus rituximab/chemotherapy alone will require a randomized phase III trial.

The authors evaluated the feasibility, toxicity, and efficacy of gefitinib added to first-line combined-modality therapy for patients with locally advanced squamous carcinoma of the head and neck.Patients with biopsy-proven locally advanced squamous carcinoma of the head and neck who had low expected cure rates with local treatment modalities alone were eligible for this treatment. All patients received a 6-week induction course of docetaxel, carboplatin, infusional 5-fluorouracil, and gefitinib (250 mg daily). Gefitinib was continued while patients received concurrent weekly docetaxel and radiation therapy. After the completion of radiation therapy, gefitinib was continued until patients developed disease progression or for a maximum of 24 months.Sixty-two patients (53% with stage IV disease) received protocol treatment, and 50 patients (81%) were able to complete the regimen. The addition of gefitinib increased the incidence of grade 3/4 mucositis (27%) and diarrhea (16%) during induction therapy but did not appear to add substantially to toxicity during concurrent chemoradiation. The estimated 3-year progression-free and overall survival rates for the entire group were 41% and 54%, respectively.The addition of gefitinib was associated with a moderate increase in toxicity with this combined modality regimen, particularly during induction therapy. Although this regimen was efficacious, the survival results overlap with results reported with chemoradiation alone. The role of epidermal growth factor receptor inhibitors in first-line, combined-modality therapy for patients with head and neck cancer remains undefined.

Stroke often results in devastating neurological disabilities with no specific treatment available to improve functional recovery. Neurite growth inhibitory proteins such as Nogo-A play a critical role in impeding regain of function after stroke. We have reported that treatment with anti-Nogo-A antibody using the intracerebroventricular route resulted in improvement of function and neuroplasticity in adult or aged rats after stroke. This present study tested a more clinically accessible route for applying anti-Nogo-A antibodies, the intrathecal route. Anti-Nogo-A or control antibody was administered intrathecally at lower lumbar levels 1 week after middle cerebral artery occlusion in adult rats. Our results show that anti-Nogo-A antibody delivered by this intrathecal route for 2 weeks penetrated into brain parenchyma and bound to myelin-enriched structures such as the corpus callosum and striatal white matter. Animals receiving anti-Nogo-A antibody treatment significantly improved recovery of function on the skilled forelimb reaching task as compared to stroke only and stroke/control antibody animals. These findings show that anti-Nogo-A antibody delivered through the intrathecal route is as effective in restoring lost functions after stroke as the intracerebroventricular route. This is of great importance for the future application of anti-Nogo-A immunotherapy for ischemic stroke treatment.

Neuronal death due to ischemic stroke results in permanent deficits in sensory, language, and motor functions. The growth-restrictive environment of the adult central nervous system (CNS) is an obstacle to functional recovery after stroke and other CNS injuries. In this regard, Nogo-A is a potent neurite growth-inhibitory protein known to restrict neuronal plasticity in adults. Previously, we have found that treatment with monoclonal antibody (mAb) IN-1 to neutralize Nogo-A immediately after stroke enhanced motor cortico-efferent plasticity and recovery of skilled forelimb function in rats. However, immediate treatment for stroke is often not clinically feasible. Thus, the present study was undertaken to determine whether cortico-efferent plasticity and functional recovery would occur if treatment with mAb IN-1 was delayed 1 week after stroke. Adult rats were trained on a forelimb-reaching task, and the middle cerebral artery was occluded to induce focal cerebral ischemia to the forelimb sensorimotor cortex. After 1 week, animals received mAb IN-1 treatment, control antibody, or no treatment, and were tested for 9 more weeks. To assess cortico-efferent plasticity, the sensorimotor cortex opposite the stroke lesion was injected with an anterograde neuroanatomical tracer. Behavioral analysis demonstrated a recovery of skilled forelimb function, and anatomical studies revealed neuroplasticity at the level of the red nucleus in animals treated with mAb IN-1, thus demonstrating the efficacy of this treatment even if administered 1 week after stroke.

CRT-D devices offer survival benefit in select NYHA class II-IV systolic heart failure patients with QRS >120ms and LVEF