A Brief History of Antimicrobial Resistance.

Despite mounting attention in recent years, health threats posed by antimicrobial resistance are not new. Antimicrobial resistance has dogged infectious disease treatment processes since the first modern antimicrobials were discovered.

Safety and immunogenicity of the H56:IC31 tuberculosis vaccine candidate in adults successfully treated for drug-susceptible pulmonary TB: a phase 1 randomized trial.

BACKGROUND: H56:IC31 is a candidate vaccine against tuberculosis (TB) with the potential to reduce TB recurrence rate. It is thus important for future clinical trials to demonstrate safety and immunogenicity of H56:IC31 in individuals treated for TB. METHODS: 22 adults confirmed to be Mtb negative (by 2 GeneXpert tests or 2 sputum cultures) after four-five months of TB treatment, and not more than 28 days after completion of TB treatment, were randomized to receive two doses of H56:IC31 (5 mg H56:500 nmol IC31; N=16) or placebo (N=6) 56 days apart. Participants were followed for 420 days for safety and immunogenicity. RESULTS: H56:IC31 vaccination was associated with an acceptable safety profile, consisting mostly of mild self-limited injection site reactions. No serious adverse events, and no vaccine-related severe adverse events, were reported. H56:IC31 induced a CD4+ T-cell response for Ag85B and ESAT-6, with ESAT-6 being immunodominant, which persisted through six months after the last vaccination. There was some evidence of CD8+ T-cell responses for both Ag85B and ESAT-6, but to a lesser extent than CD4+ responses. CONCLUSIONS: H56:IC31 was associated with an acceptable safety profile, and induced a predominant CD4+ T-cell response, in adults recently treated for drug-susceptible, uncomplicated pulmonary TB. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02375698.

Genetic Risk Factors for Early-Onset Merkel Cell Carcinoma.

Importance: Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine skin cancer. Of the patients who develop MCC annually, only 4% are younger than 50 years. Objective: To identify genetic risk factors for early-onset MCC via genomic sequencing. Design, Setting, and Participants: The study represents a multicenter collaboration between the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the National Institute of Allergy and Infectious Diseases (NIAID), and the University of Washington. Participants with early-onset and later-onset MCC were prospectively enrolled in an institutional review board-approved study at the University of Washington between January 2003 and May 2019. Unrelated controls were enrolled in the NIAID Centralized Sequencing Program (CSP) between September 2017 and September 2021. Analysis was performed from September 2021 and March 2023. Early-onset MCC was defined as disease occurrence in individuals younger than 50 years. Later-onset MCC was defined as disease occurrence at age 50 years or older. Unrelated controls were evaluated by the NIAID CSP for reasons other than familial cancer syndromes, including immunological, neurological, and psychiatric disorders. Results: This case-control analysis included 1012 participants: 37 with early-onset MCC, 45 with later-onset MCC, and 930 unrelated controls. Among 37 patients with early-onset MCC, 7 (19%) had well-described variants in genes associated with cancer predisposition. Six patients had variants associated with hereditary cancer syndromes (ATM = 2, BRCA1 = 2, BRCA2 = 1, and TP53 = 1) and 1 patient had a variant associated with immunodeficiency and lymphoma (MAGT1). Compared with 930 unrelated controls, the early-onset MCC cohort was significantly enriched for cancer-predisposing pathogenic or likely pathogenic variants in these 5 genes (odds ratio, 30.35; 95% CI, 8.89-106.30; P < .001). No germline disease variants in these genes were identified in 45 patients with later-onset MCC. Additional variants in DNA repair genes were also identified among patients with MCC. Conclusions and Relevance: Because variants in certain DNA repair and cancer predisposition genes are associated with early-onset MCC, genetic counseling and testing should be considered for patients presenting at younger than 50 years.

Chromosomal microarray analysis supplements exome sequencing to diagnose children with suspected inborn errors of immunity.

Purpose: Though copy number variants (CNVs) have been suggested to play a significant role in inborn errors of immunity (IEI), the precise nature of this role remains largely unexplored. We sought to determine the diagnostic contribution of CNVs using genome-wide chromosomal microarray analysis (CMA) in children with IEI. Methods: We performed exome sequencing (ES) and CMA for 332 unrelated pediatric probands referred for evaluation of IEI. The analysis included primary, secondary, and incidental findings. Results: Of the 332 probands, 134 (40.4%) received molecular diagnoses. Of these, 116/134 (86.6%) were diagnosed by ES alone. An additional 15/134 (11.2%) were diagnosed by CMA alone, including two likely de novo changes. Three (2.2%) participants had diagnostic molecular findings from both ES and CMA, including two compound heterozygotes and one participant with two distinct diagnoses. Half of the participants with CMA contribution to diagnosis had CNVs in at least one non-immune gene, highlighting the clinical complexity of these cases. Overall, CMA contributed to 18/134 diagnoses (13.4%), increasing the overall diagnostic yield by 15.5% beyond ES alone. Conclusion: Pairing ES and CMA can provide a comprehensive evaluation to clarify the complex factors that contribute to both immune and non-immune phenotypes. Such a combined approach to genetic testing helps untangle complex phenotypes, not only by clarifying the differential diagnosis, but in some cases by identifying multiple diagnoses contributing to the overall clinical presentation.

A Filamentous Bacteriophage Protein Inhibits Type IV Pili To Prevent Superinfection of Pseudomonas aeruginosa.

Pseudomonas aeruginosa is an opportunistic pathogen that causes infections in a variety of settings. Many P. aeruginosa isolates are infected by filamentous Pf bacteriophage integrated into the bacterial chromosome as a prophage. Pf virions can be produced without lysing P. aeruginosa. However, cell lysis can occur during superinfection, which occurs when Pf virions successfully infect a host lysogenized by a Pf prophage. Temperate phages typically encode superinfection exclusion mechanisms to prevent host lysis by virions of the same or similar species. In this study, we sought to elucidate the superinfection exclusion mechanism of Pf phage. Initially, we observed that P. aeruginosa that survive Pf superinfection are transiently resistant to Pf-induced plaquing and are deficient in twitching motility, which is mediated by type IV pili (T4P). Pf utilize T4P as a cell surface receptor, suggesting that T4P are suppressed in bacteria that survive superinfection. We tested the hypothesis that a Pf-encoded protein suppresses T4P to mediate superinfection exclusion by expressing Pf proteins in P. aeruginosa and measuring plaquing and twitching motility. We found that the Pf protein PA0721, which we termed Pf superinfection exclusion (PfsE), promoted resistance to Pf infection and suppressed twitching motility by binding the T4P protein PilC. Because T4P play key roles in biofilm formation and virulence, the ability of Pf phage to modulate T4P via PfsE has implications in the ability of P. aeruginosa to persist at sites of infection. IMPORTANCE Pf bacteriophage (phage) are filamentous viruses that infect Pseudomonas aeruginosa and enhance its virulence potential. Pf virions can lyse and kill P. aeruginosa through superinfection, which occurs when an already infected cell is infected by the same or similar phage. Here, we show that a small, highly conserved Pf phage protein (PA0721, PfsE) provides resistance to superinfection by phages that use the type IV pilus as a cell surface receptor. PfsE does this by inhibiting assembly of the type IV pilus via an interaction with PilC. As the type IV pilus plays important roles in virulence, the ability of Pf phage to modulate its assembly has implications for P. aeruginosa pathogenesis.

A three-antigen Plasmodium falciparum DNA prime-Adenovirus boost malaria vaccine regimen is superior to a two-antigen regimen and protects against controlled human malaria infection in healthy malaria-naïve adults.

BACKGROUND: A DNA-prime/human adenovirus serotype 5 (HuAd5) boost vaccine encoding Plasmodium falciparum (Pf) circumsporozoite protein (PfCSP) and Pf apical membrane antigen-1 (PfAMA1), elicited protection in 4/15 (27%) of subjects against controlled human malaria infection (CHMI) that was statistically associated with CD8+ T cell responses. Subjects with high level pre-existing immunity to HuAd5 were not protected, suggesting an adverse effect on vaccine efficacy (VE). We replaced HuAd5 with chimpanzee adenovirus 63 (ChAd63), and repeated the study, assessing both the two-antigen (CSP, AMA1 = CA) vaccine, and a novel three-antigen (CSP, AMA1, ME-TRAP = CAT) vaccine that included a third pre-erythrocytic stage antigen [malaria multiple epitopes (ME) fused to the Pf thrombospondin-related adhesive protein (TRAP)] to potentially enhance protection. METHODOLOGY: This was an open label, randomized Phase 1 trial, assessing safety, tolerability, and VE against CHMI in healthy, malaria naïve adults. Forty subjects (20 each group) were to receive three monthly CA or CAT DNA priming immunizations, followed by corresponding ChAd63 boost four months later. Four weeks after the boost, immunized subjects and 12 infectivity controls underwent CHMI by mosquito bite using the Pf3D7 strain. VE was assessed by determining the differences in time to parasitemia as detected by thick blood smears up to 28-days post CHMI and utilizing the log rank test, and by calculating the risk ratio of each treatment group and subtracting from 1, with significance calculated by the Cochran-Mantel-Haenszel method. RESULTS: In both groups, systemic adverse events (AEs) were significantly higher after the ChAd63 boost than DNA immunizations. Eleven of 12 infectivity controls developed parasitemia (mean 11.7 days). In the CA group, 15 of 16 (93.8%) immunized subjects developed parasitemia (mean 12.0 days). In the CAT group, 11 of 16 (63.8%) immunized subjects developed parasitemia (mean 13.0 days), indicating significant protection by log rank test compared to infectivity controls (p = 0.0406) and the CA group (p = 0.0229). VE (1 minus the risk ratio) in the CAT group was 25% compared to -2% in the CA group. The CA and CAT vaccines induced robust humoral (ELISA antibodies against CSP, AMA1 and TRAP, and IFA responses against sporozoites and Pf3D7 blood stages), and cellular responses (IFN-γ FluoroSpot responses to CSP, AMA1 and TRAP) that were not associated with protection. CONCLUSIONS: This study demonstrated that the ChAd63 CAT vaccine exhibited significant protective efficacy, and confirmed protection was afforded by adding a third antigen (T) to a two-antigen (CA) formulation to achieve increased VE. Although the ChAd63-CAT vaccine was associated with increased frequencies of systemic AEs compared to the CA vaccine and, historically, compared to the HuAd5 vectored malaria vaccine encoding CSP and AMA1, they were transient and associated with increased vector dosing.

Viral hepatitis C, active component, U.S. military service members and beneficiaries, 2008-2016.

Hepatitis C virus (HCV) infection remains an important concern for the Military Health System (MHS). This report updates numbers and incidence rates of HCV infection of U.S. military service members and MHS beneficiaries, incorporating a surveillance period before and after 2012 screening policy changes for military members. From 2008 to 2016, there were 342 and 1,491 incident cases of acute and chronic hepatitis C, respectively, among active component members of the U.S. Armed Forces; crude overall incidence rates during the period were 2.8 (acute) and 12.2 (chronic) cases per 100,000 person-years. Annual incidence rates of chronic hepatitis C decreased over the surveillance period; however, rates of acute hepatitis C remained steady. There were 141 acute and 587 chronic incident cases among reserve/guard service members, with annual counts of both acute and chronic cases decreasing over the surveillance period. In addition, there were 2,541 acute and 21,418 chronic cases among non-service member beneficiaries, with annual counts of acute and chronic cases also decreasing steadily over the surveillance period. Given recent pharmaceutical advances in treatment, screening and linkage to care are critical to improving health outcomes for those with HCV infection.

Diagnoses of traumatic brain injury not clearly associated with deployment, active component, U.S. Armed Forces, 2001-2016.

From 2001 through 2016, a total of 276,858 active component service members received first-time diagnoses of traumatic brain injury (TBI). Person-time and incident cases of TBI were assigned to one of three groups. Group 1 included only service members' person-time before their first-ever deployments. Group 2 included service members' person-time during their overseas deployments and the 30 days after their return from deployment. Group 3 included only service members' person-time more than 30 days after return from deployment. The crude overall incidence rate of TBI among deployed service members (1,690.5 cases per 100,000 person-years [p-yrs]) was 1.5 times that of service members in group 1 (1,141.3 cases per 100,000 p-yrs), and 1.2 times that of service members in group 3 (1,451.2 cases per 100,000 p-yrs). The portion of the surveillance period during which the annual incidence rates of TBI in groups 3 and 2 exceeded the rates in group 1 likely represents, at least in part, the increased risk of service in an active combat zone. For group 2, this period extended from 2007 through 2013. For group 3, this period lasted from 2007 through 2016. Examination of the TBI case-defining encounters with recorded injury causes yielded leading causes similar to those of TBIs in same-aged civilians (land transport and slips, trips, and falls). Factors that may explain why the TBI incidence rates among the previously deployed were higher than those of the never-deployed group are discussed.

Obstructive sleep apnea and associated attrition, active component, U.S. Armed Forces, January 2004-May 2016.

Obstructive sleep apnea (OSA) is a growing health concern in both civilian and military populations. Individuals who suffer from OSA have increased rates of cardiovascular disease, chronic fatigue, motor vehicle accidents, cognitive impairment, and post-traumatic stress disorder. Data from the Defense Medical Surveillance System (DMSS) were utilized to examine the incidence of OSA and associated attrition from service in active component military members from 1 January 2004 through 31 May 2016. The study identified 223,731 incident cases of OSA with an overall incidence rate of 139.2 per 10,000 person-years, between 2004 and 2015. Rates increased more than 3-fold between 2004 and 2015. In 2015, 48.1% of all incident cases of OSA were diagnosed in the last year of service. The high percentage of cases diagnosed prior to separation from service is concerning because OSA is a treatable and partially preventable disease. OSA represents a large health and economic burden for the armed services and yet there are persistent research gaps in appropriate screening and prevention strategies to improve both individual health and mission performance.

Post-refractive surgery complications and eye disease, active component, U.S. Armed Forces, 2005-2014.

Refractive surgery (RS) is a common procedure in the U.S. military population. This report provides an estimation of incident RS for vision correction purposes in the active component of the U.S. military from 1 January 2005 through 31 December 2014 and the prevalence of post-RS complications and eye disease in the 1-year period after RS. During the surveillance period, a total of 121,571 subjects without a diagnosis of eye disease other than hyperopia, myopia, or astigmatism in the previous year received a single incident RS procedure. In the 1-year period after RS, 5.3% of subjects with preoperative hyperopia or myopia had treatment-persistent (unresolved) hyperopia or myopia; 2.0% of subjects with preoperative astigmatism had treatment-persistent (unresolved) astigmatism; and 3.8% were diagnosed with tear film insufficiency. In general, most outcomes showed higher prevalences in Army and Air Force personnel versus Navy and Marine Corps personnel, in women versus men, in officer versus enlisted personnel, and in aviation and Special Forces personnel. A wide variation in outcome prevalences was noted by procedural military treatment facility.

Incidence of syphilis, active component, U.S. Armed Forces, 1 January 2010 through 31 August 2015.

In 2014,the Centers for Disease Control and Prevention reported significant increases in cases of primary and secondary syphilis in the U.S.; among beneficiaries of the Military Health System, monthly surveillance reports tracking reportable medical events of syphilis have reflected similar increases. This analysis reports on incident cases and rates of syphilis among active component service members of the U.S. Armed Forces from 1 January 2010 through 31 August 2015. During the surveillance period, 2,976 cases of syphilis were diagnosed. Crude incidence rates increased from 30.9 cases per 100,000 person-years (p-yrs) in 2010 to 47.4 cases per 100,000 p-yrs in 2015. Males accounted for 88.7% of cases. Incidence rates of syphilis were highest among service members who were black, non-Hispanic or who were aged 20-29 years. About one-quarter of syphilis cases (24.4%; 727 cases) were diagnosed as HIV infected. Primary and secondary syphilis cases comprised 42% of all syphilis cases. Increasing rates of primary and secondary syphilis in active component service members reflect similar trends reported in the U.S. civilian population.

Assessment of ICD-9-based case definitions for influenza-like illness surveillance.

Population-based surveillance of influenza routinely relies on administrative medical encounter databases and ICD-9 codes. However, an assessment of the ICD-9 codes used for the Department of Defense (DoD) influenza-like illness (ILI) case definition has not been conducted since 2007. As coding practices may have changed over time, this analysis was done to determine the sensitivity, specificity, and positive predictive value (PPV) of the current ILI case definition and three alternative case definitions for the 2014-2015 influenza season. Influenza laboratory tests conducted on specimens from DoD beneficiaries during the 2014-2015 season were matched to ambulatory and inpatient medical encounters. The current DoD ILI case definition had high sensitivity (92%) but low specificity (30%) and moderate PPV (63%). A more specific ILI case definition utilizing only codes with greater than 75% influenza positivity for the matched laboratory test had high specificity (96%) and PPV (96%) and moderate sensitivity (62%). The current ILI case definition is sufficient for broad, sensitive population-based surveillance; however, an alternative case definition may be more appropriate when there is a need to maximize specificity.

Durations of military service after diagnoses of HIV-1 infections among active component members of the U.S. Armed Forces, 1990-2013.

This report describes the trends in length of military service for active component members of the U.S. Armed Forces who were diagnosed with human immunodeficiency virus type 1 (HIV-1) infections during 1990-2013. Durations of service after service members' initial diagnoses of HIV-1 infection were compared for five different cohorts that corresponded to when diagnoses were made during the 5-year intervals beginning in 1990, 1995, 2000, and 2005, and the 4-year interval of 2010-2013. By several measures, the durations of service after initial diagnoses of HIV-1 infection increased from the earliest to the later cohorts. The findings are discussed in the context of changes in several factors during the surveillance period: the growing availability and effectiveness of treatments for HIV-1 disease; the stigmas associated with the diagnosis of HIV-1 infection and its link to homosexuality; and the changes in U.S. military policy about the inclusion of homosexuals in its ranks. Also discussed are the limitations of the estimates for the most recent cohorts and the future prospects for continued lengthening of service for those infected with HIV-1.

Urinary Tract Infections in Active Component U.S. Armed Forces Women Before and After Routine Screening Pap Examination.

It has been suggested that Pap tests, when used as surrogate markers for routine pelvic examinations in asymptomatic women, may be associated with an increased short-term risk of urinary tract infections (UTIs). This retrospective cohort study used Defense Medical Surveillance System (DMSS) data from 2007 through 2013 to compare the incidence of UTIs in active component women before and after receiving a routine screening Pap examination. The pre-Pap (baseline) UTI incidence rate in this cohort was 105.9 per 1,000 person-years (p-yrs) compared to 129.8 per 1,000 p-yrs post-Pap; the rate ratio was 1.23 (95% CI: 1.18-1.27). The adjusted relative risk of UTI post-Pap was 1.14 (95% CI: 1.10-1.18) and the adjusted percentage of UTIs attributable to a Pap test in the post-exposure period was 12.2% (95% CI: 9.1-15.2). Routine Pap tests, when used as a surrogate marker for pelvic examination, may be a modifiable risk factor for UTI in active component U.S. military women.

Whither the "signature wounds of the war" after the war: estimates of incidence rates and proportions of TBI and PTSD diagnoses attributable to background risk, enhanced ascertainment, and active war zone service, active component, U.S. Armed Forces, 2003-2014.

Traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD) are "signature wounds" of the Afghanistan/Iraq wars; however, many TBI/PTSD cases are not war related. During the wars, diagnoses of TBI/PTSD among military members increased because risks of TBI/PTSD, and capabilities to detect cases, increased. This report summarizes TBI/PTSD diagnosis experiences of three cohorts of overseas deployers in relation to the natures of their exposures to active war service and enhanced case ascertainment efforts. The findings suggest that, during the war, the proportions of PTSD diagnoses attributable to war zone service decreased from approximately 80% to less than 50%, while the proportions attributable to enhanced case ascertainment increased from less than 10% to nearly 50%. The proportions of TBI diagnoses attributable to war zone service more than tripled from 2003-2005 (13.1%) through 2007-2009 (44.8%); the proportions attributable to enhanced ascertainment also markedly increased, but not until after 2007. By the end of the war, war zone service and enhanced ascertainment accounted for similar proportions of all PTSD and TBI diagnoses. If programs and resources currently focused on TBI and PTSD continue, rates of diagnoses post-war will greatly exceed those pre-war.

Measles and mumps among service members and other beneficiaries of the U.S. Military Health System, January 2007-December 2014.

Measles and mumps are highly communicable infectious diseases whose causative viruses are spread through airborne droplets and infected surfaces. Individuals at highest risk are infants and unvaccinated individuals. Despite effective vaccines, there have been recent increases in incidence in the U.S. of both infections. During the surveillance period, there were 14 confirmed measles cases and 99 confirmed mumps cases among U.S. military members and other beneficiaries of the U.S. Military Health System. Only one of the confirmed cases of measles was in a service member. Children aged 5 years and younger accounted for the greatest proportion of confirmed measles cases (50.0%); the greatest proportions of confirmed mumps cases were for children aged 1-5 years and adults aged 26-30 years (22.2% and 17.2%, respectively). California had more cases of both measles and mumps than any other state. Recent trends in measles and mumps in civilian populations in the U.S. highlight the importance of primary and booster vaccinations.