Ensuring quality in AFRINEST and SATT: clinical standardization and monitoring.

BACKGROUND: Three randomized open-label clinical trials [Simplified Antibiotic Therapy Trial (SATT) Bangladesh, SATT Pakistan and African Neonatal Sepsis Trial (AFRINEST)] were developed to test the equivalence of simplified antibiotic regimens compared with the standard regimen of 7 days of parenteral antibiotics. These trials were originally conceived and designed separately; subsequently, significant efforts were made to develop and implement a common protocol and approach. Previous articles in this supplement briefly describe the specific quality control methods used in the individual trials; this article presents additional information about the systematic approaches used to minimize threats to validity and ensure quality across the trials. METHODS: A critical component of quality control for AFRINEST and SATT was striving to eliminate variation in clinical assessments and decisions regarding eligibility, enrollment and treatment outcomes. Ensuring appropriate and consistent clinical judgment was accomplished through standardized approaches applied across the trials, including training, assessment of clinical skills and refresher training. Standardized monitoring procedures were also applied across the trials, including routine (day-to-day) internal monitoring of performance and adherence to protocols, systematic external monitoring by funding agencies and external monitoring by experienced, independent trial monitors. A group of independent experts (Technical Steering Committee/Technical Advisory Group) provided regular monitoring and technical oversight for the trials. CONCLUSIONS: Harmonization of AFRINEST and SATT have helped to ensure consistency and quality of implementation, both internally and across the trials as a whole, thereby minimizing potential threats to the validity of the trials' results.

Epidemiologic and clinical features of Bell's palsy among children in Northern California.

BACKGROUND: Bell's palsy (BP) is an acute, idiopathic, and usually unilateral paralysis of the facial nerve. Large population-based studies of BP among children are lacking. We determined epidemiologic and clinical features of BP among children enrolled in a large integrated health care delivery system. METHODS: From 2001 through 2006, all children ≤18 years of age diagnosed with BP within the population of Kaiser Permanente Northern California were identified using the International Classification of Diseases, 9th Revision, code 351.0. All cases were adjudicated by an otolaryngologist and categorized as definite, probable, or rejected. Using chart abstraction forms, epidemiologic and clinical features of BP were determined. RESULTS: Of a total of 977 cases initially identified, 822 (84.1%) were adjudicated as a definite or probable case. The overall incidence rate of BP during the study period was 18.8 (95% CI 17.6-20.2) per 100,000 person-years. The incidence rate increased by age and was higher in females than males across all age strata. There was no evidence for a seasonal pattern in the occurrence of BP (p for trend = 0.81). CONCLUSIONS: BP among children may be more common than previously recognized.

Immunization and Bell's palsy in children: a case-centered analysis.

Bell's palsy (BP) is an acute and idiopathic paralysis of the facial nerve, with an estimated incidence ranging from 11.5 per 100,000 person-years to 53.3 per 100,000 person-years in different populations. BP has been reported following immunization with inactivated trivalent influenza vaccine (TIV) and hepatitis B virus (HBV) vaccine. Epidemiologic studies examining this association among children are lacking. From 2001 through 2006, all children aged ≤18 years diagnosed with BP within the Kaiser Permanente Northern California population were identified using International Classification of Diseases, Ninth Revision, code 351.0. All electronically identified cases were reviewed and adjudicated by an otolaryngologist (n = 233). Using a case-centered approach, the authors examined the risk of BP during 3 risk intervals. Immunization with TIV (odds ratio (OR) = 0.7, 95% confidence interval (CI): 0.2, 2.8), HBV vaccine (OR = 0.8, 95% CI: 0.2, 2.4), or any vaccine (treating all vaccines combined; OR = 0.9, 95% CI: 0.6, 1.4) was not associated with increased risk of BP 1-28 days after immunization. Similarly, no association was found between vaccines and BP during the periods 1-14 and 29-56 days following immunization. Results of this study suggest that there is no association between immunization and BP in children.

Clinically based surveillance of invasive meningococcal disease in young children admitted to selected US hospitals between January 2000 and June 2009: a retrospective cohort study.

Invasive meningococcal disease (IMD) is under-reported in countries that do not employ polymerase-chain reaction for surveillance because culture-negative cases are omitted. To evaluate a clinically based, case-finding method, we developed case definitions for "probable," "compatible with," and "possible, but unlikely" IMD, respectively, based on supportive documentation (e.g., discharge diagnosis of meningococcal infection, culture-negative bacterial meningitis, petechiae/purpura, Gram-negative diplococci on Gram stain) and weight of clinical evidence, which we then applied to electronic health records for all children aged ≤5 y who were admitted to approximately 100 US hospitals between January 2000 and June 2009. Among 47,863 qualifying admissions, 16 children had culture-positive IMD, 5 had "probable" IMD, and 5 had illness "compatible with" IMD. Five additional children had disease considered "possible but unlikely" IMD. Our case-finding methods suggest that culture-based ascertainment may underestimate the number of IMD cases by 31-63%, supporting findings in other nations that culture-based reporting provides incomplete information on disease incidence and therefore underestimates the potential benefits of routine vaccination of young children against meningococcal disease.

Nucleic acid transfer with hemifluorinated polycationic lipids.

In this study, the ability of synthetic fluorinated lipospermines to bind DNA and siRNA was investigated and the transfection efficiency and toxicity of the resulting lipoplexes in cell lines were evaluated. Three lipopolyamines displaying fluorous tags close to their cationic polar head ("HFP" polyamines) were synthesized. Their ability to condense pDNA and siRNA, and to form nanoparticles were characterized. Lipoplex stability was investigated in the presence of different surface active compounds and was shown to be significantly improved due to the presence of the fluorous tags. Transfection efficiencies were studied in HepG2 and 911 cell lines, and compared to that of DOGS, DOTAP, and Lipofectamine 2000. Also, the ability of these compounds to deliver nucleic acids into cells in the presence of high concentration of serum was quantified. By incorporating two fluorous tags in the direct vicinity of the polycationic head group of the lipospermines, we show efficient pDNA and siRNA formulation, and delivery to cultured cells. Fluorinated lipoplexes exhibit improved stability in the presence of amphiphilic compounds and retain high transfection efficiency in the presence of 50-75% serum. These results demonstrate that lipospermines displaying fluorous tags close to their cationic polar head bind to and deliver pDNA and siRNA with high cell viability in different cell lines. They are efficient non-viral vectors that exhibit remarkable serum compatibility.

"HFP" fluorinated cationic lipids for enhanced lipoplex stability and gene delivery.

Although a great number of cationic lipids have been designed and evaluated as gene delivery systems, there is still a need for improvement of nonviral vectors. Recently, cationic lipids incorporating terminal fluoroalkyl segments ("FHP" lipids) have been described to display remarkable transfection potency. Here, we describe the synthesis of a new family of fluorinated triblock cationic lipids in which a fluorous segment lays between the cationic and the lipophilic parts of the molecule ("HFP" lipids). The compounds were designed so their self-assembly would offer enhanced resistance toward the host's degradation mechanisms mediated by lipophilic insertion. Self-assembly properties of these cationic lipids were evaluated at the air-water interface where they collapse in a highly ordered liquid phase. The HFP lipids efficiently condense DNA, and the resulting lipoplexes display enhanced resistance to amphiphilic agents when compared to nonfluorinated or FHP cationic lipids. Transfection properties of the fluorinated vectors, alone or as mixtures with different helper lipids (DOPE and a fluorinated analogue of DOPE), were then investigated on different cell lines (BHK-21, HepG2, and HeLa) and compared to those of the reference cationic lipid DOTAP. Data show that impermeabilization of the lipidic phase by fluorous segments alter significantly the gene transfection activities. Remarkably, incorporation of DOPE within the lipoplexes provides the particles with high gene transfection activity without reducing their resistance to amphiphilic agents.

Benefits and risks of live attenuated influenza vaccine in young children.

OBJECTIVE: To examine the benefit-risk profile of live attenuated influenza vaccine (LAIV) across a range of clinical scenarios in which we varied assumptions regarding both the percentage of children who would receive LAIV in lieu of trivalent inactivated influenza virus (TIV) and the extent of off-label use. STUDY DESIGN: Model of expected benefits and risks of immunization of young children against influenza. METHODS: We estimated expected numbers of cases of influenza illness (FLU), medically significant wheezing (MSW), and hospitalization in a single influenza season under alternative assumptions regarding use of LAIV in lieu of TIV, based on projections from a large phase III trial. RESULTS: Assuming no use of LAIV in nonindicated children (aged <24 months and those with history of recurrent wheezing or asthma), and 50% use in lieu of TIV among children in the indicated population, there would be 2099 fewer FLU cases per 100,000 children aged 12 to 59 months, and no change in MSW or hospitalization. If LAIV also were used in lieu of TIV among 20% of children aged 12 to 23 months and 20% of children aged 24 to 59 months with a history of recurrent wheezing or asthma, there would be a further reduction of 397 FLU cases and 12 hospitalizations per 100,000 children aged 12 to 59 months, but 51 additional MSW cases. CONCLUSIONS: Our study suggests that even if LAIV were sometimes used inadvertently in clinical practice in young children for whom it is not indicated, the overall balance of expected benefits and risks would remain favorable.

7-Valent pneumococcal conjugate vaccine and lower respiratory tract infections: effectiveness of a 2-dose versus 3-dose primary series.

BACKGROUND: Immunogenicity studies suggest antibody responses from a 7-valent pneumococcal conjugate vaccine (PCV7) regimen consisting of 2 doses in the primary series are less immunogenic, for at least several vaccine serotypes, compared with a regimen consisting of 3 doses; evidence of effectiveness for prevention of invasive pneumococcal disease for both regimens is available but comparative data are lacking for prevention of lower respiratory tract diseases (LRTD). METHODS: We compared rates of LRTD between children who were born in 2002 and received 2 versus 3 PCV7 doses in the primary series, both before and after receipt of the booster dose, using a retrospective matched-cohort design and health insurance claims data. Two-dose and 3-dose children were matched (1:1) using propensity scoring. Cumulative rates of hospital admissions and outpatient visits for LRTD were tallied during the post-primary/pre-booster period and the post-booster period (to age 3 years), respectively. RESULTS: During the post-primary/pre-booster period, 3-dose children (n=3293) had 7.8 (95% CI: 0.8 to 14.8) fewer LRTD-related hospital admissions (per 1000 children) and 57 (95% CI: -6 to 128) fewer LRTD-related outpatient visits (per 1000 children) than matched 2-dose subjects (n=3293). During the post-booster period, the numbers of LRTD-related hospital admissions and outpatient visits did not differ significantly between 3-dose and 2-dose children. CONCLUSIONS: Our findings suggest that a 2-dose PCV7 primary series, while conferring savings from reduced vaccine costs in comparison with a 3-dose primary series, also may confer less protection against LRTD in the first year of life, at least during the period soon after the vaccine is introduced.

Strengthening the supply of routinely administered vaccines in the United States: problems and proposed solutions.

At the request of the Assistant Secretary for Health of the United States Department of Health and Human Services, the National Vaccine Advisory Committee organized workshops in February 2002 and January 2005 to identify the reasons for vaccine shortages and to develop strategies to prevent shortages in the future. This supplement to Clinical Infectious Diseases includes presentations outlining the problems associated with and proposed solutions for strengthening the supply of routinely administered vaccines in the United States.

Personal dosimetry of exposure to mobile telephone base stations? An epidemiologic feasibility study comparing the Maschek dosimeter prototype and the Antennessa SP-090 system.

The aim of our study was to test the feasibility and reliability of personal dosimetry. Twenty-four hour exposure assessment was carried out in 42 children, 57 adolescents, and 64 adults using the Maschek dosimeter prototype. Self-reported exposure to mobile phone frequencies were compared with the dosimetry results. In addition, dosimetry readings of the Maschek device and those of the Antennessa DSP-090 were compared in 40 subjects. Self-reported exposures were not associated with dosimetry readings. The measurement results of the two dosimeters were in moderate agreement (r(Spearman) = 0.35; P = .03). Personal dosimetry for exposure to mobile phone base station might be feasible in epidemiologic studies. However, the consistency seems to be moderate.

Population-based surveillance for childhood invasive pneumococcal disease in the era of conjugate vaccine.

BACKGROUND: Heptavalent pneumococcal conjugate vaccine was licensed in the United States in February 2000 and, following national guidelines, universally distributed in Massachusetts starting in July 2000 to children younger than 2 years of age and selected children 2-5 years of age. We performed statewide surveillance for all cases of invasive pneumococcal disease (IPD) in children younger than 18 years of age to determine risk features and contribution of vaccine failure to ongoing pneumococcal invasive disease. METHODS: Massachusetts pediatric IPD cases were identified via enhanced passive surveillance of microbiology laboratory reports of pneumococcal isolates from sterile body sites of children younger than 18 years for 2 years starting in October 2001. Serotyping was performed on isolates of Streptococcus pneumoniae from normally sterile body fluid. Case demographic and clinical data (including dates of prior doses of PCV7) were collected via follow-up telephone interviews with case primary care providers and/or parents. RESULTS: Between October 1, 2001 and September 30, 2003, 191 cases of IPD were identified statewide (138 in children younger than 5 years). Annual incidence rate for IPD was 17.4 per 100,000 children younger than 5 years, representing a decline of 69% when compared with annual incidence rate of 56.9 per 100,000 from Massachusetts statewide active surveillance performed 1990-1991. In 2001-2003, 30% of cases occurred in the first year of life (36.5 per 100,000), representing a 7.8-fold increased risk compared with children older than 1 year of age. Race-specific annual incidence rates in blacks and Hispanics were 2.3-fold (95% confidence interval, 1.21-4.42) and 1.9-fold (95% confidence interval, 1.06-3.37), greater than in whites. Fifty-nine cases were reported to have underlying comorbid conditions. Serotyping was available for 136 of 191 (71%) cases younger than 18 years; of isolates available for serotyping, 40 (29%) were vaccine serotype (ST), 31 (23%) vaccine-related ST and 65 (48%) nonvaccine ST. Seven of 40 cases with IPD caused by vaccine ST received at least 3 doses of PCV7 vaccine before IPD. CONCLUSIONS: Universal administration of PCV7 to children younger than 2 years of age and selective administration to children 2-5 years of age has resulted in a significant decline in IPD in Massachusetts. Children younger than 1 year of age, African American and Hispanic children and those with recognized comorbid illnesses (malignancy, human immunodeficiency virus, immune deficiency, nephrotic syndrome, etc.) continue to remain at risk for IPD. These risk features should be considered when evaluating febrile infants and children.