Risk factors for sporadic Giardia infection in the USA: a case-control study in Colorado and Minnesota.

Giardia duodenalis is the most common intestinal parasite of humans in the USA, but the risk factors for sporadic (non-outbreak) giardiasis are not well described. The Centers for Disease Control and Prevention and the Colorado and Minnesota public health departments conducted a case-control study to assess risk factors for sporadic giardiasis in the USA. Cases (N = 199) were patients with non-outbreak-associated laboratory-confirmed Giardia infection in Colorado and Minnesota, and controls (N = 381) were matched by age and site. Identified risk factors included international travel (aOR = 13.9; 95% CI 4.9-39.8), drinking water from a river, lake, stream, or spring (aOR = 6.5; 95% CI 2.0-20.6), swimming in a natural body of water (aOR = 3.3; 95% CI 1.5-7.0), male-male sexual behaviour (aOR = 45.7; 95% CI 5.8-362.0), having contact with children in diapers (aOR = 1.6; 95% CI 1.01-2.6), taking antibiotics (aOR = 2.5; 95% CI 1.2-5.0) and having a chronic gastrointestinal condition (aOR = 1.8; 95% CI 1.1-3.0). Eating raw produce was inversely associated with infection (aOR = 0.2; 95% CI 0.1-0.7). Our results highlight the diversity of risk factors for sporadic giardiasis and the importance of non-international-travel-associated risk factors, particularly those involving person-to-person transmission. Prevention measures should focus on reducing risks associated with diaper handling, sexual contact, swimming in untreated water, and drinking untreated water.

Declines in Pregnancies among U.S. Adolescents from 2007 to 2017: Behavioral Contributors to the Trend.

STUDY OBJECTIVES: Adolescent pregnancies and births in the United States have undergone dramatic declines in recent decades. We aimed to estimate the contribution of changes in 3 proximal behaviors to these declines among 14- to 18-year-olds for 2007-2017: 1) delays in age at first sexual intercourse, 2) declines in number of sexual partners, and 3) changes in contraceptive use, particularly uptake of long-acting reversible contraception (LARC). DESIGN: We adapted an existing iterative dynamic population model and parameterized it using 6 waves of the Centers for Disease Control and Prevention's Youth Risk Behavior Survey. We compared pregnancies from observed behavioral trends with counterfactual scenarios that assumed constant behaviors over the decade. We calculated outcomes by cause, year, and age. RESULTS: We found that changes in these behaviors could explain pregnancy reductions of 496,200, 78,500, and 40,700 over the decade, respectively, with total medical and societal cost savings of $9.71 billion, $1.54 billion, and $796 million. LARC adoption, particularly among 18-year-olds, could explain much of the improvement from contraception use. The 3 factors together did not fully explain observed birth declines; adding a 50% decline in sex acts per partner did. CONCLUSIONS: Delays in first sexual intercourse contributed the most to declining births over this decade, although all behaviors considered had major effects. Differences from earlier models could result from differences in years and ages covered. Evidence-based teen pregnancy prevention programs, including comprehensive sex education, youth-friendly reproductive health services, and parental and community support, can continue to address these drivers and reduce teen pregnancy.

Substantial differences in specificity of HIV-specific cytotoxic T cells in acute and chronic HIV infection.

Cytotoxic T lymphocytes (CTLs) play a vital part in controlling viral replication during human viral infections. Most studies in human infections have focused on CTL specificities in chronic infection and few data exist regarding the specificity of the initial CTL response induced in acute infection. In this study, HIV-1 infection in persons expressing human histocompatibility leukocyte antigen (HLA)-A*0201 was used as a means of addressing this issue. In chronic infection, the dominant HLA-A*0201-restricted CTL response is directed towards the epitope SLYNTVATL ("SL9") in p17 Gag (residues 77-85). This epitope is targeted by 75% of HLA-A*0201-positive adults, and the magnitude of this A*0201-SL9 response shows a strong negative association with viral load in progressive infection. Despite using the highly sensitive peptide-major histocompatibility complex tetramer and intracellular cytokine assays, responses to the SL9 epitope were not detectable in any of 11 HLA-A*0201-positive subjects with acute HIV-1 infection (P = 2 x 10(-6)), even when assays were repeated using the SL9 peptide variant that was encoded by their autologous virus. In contrast, multiple responses (median 3) to other epitopes were evident in 7 of the 11 A*0201-positive subjects. Longitudinal study of two subjects confirmed that the A*0201-SL9 response emerged later than other CTL responses, and after viral set point had been reached. Together, these data show that the CTL responses that are present and that even may dominate in chronic infection may differ substantially from those that constitute the initial antiviral CTL response. This finding is an important consideration in vaccine design and in the evaluation of vaccine candidates.

Cellular immune responses and viral diversity in individuals treated during acute and early HIV-1 infection.

Immune responses induced during the early stages of chronic viral infections are thought to influence disease outcome. Using HIV as a model, we examined virus-specific cytotoxic T lymphocytes (CTLs), T helper cells, and viral genetic diversity in relation to duration of infection and subsequent response to antiviral therapy. Individuals with acute HIV-1 infection treated before seroconversion had weaker CTL responses directed at fewer epitopes than persons who were treated after seroconversion. However, treatment-induced control of viremia was associated with the development of strong T helper cell responses in both groups. After 1 yr of antiviral treatment initiated in acute or early infection, all epitope-specific CTL responses persisted despite undetectable viral loads. The breadth and magnitude of CTL responses remained significantly less in treated acute infection than in treated chronic infection, but viral diversity was also significantly less with immediate therapy. We conclude that early treatment of acute HIV infection leads to a more narrowly directed CTL response, stronger T helper cell responses, and a less diverse virus population. Given the need for T helper cells to maintain effective CTL responses and the ability of virus diversification to accommodate immune escape, we hypothesize that early therapy of primary infection may be beneficial despite induction of less robust CTL responses. These data also provide rationale for therapeutic immunization aimed at broadening CTL responses in treated primary HIV infection.

Functionally inert HIV-specific cytotoxic T lymphocytes do not play a major role in chronically infected adults and children.

The highly sensitive quantitation of virus-specific CD8(+) T cells using major histocompatibility complex-peptide tetramer assays has revealed higher levels of cytotoxic T lymphocytes (CTLs) in acute and chronic virus infections than were recognized previously. However, studies in lymphocytic choriomeningitis virus infection have shown that tetramer assays may include measurement of a substantial number of tetramer-binding cells that are functionally inert. Such phenotypically silent CTLs, which lack cytolytic function and do not produce interferon (IFN)-gamma, have been hypothesized to explain the persistence of virus in the face of a quantitatively large immune response, particularly when CD4 help is impaired. In this study, we examined the role of functionally inert CTLs in chronic HIV infection. Subjects studied included children and adults (n = 42) whose viral loads ranged from <50 to >100,000 RNA copies/ml plasma. Tetramer assays were compared with three functional assays: enzyme-linked immunospot (Elispot), intracellular cytokine staining, and precursor frequency (limiting dilution assay [LDA]) cytotoxicity assays. Strong positive associations were observed between cell numbers derived by the Elispot and the tetramer assay (r = 0.90). An even stronger association between tetramer-derived numbers and intracellular cytokine staining for IFN-gamma was present (r = 0.97). The majority (median 76%) of tetramer-binding cells were consistently detectable via intracellular IFN-gamma cytokine staining. Furthermore, modifications to the LDA, using a low input cell number into each well, enabled LDAs to reach equivalence with the other methods of CTL enumeration. These data together show that functionally inert CTLs do not play a significant role in chronic pediatric or adult HIV infection.

Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia.

Virus-specific CD4+ T helper lymphocytes are critical to the maintenance of effective immunity in a number of chronic viral infections, but are characteristically undetectable in chronic human immunodeficiency virus-type 1 (HIV-1) infection. In individuals who control viremia in the absence of antiviral therapy, polyclonal, persistent, and vigorous HIV-1-specific CD4+ T cell proliferative responses were present, resulting in the elaboration of interferon-gamma and antiviral beta chemokines. In persons with chronic infection, HIV-1-specific proliferative responses to p24 were inversely related to viral load. Strong HIV-1-specific proliferative responses were also detected following treatment of acutely infected persons with potent antiviral therapy. The HIV-1-specific helper cells are likely to be important in immunotherapeutic interventions and vaccine development.

A Model for HCMV Infection in Immunosuppressed Patients.

We propose a model for HCMV infection in healthy and immunosuppressed patients. First, we present the biological model and formulate a system of ordinary differential equations to describe the pathogenesis of primary HCMV infection in immunocompetent and immunosuppressed individuals. We then investigate how clinical data can be applied to this model. Approximate parameter values for the model are derived from data available in the literature and from mathematical and physiological considerations. Simulations with the approximated parameter values demonstrates that the model is capable of describing primary, latent, and secondary (reactivated) HCMV infection. Reactivation simulations with this model provide a window into the dynamics of HCMV infection in (D-R+) transplant situations, where latently-infected recipients (R+) receive transplant tissue from HCMV-naive donors (D-).

The role of CD4(+) T helper cells in the cytotoxic T lymphocyte response to HIV-1.

Virus-specific CD4(+) T cell help and CD8(+) cytotoxic T cell (CTL) responses are critical for the maintenance of effective immunity in chronic viral infections. HIV-1 infection presents a unique situation in which HIV-1-specific T helper cell responses are characteristically impaired and virus-specific CTLs wane over time as disease progresses; a relationship exists between T cell help and CTL responses in HIV-1 infection.

Improving influenza and Tdap vaccination during pregnancy: A cluster-randomized trial of a multi-component antenatal vaccine promotion package in late influenza season.

BACKGROUND: Evidence-based interventions to improve influenza vaccine coverage among pregnant women are needed, particularly among those who remain unvaccinated late into the influenza season. Improving rates of antenatal tetanus, diphtheria and acellular pertussis (Tdap) vaccination is also needed. PURPOSE: To test the effectiveness of a practice-, provider-, and patient-focused influenza and Tdap vaccine promotion package on improving antenatal influenza and Tdap vaccination in the obstetric setting. METHODS: A cluster-randomized trial among 11 obstetric practices in Georgia was conducted in 2012-2013. Intervention practices adopted the intervention package that included identification of a vaccine champion, provider-to-patient talking points, educational brochures, posters, lapel buttons, and iPads loaded with a patient-centered tutorial. Participants were recruited from December 2012-April 2013 and included 325 unvaccinated pregnant women in Georgia. Random effects regression models were used to evaluate primary and secondary outcomes. RESULTS: Data on antenatal influenza and Tdap vaccine receipt were obtained for 300 (92.3%) and 291 (89.5%) women, respectively. Although antenatal influenza and Tdap vaccination rates were higher in the intervention group than the control group, improvements were not significant (For influenza: risk difference (RD)=3.6%, 95% confidence interval (CI): -4.0%, 11.2%; for Tdap: RD=1.3%, 95% CI: -10.7%, 13.2%). While the majority of intervention package components were positively associated with antenatal vaccine receipt, a provider's recommendation was the factor most strongly associated with actual receipt, regardless of study group or vaccine. CONCLUSIONS: The intervention package did not significantly improve antenatal influenza or Tdap vaccine coverage. More research is needed to determine what motivates women remaining unvaccinated against influenza late into the influenza season to get vaccinated. Future research should quantify the extent to which clinical interventions can bolster a provider's recommendation for vaccination. This study is registered with clinicaltrials.gov, study ID NCT01761799.

Cellular immune response to human immunodeficiency virus.

Despite recent success with the use of highly active antiretroviral therapy, eradication of HIV type 1 appears beyond the capabilities of presently available therapy. Therefore, greater emphasis has been given to finding mechanisms that promote immunologic control of viral replication rather than eradication. Although the correlates of immune protection in HIV-1 infection remain undefined, increasing evidence indicates that HIV-1-specific cellular immune responses may play a critical role in antiviral control. Vigorous HIV-1-specific CD4+ T-helper cell and CD8+ cytotoxic T-lymphocyte responses may play a critical role in control of viral replication in the absence of antiretroviral therapy, which has been demonstrated in individuals with long-term nonprogressive infection. However, in chronic, progressive HIV-1 infection, virus-specific T-helper cell responses are typically weak or absent in all stages of disease, and HIV-1-specific cytotoxic T-lymphocyte responses wane over time, presumably due to the lack of HIV-1-specific T helper cells. Effective treatment of individuals during acute HIV-1 seroconversion syndrome appears to restore HIV-1-specific T-helper cell responses, which are otherwise only observed in persons with long-term nonprogressive infection. This observation, along with anecdotal reports of individuals successfully controlling viral replication after treating acute HIV-1 infection, provides immunologic rationale for structured treatment interruption and other immunotherapeutic approaches designed to augment HIV-1-specific immune responses.

Characterization of HIV-1-specific T-helper cells in acute and chronic infection.

HIV-1 infection is associated with progressive and relentless destruction of the immune system in the majority of infected persons, but some persons appear to be able to successfully contain the virus in the absence of antiviral therapy. Such cases suggest that the host immune response can successfully contain the virus, and provide the rationale for concerted efforts to understand the host immune response to the virus and to develop new strategies to combat the infection with immune based therapies. Historically, the greatest hole in the immune repertoire in HIV-1 infection has been the lack of strong virus-specific proliferative responses. However, new studies have identified a potent Th cell response in some infected persons, and have shown a statistically significant negative correlation between plasma viremia and virus-specific CD4 T-helper cells directed at the p24 protein. Moreover, early institution of potent antiviral therapy in the earliest stages of acute HIV-1 infection have led to persistent, strong HIV-1-specific T-helper cell responses, analogous to those seen in persons who are able to control viremia in the absence of antiviral therapy. We hypothesize that this is because potent antiviral therapy is able to protect virus-specific Th cells as they become activated, and thus these cells are not lost in the earliest stages of infection.

Mother-to-child transmission of HIV infection and CTL escape through HLA-A2-SLYNTVATL epitope sequence variation.

Cytotoxic T lymphocytes (CTL) play a central role in containment of HIV infection. Evasion of the immune response by CTL escape is associated with progression to disease. It is therefore hypothesised that transmitted viruses encode escape mutations within epitopes that are required for successful control of viraemia. In order to test this hypothesis, escape through the dominant HLA-A2-restricted CTL epitope SLYNTVATL (p17 Gag residues 77-85 SL9) in the setting of mother-to-child-transmission (MTCT) was investigated. Initial data from two families in which the HIV-infected mother expressed HLA-A*0201 and had transmitted the virus to other family members were consistent with this hypothesis. In addition, analysis of the gag sequence phylogeny in one family demonstrated that CTL escape variants can be successfully transmitted both horizontally and vertically. To test the hypothesis further, a larger cohort of transmitting mothers (n=8) and non-transmitters (n=14) were studied. Variation within the SL9 epitope was associated with expression of HLA-A2 (P=0.04) but overall no clear link between variation from the SL9 consensus sequence and MTCT was established. However, the high level of background diversity within p17 Gag served to obscure any possible association between escape and MTCT. In conclusion, these studies highlighted the obstacles to demonstrating CTL escape arising at this particular epitope. Alternative strategies likely to be more definitive are discussed.

The war against junk science: the use of expert panels in complex medical-legal scientific litigation.

In the legal context, junk science is defined as evidence that is outside of mainstream scientific or medical views. Junk science does not have indicia of reliability and is not generally accepted. Despite the lack of scientific reliability, US courts, expert witnesses and juries are increasingly reliant on junk science in making causation decisions in complex medical liability cases. Courts have accepted junk science even where reliable scientific evidence is available. The United States silicone gel breast implant litigation is a prime example of this phenomenon. The issue of whether silicone breast implants are associated with disease has been a controversial subject for scientists and physicians, an emotional issue for women who have breast implants, and a lucrative business for the lawyers and expert witnesses who are the proponents of junk science. Junk science has provided to juries a quick and convenient explanation for claimed diseases or syndromes which have required years for reliable scientists to conclude are not related to breast implants. The breast implant litigation highlights the often dramatic difference between decisions based upon junk science and decisions grounded in scientific method, fact and reality. Recently, judges involved in the breast implant litigation have become concerned about the use of junk science in light of the growing body of legitimate scientific evidence that breast implants do not cause disease. Several judges have been motivated to take the unique and novel approach of convening scientific panels of independent experts to study the scientific issues and make findings to the court. Through the use of independent scientific experts, several judges have meaningfully assessed the evidence that the litigants present and have prevented or strictly limited the use of junk science in the courtroom. Using this procedure, other judges are weighing the evidence for future cases. This paper will briefly explore the background of mass tort medical products litigation and the development of junk science. The paper will then focus on the history of the breast implant litigation and the steps that the courts have already taken to combat junk science, including the use of scientific panels.

Cytotoxic T-lymphocyte (CTL) responses directed against regulatory and accessory proteins in HIV-1 infection.

The HIV-1 regulatory proteins Tat and Rev and the accessory proteins Vpr, Vpu, and Vif are essential for viral replication, and their cytoplasmic production suggests that they should be processed for recognition by cytotoxic T lymphocytes. However, only limited data is available evaluating to which extent these proteins are targeted in natural infection and optimal cytotoxic T lymphocyte (CTL) epitopes within these proteins have not been defined. In this study, CTL responses against HIV-1 Tat, Rev, Vpr, Vpu, and Vif were analyzed in 70 HIV-1 infected individuals and 10 HIV-1 negative controls using overlapping peptides spanning the entire proteins. Peptide-specific interferon-gamma (IFN-gamma) production was measured by Elispot assay and flow-based intracellular cytokine quantification. HLA class I restriction and cytotoxic activity were confirmed after isolation of peptide-specific CD8+ T-cell lines. All regulatory and accessory proteins served as targets for HIV-1- specific CTL and multiple CTL epitopes were identified in functionally important regions of these proteins. In certain individuals HIV-1-specific CD8+ T-cell responses to these accessory and regulatory proteins contributed up to a third to the magnitude of the total HIV-1-specific CTL response. These data indicate that despite the small size of these proteins regulatory and accessory proteins are targeted by CTL in natural HIV-1 infection, and contribute importantly to the total HIV-1-specific CD8+ T-cell responses. These findings are relevant for the evaluation of the specificity and breadth of immune responses during acute and chronic#10; infection, and will be useful for the design and testing of candidate human immunodeficiency virus (HIV) vaccines.

Subcutaneous emphysema during periodontal surgery: report of a case.

Subcutaneous emphysema (S.E.) of the facial region is an uncommon complication of dental procedures. A case is presented which details the development of S.E. following use of an air-water syringe during periodontal surgery. Differential diagnosis of the condition depends upon accurate historical data and the finding of crepitus on palpation of the involved tissues. Treatment is supportive in nature, although prophylactic antibiotic coverage is suggested. The etiology of S.E. is discussed and judicious use of compressed air or gas-producing medicaments during dental treatment is stressed.

Bacterial variability within diseases periodontal sites.

The purpose of this study was to examine the variability in bacterial proportions between individual periodontal sites in patients with chronic periodontitis by means of differential dark-field microscopy. Fourteen patients with untreated, moderate to advanced disease were included. Probing depth, plaque and gingival index scores were recorded for each patient. Microbial samples were collected from the tooth surface with the greatest proving depth in each sextant and examined individually by dark-field microscopy. The results indicated that proportions of spirochetes and motile rods at any given probing depth varied considerably, ranging from those expected at healthy sites to those expected at diseased sites. In accordance with previous studies, mean percentages of spirochetes tended to vary directly with increased PD, PlI and GI scores, while mean percentages of coccoid cells tended to follow a reverse pattern. However, no significant correlations could be demonstrated when measurements from individual sites were analyzed. Most of the variance in the data was due to differences between subjects rather than differences between sites. It is postulated that the large variance between subjects and sites is due in part to the cyclical nature of the disease and to the lack of synchrony between remissions and exacerbations at different sites and in different patients.

The osteogenic activity of bone removed from healing extraction sockets in humans.

Cores of bone from healing extraction sites were studied at time intervals of 4, 6, 8, 10, 12 and 16 weeks. The results revealed that between 4 and 8 weeks proliferation of cellular and connective tissue elements occur within the healing socket. Islands of new bone with an osteoid seam surrounded by osteoblasts are present within the connective tissue. From 8 to 12 weeks the bone undergoes maturation and forms a trabecular pattern. Although less pronounced, and osteoid seam is still present and osteoblasts occur in fewer numbers. By 12 to 16 weeks the bony trabeculae are mature with very little osteoid and few osteoblasts. This bone resembles alveolar trabecular bone. Two phases of bony regeneration are apparent from the present study. From 4 to 8 weeks there is a progressive osteogenic phase with proliferation of osteogenic cells and immature bone formation. From 8 to 12 weeks the osteogenesis slows down and the trabeculae mature and increase in volume. From 12 to 16 weeks the bone appears to stabilize with an established alveolar trabecular bone being present. Very little osteogenesis occurs as evidenced by minimal or no osteoid seam with only occasional osteoblasts. It is apparent that in the period between 8 and 12 weeks a substantial quantity of relatively mature well formed bone is present which contains osteoblasts and an osteoid seam. This appears to be an optimal time period to secure bone from a healing extraction site for grafting purposes.

Comparative differential dark-field microscopy of subgingival bacteria from tooth surfaces with recent evidence of recurring periodontitis and from nonaffected surfaces.

Ninety-two subjects with a history of treatment for chronic periodontitis were monitored on a regular basis for an average period of 10.7 months. During this monitoring period, in spite of their participation in a preventive maintenance program, 19 subjects out of 92 showed evidence of significantly increased probing depth (greater than or equal to 3 mm from base line measurements) on at least one tooth surface, or approximately 1% of the dental units at risk in this population. A comparison of differential microscopic counts of subgingival bacteria from the affected tooth surfaces with a pooled sample of 6 other surfaces with the greatest probing depth, in the same mouth, taken at the same appointment, revealed no significant differences between proportions of coccoid cells, spirochetes, motile rods or other cell types. These findings suggest that disease recurrence, as measured by a comparatively rapid increase in probing depth, might be accounted for on the basis of the following hypotheses: an alteration in the host response without a detectable change in the composition of the subgingival microbiota, a qualitative change in the microbial flora not detectable by a microscopic assay, relatively brief episodes of disease activity which may be accompanied by brief, transient, qualitative changes in the local microbiota that cannot be readily detected by biannual examinations.

Multidisciplinary approach to the repair of vertically fractured teeth.

This case report describes the treatment of a vertically fractured upper left second molar. The two segments were extracted separately. The periodontal ligament was protected from damage extraorally by soaking it with Hanks' balanced salt solution. The two segments were bonded with the use of a biocompatible glass ionomer bone cement and replanted in conjunction with an expanded polytetrafluoroethylene (gore-tex) membrane. After 1 yr the tooth functions normally and is clinically and radiographically within normal limits.