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.

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 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.

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.

Measurement of the electric quadrupole moment of the 4d2D5/2 level in 88Sr+.

The quadrupole moment of the 4d (2)D(5/2) level in 88Sr+ has been measured to be 2.6(3)ea(2)(0), where a(0) is the Bohr radius and e the elementary charge. A single laser-cooled strontium ion was confined in an end cap trap with a variable dc quadrupole potential, and measurements were made on the 5s (2)S(1/2)-4d (2)D(5/2) transition at 674 nm using a femtosecond optical frequency comb. This work shows that measurements of the unperturbed 88Sr+ transition frequency with sub-Hz uncertainty are possible and is important in understanding the reproducibility of ion trap optical frequency standards.

Hertz-level measurement of the optical clock frequency in a single 88Sr+ ion.

The frequency of the 5s 2S(1/2)-4d 2D(5/2) electric quadrupole clock transition in a single, trapped, laser-cooled 88Sr+ ion has been measured by using an optical frequency comb referenced to a cesium fountain primary frequency standard. The frequency of the transition is measured as 444,779,044,095,484.6 (1.5) hertz, with a fractional uncertainty within a factor of 3 of that of the cesium standard. Improvements required to obtain a cesium-limited frequency measurement are described and are expected to lead to a 88Sr+ optical clock with stability and reproducibility exceeding that of the primary cesium standard.

Control of hepatitis A through routine vaccination of children.

CONTEXT: The impact of routine hepatitis A vaccination of children living in large communities with elevated disease rates has not been evaluated. OBJECTIVE: To determine the effect of routine vaccination of children on disease incidence in a community with recurrent hepatitis A epidemics. DESIGN, SETTING, AND PARTICIPANTS: Community-based demonstration project conducted from January 12, 1995, through December 31, 2000, in Butte County, California, among children aged 2 to 17 years. INTERVENTION: In 1995, vaccination was offered to children aged 2 to 12 years during vaccination clinics conducted on 2 occasions 6 to 12 months apart at most schools in the county. In 1996-2000, vaccine was distributed to community health care clinicians, who vaccinated eligible children without charge. Vaccine was also available at health department clinics, selected child care centers, and other sites. MAIN OUTCOME MEASURES: Hepatitis A vaccination coverage, hepatitis A incidence, and vaccine effectiveness. RESULTS: During the study period, 29 789 (66.2%) of an estimated 44 982 eligible children received at least 1 vaccine dose; 17 681 (39.3%) received a second dose. The number of hepatitis A cases among the entire county population declined 93.5% during the study period, from 57 cases in 1995 to 4 in 2000, the lowest number of cases reported in the county since hepatitis A surveillance began in 1966. The 2000 incidence rate of 1.9 per 100 000 population was the lowest of any county in the state. Of the 245 cases reported during the 6-year period, 40 (16.3%) occurred among children 17 years of age or younger, of which 16 (40%) occurred in 1995 and only 1 in 2000. One of the 27 case patients eligible for vaccination had been vaccinated, having received the first dose 3 days before symptom onset. The estimated protective vaccine efficacy was 98% (95% confidence interval, 86%-100%). CONCLUSIONS: In this population, hepatitis A vaccine was highly effective in preventing disease among recipients. Childhood vaccination appears to have decreased hepatitis A incidence among children and adults and controlled the disease in a community with recurrent epidemics.

Hepatitis E virus antibody prevalence among persons who work with swine.

Prevalence of antibody and risk factors to hepatitis E virus (HEV) infection were determined in a cross-sectional study of 2 group-matched populations: swine farmers (n=264) and persons without occupational exposure to swine (n=255) in Moldova, a country without reported cases of hepatitis E. The prevalence of HEV infection was higher among swine farmers than among the comparison group (51.1% vs. 24.7%; prevalence ratio, 2.07; 95% confidence interval [CI], 1.62-2.64). In multivariate analysis, HEV infection was associated with an occupational history of cleaning barns or assisting sows at birth (odds ratio [OR], 2.46; 95% CI, 1.52-4.01), years of occupational exposure (OR, 1.04 per year; 95% CI, 1.01-1.07), and a history of drinking raw milk (OR, 1.61; 95% CI, 1.08-2.40). HEV infection was not associated with civilian travel abroad or having piped water in the household. The increased prevalence of HEV infection among persons with occupational exposure to swine suggests animal-to-human transmission of this infection.

Childhood hepatitis B virus infections in the United States before hepatitis B immunization.

OBJECTIVE: To estimate the number of hepatitis B virus (HBV) infections among US children younger than 10 years before implementation of routine childhood hepatitis B immunization. METHODS: Incidence of HBV infection in children was modeled from existing prevalence data by means of regression analysis. Sources of data for the models included published and unpublished surveys that determined the prevalence of HBV infection in US-born children. The number of nonperinatal HBV infections in children younger than 10 years was estimated by applying these infection rates to 1991 population data according to maternal race, ethnicity, and birthplace. RESULTS: Estimated annual rates of infection ranged from 24 per 100 000 in non-Asian children to 2580 per 100 000 in children of Southeast Asian immigrant mothers. These rates indicate that by the early 1990s, HBV was infecting 16 000 children who were younger than 10 years (8700 non-Asian children and 7300 Asian-American children) annually. The total estimate, not including perinatal infections, ranged from 12 000 (95% confidence interval: 5500-27 700) to 24 900 (95% confidence interval: 16 700-42 300) infections and depended on how the estimated rates were applied to the population data. CONCLUSION: Thousands of US children were infected each year with HBV before routine infant hepatitis B immunization, placing them at high risk of death from cirrhosis or hepatocellular carcinoma later in life.

Evaluation of the response to a booster dose of hepatitis B vaccine in previously immunized healthcare workers.

INTRODUCTION: Hepatitis B vaccination is recommended for all healthcare workers (HCW) at risk of exposure to infectious body fluids. However, the absolute duration of protection from immunization is unknown. The purpose of this randomized comparison trial was to determine how previously immunized HCW respond to different booster doses of hepatitis B vaccine. METHOD: Adult HCW (n=59) were classified by level of hepatitis B surface antigen (anti-HBs), either <10 milli-International Units per milliliter (mIU/ml) or 10-50 mIU/ml. Participants were then randomized to receive a 2.5 or 10 microg dose of hepatitis B vaccine. Evaluation of anti-HBs levels were conducted 10 to 14 days, one month and one year postbooster. RESULTS AND DISCUSSION: All participants responded to the booster dose with increased anti-HBs levels. At 14 days, mean anti-HBs levels were significantly higher for those with higher levels at baseline (P=0.004) and those receiving the 10 microg dose (P=0.016). At one month, those with higher anti-HBs levels at baseline and those receiving the 10 microg dose were significantly higher (P<0.01 for both). At one year, the increase for the higher dose was no longer statistically significant when examined by itself (P=0.081); statistical significance (P=0.021) was achieved after adjusting for anti-HBs level at baseline. For all participants, the geometric mean anti-HBs level was 2618 mIU/ml at 14 days, 2175 mIU/ml at one month and 88.9 mIU/ml at one year. At all time points the increase in anti-HBs levels represented an increase over the geometric mean baseline level of anti-HBs (7.4 mIU/ml). Hepatitis B immunized adults responded to a booster dose of hepatitis B vaccine from 3 to 13 yr postvaccination series. Data support current recommendations that immunized HCW do not require periodic antibody testing or vaccine boosters.

Screening for chronic hepatitis B and C virus infections in an urban sexually transmitted disease clinic: rationale for integrating services.

BACKGROUND AND OBJECTIVES: Clients attending sexually transmitted disease (STD) clinics are at risk for multiple infections (e.g., STDs, HIV, and infectious viral hepatitis). Risk assessment and serosurveys can document the need for hepatitis screening and vaccination services. GOAL: To determine hepatitis C and B virus seroprevalence, identify predictive risk factors, and provide a rationale for integrating hepatitis services in an STD clinic. METHODS: During various periods in 1998, consecutive clients completed a self-administered risk assessment and were offered screening for markers of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection (HBV core antibody and anti-HCV [enzyme-linked immunosorbent assay 3.0, confirmed by recombinant immunoblot assay 2.0]). RESULTS: Sixteen percent of 300 clients tested for an anti-HBV core were positive, with injecting-drug users (IDUs) and men who have sex with men (MSM) having higher prevalences (50% and 37%, respectively). Of 615 clients tested for anti-HCV, 21 (3.4%) were positive. Injecting-drug users (n = 34) had a 38% anti-HCV prevalence compared with 1.1% for non-IDUs. Of 66 non-IDU MSM tested, none was HCV infected. IDUs had a high prevalence of past STDs (> 50%) and unsafe sexual behavior. CONCLUSIONS: Injecting drug users and MSM are at high risk for STDs, HIV, and hepatitis infections and could benefit from a "one-stop" STD clinic that included hepatitis prevention services.

[Prevalence of mutants in the determinant region of hepatitis B surface antigen among Chinese carriers after receiving only active postexposure immunoprophylaxis].

OBJECTIVE: To determine the frequency of hepatitis B surface antigen (HBsAg) mutations in the alpha determinant region among children who developed chronic hepatitis B virus (HBV) infection after receiving only active postexposure immunoprophylaxis. METHODS: HBsAg mutations were determined by PCR-directed nucleotide sequencing and sequence-specific solid-phase PCR analysis(SS-SPPCR) for 97 Chinese carrier cases after hepatitis B vaccination, for 88 children born aged women controls, and for 95 population based children controls. RESULTS: Prevalence of amino acid substitutions as detected by direct sequencing among carrier cases, women controls, and children controls were 30.9%, 10.2%, and 5.3%, respectively. The most frequent amino acid substitutions observed were at residues 145, 126, and 133. However, there was no difference in the prevalence of 145 and 126 amino acid mutants as detected by a sensitive SS-SPPCR method between carrier cases and controls. The prevalence of 145 Arg and 145 Ala mutants that were detected by SS-SPPCR was 39.2%, 33.0% and 32.6% among carrier cases, women controls, and children controls, respectively. The total odds ratio was 5.41 for mutants detected by direct sequencing. Odds ratio were 34.55 and 33.39 among adw2 subtype and genotype B subjects for mutants detected by direct sequencing, respectively. CONCLUSIONS: The results show that hepatitis B virus mutants in the determinant are fairly consistent observed but without immune selective pressures; HBV variant strains may pre-existent as minor quasispecies. The prevalence of mutants is related to HBV subtypes and genotypes.

Evaluation of the effectiveness of targeted lookback for HCV infection in the United States-interim results.

BACKGROUND: As part of a nationwide program to identify persons at increased risk for HCV infection, persons who received blood from donors who later tested positive for anti-HCV are being directly notified. STUDY DESIGN AND METHODS: In December 1999, all 198 blood collection establishments (BCEs) and 5442 hospital transfusion services (TSs) in the United States were surveyed by mailed questionnaire to evaluate their progress in carrying out this notification. RESULTS: Eighty-one percent of the BCEs and 64 percent of the TSs responded. After correcting for nonresponse, an estimated 98,484 components at potential risk for transmitting HCV, according to previous testing of multiantigen-screened donors, were identified nationwide, of which 85 percent had been transfused to recipients. Lookback for these recipients was completed for 80 percent, of whom 69 percent had died. Of those living, 78 percent were successfully notified. An estimated 49.5 percent of those notified were tested; 18.9 percent of those tested were anti-HCV positive, and 32 percent of that group knew they were positive before notification. On the basis of an 85.5 percent reported completion rate for component notifications back through 1988, an estimated 1520 persons will have been newly identified as anti-HCV-positive when lookback related to multiantigen screening of donors is completed. CONCLUSION: Targeted lookback related to previous multiantigen screening of donors will identify <1 percent of the estimated 300,000 HCV-positive persons in the United States who may have acquired their infection via blood transfusion.

Genetic relatedness of hepatitis A virus isolates during a community-wide outbreak.

In 1993-94, a community-wide outbreak of hepatitis A occurred in Stanislaus County, California. Stool specimens collected from a sample of 33 case patients were used to evaluate the duration of hepatitis A virus (HAV) excretion and the genetic relatedness of HAV isolates. Twenty-four percent of the patients had a stool sample positive for HAV antigen by enzyme immunoassay, whereas 91% had at least one stool positive for HAV RNA by RT-PCR amplification. Children were found to excrete low levels of HAV RNA for up to 10 weeks after the onset of symptoms. Analysis of the HAV VP1 amino terminus and VP1/P2A regions showed that a limited number of HAV isolates circulated during the epidemic and the majority of the cases were infected with the same strain.

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

Duration of viremia in hepatitis A virus infection.

The duration of viremia and time course for development of IgM antibodies were determined prospectively in natural and experimental hepatitis A virus (HAV) infection. Serial serum samples from HAV-infected men (n=13) and experimentally infected chimpanzees (n=5) were examined by nested reverse-transcriptase polymerase chain reaction analysis to detect HAV RNA and by ELISA to detect IgM antibodies to HAV. Among infected humans, HAV RNA was detected an average of 17 days before the alanine aminotransferase peak, and viremia persisted for an average of 79 days after the liver enzyme peak. The average duration of viremia was 95 days (range, 36-391 days). Results were similar in chimpanzees. In addition, HAV RNA was detected in serum of humans and chimpanzees several days before IgM antibodies to HAV were detected. These results indicate that adults with HAV infection are viremic for as long as 30 days before the onset of symptoms and that the duration of viremia may be longer than previously described.

Identification of hepatitis B virus indigenous to chimpanzees.

Hepatitis B viruses (HBV) and related viruses, classified in the Hepadnaviridae family, are found in a wide variety of mammals and birds. Although the chimpanzee has been the primary experimental model of HBV infection, this species has not been considered a natural host for the virus. Retrospective analysis of 13 predominantly wild-caught chimpanzees with chronic HBV infection identified a unique chimpanzee HBV strain in 11 animals. Nucleotide and derived amino acid analysis of the complete HBV genome and the gene coding for the hepatitis B surface antigen (S gene) identified sequence patterns that could be used to reliably identify chimpanzee HBV. This analysis indicated that chimpanzee HBV is distinct from known human HBV genotypes and is closely related to HBVs previously isolated from a chimpanzee, gibbons, gorillas, and orangutans.

The past incidence of hepatitis C virus infection: implications for the future burden of chronic liver disease in the United States.

Because chronic liver disease may develop many years after acute hepatitis C virus (HCV) infection, the past incidence of acute infections is a major determinant of the future burden of HCV-associated complications. We estimated past incidence of acute HCV infection using national seroprevalence data and relative age-specific incidence data from a sentinel counties surveillance system. Projections of the future prevalence of HCV-infected patients were derived from models that included an 85% drop in HCV infection incidence as observed for reported cases in the early 1990s. The models showed a large increase in the incidence of HCV infections from the late 1960s to the early 1980s. The degree of increase was dependent on the assumed rate of antibody loss; a model with 2.5% annual antibody loss showed annual incidence increasing from 45,000 infections (95% confidence interval [95% CI]: 0-110,000) in the early 1960s to 380,000 infections (95% CI: 250,000 to 500, 000) in the 1980s. Projections showed that although the prevalence of HCV infection may be declining currently because of the decline in incidence in the 1990s, the number of persons infected for >/=20 years could increase substantially before peaking in 2015. If the incidence of new HCV infections does not increase in the future, persons born between 1940 and 1965 will be at highest lifetime risk of acquiring the infection.