Test of Special Relativity Using a Fiber Network of Optical Clocks.

Phase compensated optical fiber links enable high accuracy atomic clocks separated by thousands of kilometers to be compared with unprecedented statistical resolution. By searching for a daily variation of the frequency difference between four strontium optical lattice clocks in different locations throughout Europe connected by such links, we improve upon previous tests of time dilation predicted by special relativity. We obtain a constraint on the Robertson-Mansouri-Sexl parameter |α|≲1.1×10^{-8}, quantifying a violation of time dilation, thus improving by a factor of around 2 the best known constraint obtained with Ives-Stilwell type experiments, and by 2 orders of magnitude the best constraint obtained by comparing atomic clocks. This work is the first of a new generation of tests of fundamental physics using optical clocks and fiber links. As clocks improve, and as fiber links are routinely operated, we expect that the tests initiated in this Letter will improve by orders of magnitude in the near future.

Frequency ratio of two optical clock transitions in 171Yb+ and constraints on the time variation of fundamental constants.

Singly ionized ytterbium, with ultranarrow optical clock transitions at 467 and 436 nm, is a convenient system for the realization of optical atomic clocks and tests of present-day variation of fundamental constants. We present the first direct measurement of the frequency ratio of these two clock transitions, without reference to a cesium primary standard, and using the same single ion of 171Yb+. The absolute frequencies of both transitions are also presented, each with a relative standard uncertainty of 6×10(-16). Combining our results with those from other experiments, we report a threefold improvement in the constraint on the time variation of the proton-to-electron mass ratio, µ/µ=0.2(1.1)×10(-16) yr(-1), along with an improved constraint on time variation of the fine structure constant, α/α=-0.7(2.1)×10(-17) yr(-1).

Transportable cavity-stabilized laser system for optical carrier frequency transmission experiments.

We report the design and performance of a transportable laser system at 1543 nm, together with its application as the source for a demonstration of optical carrier frequency transmission over 118 km of an installed dark fiber network. The laser system is based around an optical reference cavity featuring an elastic mounting that bonds the cavity to its support, enabling the cavity to be transported without additional clamping. The cavity exhibits passive fractional frequency insensitivity to vibration along the optical axis of 2.0×10(-11) m(-1) s(2). With active fiber noise cancellation, the optical carrier frequency transmission achieves a fractional frequency instability, measured at the user end, of 2.6×10(-16) at 1 s, averaging down to below 3×10(-18) after 20,000 s. The fractional frequency accuracy of the transfer is better than 3×10(-18). This level of performance is sufficient for comparison of state-of-the-art optical frequency standards and is achieved in an urban fiber environment.

Under-recognition and reporting of dengue in Cambodia: a capture-recapture analysis of the National Dengue Surveillance System.

Robust disease burden estimates are important for decision-making concerning introduction of new vaccines. Dengue is a major public health problem in the tropics but robust disease burden estimates are lacking. We conducted a two-sample, capture-recapture study in the largest province in Cambodia to determine disease under-recognition to the National Dengue Surveillance System (NDSS). During 2006-2008, community-based active surveillance for acute febrile illness was conducted in 0- to 19-year-olds in rural and urban areas combined with testing for dengue virus infection. Of 14 354 individuals under active surveillance (22 498 person-seasons), the annual incidence ranged from 13·4 to 57·8/1000 person-seasons. During the same period, NDSS incidence rates ranged from 1·1/1000 to 5·7/1000, which was 3·9- to 29·0-fold lower than found in the capture-recapture study. In hospitalized cases, the rate of under-recognition was 1·1- to 2·4-fold. This study shows the substantial degree of under-recognition/reporting of dengue and that reported hospitalized cases are not a good surrogate for estimating dengue disease burden.

Comparing ultrastable lasers at 7 × 10-17 fractional frequency instability through a 2220 km optical fibre network.

Ultrastable lasers are essential tools in optical frequency metrology enabling unprecedented measurement precision that impacts on fields such as atomic timekeeping, tests of fundamental physics, and geodesy. To characterise an ultrastable laser it needs to be compared with a laser of similar performance, but a suitable system may not be available locally. Here, we report a comparison of two geographically separated lasers, over the longest ever reported metrological optical fibre link network, measuring 2220 km in length, at a state-of-the-art fractional-frequency instability of 7 × 10-17 for averaging times between 30 s and 200 s. The measurements also allow the short-term instability of the complete optical fibre link network to be directly observed without using a loop-back fibre. Based on the characterisation of the noise in the lasers and optical fibre link network over different timescales, we investigate the potential for disseminating ultrastable light to improve the performance of remote optical clocks.

Frequency Comparison of [Formula: see text] Ion Optical Clocks at PTB and NPL via GPS PPP.

We used precise point positioning, a well-established GPS carrier-phase frequency transfer method to perform a direct remote comparison of two optical frequency standards based on single laser-cooled [Formula: see text] ions operated at the National Physical Laboratory (NPL), U.K. and the Physikalisch-Technische Bundesanstalt (PTB), Germany. At both institutes, an active hydrogen maser serves as a flywheel oscillator which is connected to a GPS receiver as an external frequency reference and compared simultaneously to a realization of the unperturbed frequency of the (2)S1/2(F=0)-(2)D3/2(F=2) electric quadrupole transition in [Formula: see text] via an optical femtosecond frequency comb. To profit from long coherent GPS-link measurements, we extrapolate the fractional frequency difference over the various data gaps in the optical clock to maser comparisons which introduces maser noise to the frequency comparison but improves the uncertainty from the GPS-link instability. We determined the total statistical uncertainty consisting of the GPS-link uncertainty and the extrapolation uncertainties for several extrapolation schemes. Using the extrapolation scheme with the smallest combined uncertainty, we find a fractional frequency difference [Formula: see text] of -1.3×10(-15) with a combined uncertainty of 1.2×10(-15) for a total measurement time of 67 h. This result is consistent with an agreement of the frequencies realized by both optical clocks and with recent absolute frequency measurements against caesium fountain clocks within the corresponding uncertainties.

Iron deficiency in children: the relationship between pretreatment laboratory tests and subsequent hemoglobin response to iron therapy.

The goal of detecting iron deficiency in children is to identify those whose Hb concentration will rise in response to treatment with iron. In a controlled treatment trial conducted among Eskimo children, we examined the effectiveness of various measures of iron nutrition in predicting a response to iron therapy (greater than 1.0 g/dl rise in Hb). A response was seen in 43%, and an additional 26% had an intermediate response (0.5 to 1.0 g/dl rise). When individual Hb values were expressed as SD scores of the Hb distribution of a reference population, a marked skew toward low scores was seen before treatment. After treatment, the distribution became more Gaussian, indicating that iron deficiency had been the major cause of anemia. Serum ferritin, transferrin saturation, and free erythrocyte protoporphyrin levels moved toward normal with treatment, however, none of the tests used was very effective in distinguishing individuals who would have a response t Hb from those who would not (sensitivities: 63 to 42%, specificities: 45 to 61%). Laboratory measures of iron nutrition were far more helpful in depicting the iron status of the population than they were in distinguishing iron-responsive from nonresponsive individuals.

Characteristics of chemically aggregated IgM in an immunoglobulin class-specific immune complex assay.

Immune complexes have been implicated in the pathogenesis of a number of infectious diseases. The predominant immunoglobulin class associated with circulating immune complexes is IgG, although immune complexes containing IgM have been described. The role of IgM immune complexes in disease pathogenesis has been difficult to characterize due to the lack of a reliable in vitro model. Immunoglobulins aggregated with bis-diazotized benzidine (BDB) are known to function as model immune complexes. We have developed an IgM immune complex using BDB-aggregated IgM which can be used as a reference in a conglutinin-based immune complex assay. Using this assay system, humans and chimpanzees with acute hepatitis A were found to have circulating immune complexes that contained IgM as the predominant antibody.

Hepatitis B infection in the United States. Recent trends and future strategies for control.

Viral hepatitis is the second most common reportable infectious disease in the United States, with hepatitis B accounting for about 45 percent of cases. Although approximately 25,000 cases of hepatitis B are reported to the Centers for Disease Control each year, it is estimated that there are actually about 300,000 annual infections (up from 200,000 in the early 1980s). This increase has occurred despite the availability of a safe and effective hepatitis B vaccine since 1982. Hepatitis B occurs primarily in young adults because of lifestyle or occupationally related exposure. Reported cases in homosexual men have decreased, probably because of changes in behavior related to the acquired immunodeficiency syndrome epidemic. Cases due to heterosexual transmission and intravenous drug use are increasing. The proportion of cases in health care workers has decreased, possibly because 30 to 40 percent of high-risk health care workers have been vaccinated. Because of the increase in hepatitis B infection, the strategy of controlling this disease by vaccinating high-risk groups must be reconsidered. Alternative strategies include selective or universal immunization of infants or adolescents. Although integrating hepatitis B vaccine into infant immunization programs takes advantage of the existing system, it would not lead to measurable disease reduction for two decades. Immunizing adolescents would more rapidly reduce the incidence of hepatitis B, but currently no structured health care setting reaches them.

Hepatitis B vaccine administered to children and adolescents at yearly intervals.

OBJECTIVE: Hepatitis B vaccines are usually administered on a schedule of 0, 1 to 2, and 6 months. Longer intervals between the second and third doses have been studied, but the effectiveness of hepatitis B vaccine administered at intervals of >2 months between the first and second doses have not been studied. Our objective was to compare the antibody response in recipients of Engerix-B hepatitis B vaccine administered at 12-month intervals to the response to vaccine administered at 0-, 1-, and 6-month intervals. METHODS: A total of 389 children, 5 through 16 years of age, were randomized to receive Engerix-B (10 mg) at a schedule of either 0-, 1-, and 6-month intervals or 0-, 12-, and 24-month intervals. Blood was drawn before and 1 month after the third dose. RESULTS: Immediately before the third dose of vaccine, 92.3% of children who received vaccine on the 0-, 1-, and 6-month schedule and 88.8% of children who received the 0-, 12-, and 24-month schedule had antibody to hepatitis B surface (anti-HBs) antigen concentrations >/=10 mIU/mL. Of the children in the 0-, 1-, and 6-month schedule, 95% received the third dose according to protocol versus 90% of those in the 0-, 12-, 24-month schedule. The geometric mean anti-HBs concentration just before the third dose for recipients of the 0-, 1-, and 6-month schedule (117.9 mIU/mL) was somewhat lower than that for the children who had received vaccine on the 0-, 12-, and 24-month schedule (162.1 mIU/mL). One month after the third dose, >98% of all children had anti-HBs concentrations >/=10 mIU/mL and high geometric mean antibody concentrations were observed in both groups: 5687 mIU/mL for children on the 0-, 1-, and 6-month schedule and 3159 mIU/mL for children on the 0-, 12-, and 24-month schedule. Body mass index was correlated inversely with final antibody concentration, but age was not a factor after adjustment for body mass index. DISCUSSION: Engerix-B administered on a 0-, 12-, and 24-month schedule is highly immunogenic. Providers should consider this alternate immunization schedule for children who are at low risk of immediate exposure to hepatitis B infections.

Prevention of perinatal acquisition of hepatitis B virus carriage using vaccine: preliminary report of a randomized, double-blind placebo-controlled and comparative trial.

Hepatitis B is a serious disease of global significance. In developing countries, hepatitis B virus (HBV) infection and its sequelae rank among the public health problems of highest priority. Infants born to mothers who are chronic carriers of HBV are at particularly high risk of acquiring infection and becoming chronic HBV carriers. The efficacy of hepatitis B vaccine alone in preventing the transmission of HBV to infants born to HBV carrier mothers was determined in a double-blind placebo-controlled trial. Infants received plasma-derived vaccine at birth, 1 month, and 6 months of age. Of 180 infants born to hepatitis B surface antigen (HBsAg)-positive mothers, equal numbers received National Institute of Allergy and Infectious Disease (NIAID) vaccine, Beijing Institute of Vaccine and Serum (BIVS) vaccine, and placebo. The cumulative seroconversion to the vaccines at 1 year of age was 95% and 75%, respectively. Vaccine efficacy as measured by the prevention of HBsAg-positive events was 88% for the NIAID vaccine and 51% for the BIVS vaccine. Vaccine efficacy was similar among infants born to hepatitis Be antigen-positive mothers. Because of the low efficacy of the BIVS vaccine, an additional group of 28 infants was given vaccine and hepatitis B immune globulin at birth. The resulting efficacy was 83%. The results of this trial indicate that hepatitis B vaccine alone can substantially reduce perinatally acquired HBV infection and the resulting chronic carrier state.

The sequence of hepatitis E virus isolated directly from a single source during an outbreak in China.

In this study an IgM antibody-mediated antigen-capture procedure for direct extraction of hepatitis E virus (HEV) RNA from clinical specimens was developed and used with an efficient method for generating viral cDNA that was subsequently sequenced using the dideoxy chain termination method. This is the first time the complete HEV genome has been isolated directly from a single human clinical specimen obtained during an outbreak of enterically transmitted non-A, non-B hepatitis. When the Chinese-derived sequence was compared with the original isolate of Burmese HEV from an experimentally infected cynomolgus macaque, the homology between the two sequences was 94% and 98.5% at the nucleotide and amino acid levels, respectively. The methods we developed for generating and sequencing genomic HEV cDNA dramatically improved the efficiency of cloning the viral genome and should be helpful for continued analysis of this virus as well as other RNA viruses that have proven to be difficult to clone and sequence directly.

Comparative safety and immunogenicity of two recombinant hepatitis B vaccines given to infants at two, four and six months of age.

OBJECTIVES: To evaluate the relative safety and immunogenicity of the two recombinant hepatitis B vaccines licensed in the United States with doses recommended for routine immunization of low risk infants and a schedule that corresponds with routine pediatric visits. METHODS: Healthy infants were immunized at 2, 4 and 6 months of age with hepatitis B vaccine manufactured by either SmithKline Beecham (Engerix-B, 10 micrograms/dose, n = 228) or Merck and Co. (Recombivax HB, 2.5 micrograms/dose, n = 200). Adverse reactions were ascertained by parental reports and interviews and by review of medical records. Antibody concentrations to hepatitis B surface antigen (anti-HBs) were measured in sequential serum specimens by enzyme immunoassay. RESULTS: Adverse reactions were mild and the rates were not significantly different between the two groups. After the first and second doses the rates of seropositivity (> or = 10 mIU/ml) and seroprotection (> or = 10 mIU/ml) were significantly higher in infants given SmithKline Beecham vaccine (P < 0.01). After the second and third doses infants given SmithKline Beecham vaccine also had significantly higher geometric mean anti-HBs concentrations compared with those given Merck vaccine (348.0 mIU/ml vs. 66.9 and 1914.8 mIU/ml vs. 514.8 mIU/ml, respectively, P < 0.001). Nevertheless after the third dose 99% of infants in both vaccine groups achieved seroprotective antibody concentrations. CONCLUSIONS: Both recombinant hepatitis B vaccines were safe and immunogenic when administered concurrently with other pediatric vaccines at 2, 4 and 6 months of age, but earlier protective responses were observed with the SmithKline Beecham vaccine than with the Merck vaccine.

The cost-effectiveness of adolescent hepatitis A vaccination in states with the highest disease rates.

BACKGROUND: The Advisory Committee on Immunization Practices has recommended routine childhood hepatitis A vaccination in states and communities where the incidence of disease exceeds the national average, but most adolescents are currently unprotected from infection. OBJECTIVE: To estimate clinical and economic consequences of vaccinating adolescents against hepatitis A in the 10 states with the highest disease rates. DESIGN: Decision analysis was used to assess cost-effectiveness from societal and health system perspectives. Parameter estimates were obtained from national surveillance data, a study of hepatitis A cases, and an expert panel. MAIN OUTCOME MEASURES: Reduction in disease incidence; costs of vaccination, treatment, and work loss; years of life saved (YOLS); and costs per YOLS. RESULTS: In states with the highest disease rates, vaccination of adolescents against hepatitis A would reduce the lifetime risk of symptomatic infection from 3.3% to 0.7% and prevent loss of 2117 years of life. Vaccination of a single birth cohort would cost $30.9 million, yet treatment and work loss costs would decline $14.2 million and $23.8 million, respectively. Hepatitis A vaccination would cost the health system $7902 per YOLS or $13,722 per discounted YOLS. Results are most sensitive to variation in the discount rate and assumptions regarding long-term vaccine protective efficacy. CONCLUSIONS: Hepatitis A vaccination of adolescents in states with high disease rates would reduce costs to society. Although health system costs would increase, cost-effectiveness is comparable to other recommended vaccines and superior to many commonly used medical interventions. Arch Pediatr Adolesc Med. 2000;154:763-770

Impact of hepatitis B virus infection on women and children.

HBV infection acquired during infancy and early childhood has a high likelihood of progressing to chronic infection, which can lead to chronic hepatitis, cirrhosis, and primary hepatocellular carcinoma. In areas of the world where HBV infection occurs predominantly in infants and young children, routine infant immunization with hepatitis B vaccine is the most appropriate vaccination strategy. In the United States, the majority of HBV infections occur in adults with behaviors or occupations that put them at risk for HBV infection. Nevertheless, infection acquired during infancy and early childhood contributes significantly to the burden of chronic liver disease in the United States. Until recently, the vaccination strategy in the United States has included HBsAg screening of pregnant women and vaccination of infants born to infected women and vaccination of people in groups at high risk for HBV infection. Because of the difficulties in accessing and vaccinating persons from high-risk groups and the recent findings that HBV infection occurs more commonly among children in some groups in the United States than previously appreciated, the Immunization Practices Advisory Committee of the US Public Health Service and the American Academy of Pediatrics in 1991 endorsed a strategy of universal immunization of infants for hepatitis B. This strategy has the advantages of accessing infants in the United States through preexisting vaccine delivery systems and vaccinating individuals prior to their engaging in high-risk behavior. Continued screening of pregnant women for HBsAg is necessary to prevent perinatal HBV transmission and to identify for vaccination those household and sexual contacts of HBV carriers, a group that is also at high risk of HBV infection.

Hepatitis C.

Hepatitis C virus (HCV) has emerged as a major cause of chronic liver disease worldwide. The widespread endemicity of HCV infection is the result of a combination of factors, including those related to the genetic diversity of the virus and the host response and those related to the specific settings and behaviors that have facilitated transmission. Most people who contract HCV infection become persistently infected, and the mechanism by which persistent infection is established seems to be related to the lack of development of an effective neutralizing immune response. The magnitude of the spread of HCV infection primarily is related to specific risk factors for transmission. The most important human behavior related to the transmission of HCV has been injection drug use, which in many developed countries has been the leading source of HCV infection during the past 20 to 30 years. The recognition of the clinical importance of HCV infection has resulted in a substantial amount of attention and resources rapidly directed toward developing new and improved therapies. The perception, however, of the public health importance of HCV infection is still limited. Despite the knowledge that injection drug use is the major source of HCV infection in the United States, this message has not been included in prevention and treatment programs, and the resources needed to support strong public health programs have yet to be identified.

Sequence-specific, single-primer amplification and detection of PCR products for identification of hepatitis viruses.

A simple system to detect polymerase chain reaction (PCR) amplification products was developed. This detection method has the sensitivity and the specificity of nested primer PCR amplification or Southern blot hybridization of PCR product. Digoxigenin-labeled PCR products were hybridized with a biotinylated probe in liquid phase and captured on to microtiter wells coated with antidigoxigenin followed by detection with streptavidin-peroxidase. The sensitivity of this assay for the detection of hepatitis A virus, hepatitis B virus, and hepatitis C virus is equal to that of existing nucleic acid detection systems.

The emergence of hepatitis B as a sexually transmitted disease.

In the United States, approximately 300,000 cases of hepatitis B virus infection occur annually, and heterosexual activity is one of the most commonly reported risk factors for acquiring disease. Until the number of infections transmitted through heterosexual contact can be reduced through hepatitis B vaccination, there is little chance of controlling this infection.

Decline in infant mortality of Alaskan Yupik Eskimos from 1960 to 1980.

A 1960-62 study of southwestern Alaskan Eskimos documented an infant mortality rate--102.6 deaths per 1,000 live births--that was four times greater than that of U.S. whites. In 1980-81, 20 years after the original study, a similar cohort was identified in this population so that changes in infant mortality and other birth characteristics could be examined. Average birth weight and the amount of prenatal care received by the mothers increased from 1960 to 1980. Birth weight and prenatal visits were positively correlated. Results of the followup also revealed a 1980-81 infant mortality rate--17.1 deaths per 1,000 live births--that was less than a fifth of the 1960-62 rate and no longer significantly different from the national rate. Major changes associated with the decrease in mortality during the first 28 days of life (neonatal mortality) were a significant increase in the proportion of infants born in hospitals and an associated decrease in the number of deaths of infants weighing less than 2,500 grams at birth. The reduction in mortality during the rest of the first year of life was related to a decrease in deaths due to infectious diseases, particularly measles and pertussis. Changes in infant mortality reflect the increased availability of health care in this region, improved immunization programs, and the establishment of the Bethel Prematernal Home in Bethel, AK.