A rare cutaneous infection with Mycobacterium chelonae in a pediatric patient treated with trametinib for KRAS-mutated diffuse glioma.

Mitogen-activated extracellular signal-regulated kinase inhibitors (MEKi) represent a promising new therapy for pediatric patients with low-grade gliomas, which frequently have abnormal signaling within the mitogen-activated protein kinase (MAP kinase) pathway. However, understanding of long-term efficacy and toxicity is limited in pediatric glioma patients. This article describes a rare presentation of a widespread cutaneous infection with Mycobacterium chelonae in a pediatric patient with a low-grade glioma treated with trametinib.

Cystic Echinococcosis in Northern New Hampshire, USA.

In April 2022 and December 2022, the New Hampshire Department of Health and Human Services confirmed 2 cases of locally acquired human pulmonary cystic echinococcosis caused by Echinococcus granulosus tapeworms. Both patients reported dressing locally hunted moose and exposure to dogs.

Tracking Substance Use Complications: A Collaborative Analysis of Public Health and Academic Medical Center Records on Drug Use-Associated Infective Endocarditis.

BACKGROUND: Healthcare systems and public health agencies use different methods to measure the impact of substance use (SU) on population health. We studied the ability of systems to accurately capture data on drug use-associated infective endocarditis (DUA-IE). METHODS: We conducted a retrospective analysis of patients with IE discharge diagnosis from an academic medical center, 2011-2017, comparing data from hospital Electronic Health Record (EHR) to State Uniform Hospital Discharge Data Set (UHDDS). To identify SU we developed a composite measure. RESULTS: EHR identified 472 IE discharges (430 of these were captured in UHDDS); 406 (86.0%) were correctly coded based on chart review. IE discharges increased from 57 to 92 (62%) from 2012 to 2017. Hospitalizations for the subset of DUA-IE identified by any measure of SU increased from 10 to 54 (440%). Discharge diagnosis coding identified 128 (60.7%) of total DUA-IE hospitalizations. The composite measure identified an additional 65 (30.8%) DUA-IE hospitalizations and chart review an additional 18 (8.5%). CONCLUSIONS: The failure of discharge diagnosis coding to identify DUA-IE in 40% of hospitalizations demonstrates the need for better systems to capture the impact of SU. Collaborative data sharing could help improve surveillance responsiveness to address an emerging public health crises.

Large Outbreak of Hepatitis C Virus Associated With Drug Diversion by a Healthcare Technician.

Background: In May 2012, the New Hampshire (NH) Division of Public Health Services (DPHS) was notified of 4 persons with newly diagnosed hepatitis C virus (HCV) infection at hospital X. Initial investigation suggested a common link to the hospital cardiac catheterization laboratory (CCL) because the infected persons included 3 CCL patients and a CCL technician. NH DPHS initiated an investigation to determine the source and control the outbreak. Methods: NH DPHS conducted site visits, case patient and employee interviews, medical record and medication use review, and employee and patient HCV testing using enzyme immunoassay for anti-HCV, reverse-transcription polymerase chain reaction for HCV RNA, nonstructural 5B (NS5B) and hypervariable region 1 (HVR1) sequencing, and quasispecies analysis. Results: HCV HVR1 analysis of the first 4 cases confirmed a common source of infection. HCV testing identified 32 of 1074 CCL patients infected with the outbreak strain, including 3 patients coinfected with >1 HCV strain. The epidemiologic investigation revealed evidence of drug diversion by the HCV-infected technician, evidenced by gaps in controlled medication control, higher fentanyl use during procedures for confirmed cases, and building card key access records documenting the presence of the technician during days when transmission occurred. The employee's status as a traveling technician led to a multistate investigation, which identified additional cases at prior employment sites. Conclusions: This is the largest laboratory-confirmed drug diversion-associated HCV outbreak published to date. Recommendations to reduce drug diversion risk and to conduct outbreak investigations are provided.

Workplace Safety Concerns among Co-workers of Responder Returning from Ebola-Affected Country.

We surveyed public health co-workers regarding attitudes toward a physician who returned to New Hampshire after volunteering in the West African Ebola outbreak. An unexpectedly large (18.0%) proportion of staff expressed discomfort with the Ebola responder returning to work. Employers should take proactive steps to address employee fears and concerns.

Performance of the OraQuick HCV rapid antibody test for screening exposed patients in a hepatitis C outbreak investigation.

During a nosocomial hepatitis C outbreak, emergency public clinics employed the OraQuick HCV rapid antibody test on site, and all results were verified by a standard enzyme immunoassay (EIA). Of 1,157 persons, 1,149 (99.3%) exhibited concordant results between the two tests (16 positive, 1,133 negative). The sensitivity, specificity, positive predictive value, and negative predictive value were 94.1%, 99.5%, 72.7%, and 99.9%, respectively. OraQuick performed well as a screening test during an outbreak investigation and could be integrated into future hepatitis C virus (HCV) outbreak testing algorithms.

Interventions to improve delivery of isoniazid preventive therapy: an overview of systematic reviews.

BACKGROUND: Uptake of isoniazid preventive therapy (IPT) to prevent tuberculosis has been poor, particularly in the highest risk populations. Interventions to improve IPT delivery could promote implementation. The large number of existing systematic reviews on treatment adherence has made drawing conclusions a challenge. To provide decision makers with the evidence they need, we performed an overview of systematic reviews to compare different organizational interventions to improve IPT delivery as measured by treatment completion among those at highest risk for the development of TB disease, namely child contacts or HIV-infected individuals. METHODS: We searched the Cochrane Database of Systematic Reviews, the Database of Abstracts of Reviews of Effects (DARE), and MEDLINE up to August 15, 2012. Two authors used a standardized data extraction form and the AMSTAR instrument to independently assess each review. RESULTS: Six reviews met inclusion criteria. Interventions included changes in the setting/site of IPT delivery, use of quality monitoring mechanisms (e.g., directly observed therapy), IPT delivery integration into other healthcare services, and use of lay health workers. Most reviews reported a combination of outcomes related to IPT adherence and treatment completion rate but without a baseline or comparison rate. Generally, we found limited evidence to demonstrate that the studied interventions improved treatment completion. CONCLUSIONS: While most of the interventions were not shown to improve IPT completion, integration of tuberculosis and HIV services yielded high treatment completion rates in some settings. The lack of data from high burden TB settings limits applicability. Further research to assess different IPT delivery interventions, including those that address barriers to care in at-risk populations, is urgently needed to identify the most effective practices for IPT delivery and TB control in high TB burden settings.

Variation in Mpox Vaccine Coverage in the United States: Influence of Political Orientation and Public Health Resources.

During the 2022-2023 mpox outbreak in the United States, the federal government distributed mpox vaccines to individual states. Significant variation in vaccine coverage was noted across states. State-level factors associated with higher vaccine coverage were Democratic political orientation, higher public health spending, higher proportion of at-risk population, and higher mpox cases.

Understanding Barriers to Establishing Public JYNNEOS Mpox Vaccination Clinics in New Hampshire: Mpox vaccine clinic NH.

OBJECTIVE: 2022 - 2023 mpox outbreak necessitated rapid distribution of JYNNEOS vaccines from US Strategic National Stockpile to state and local public health agencies. New Hampshire's centralized public health structure required partnering with healthcare facilities to reach at-risk persons. Among the 67 organizations contacted to partner with, only 7 established public JYNNEOS vaccine clinics. The study objective was to identify barriers and resources needed for emergency public vaccination. METHODS: In March 2023, mixed-method surveys were developed and sent to 20 non-participating organizations and 7 participating organizations ("vaccine-partners"). RESULTS: 35% (7/20) of non-participating organizations and 100% (7/7) vaccine-partners responded. Non-participating organizations (n = 5) identified lack of staffing (100%) and insufficient provider time or clinical resources (80%) as the most common barriers. Staffing needs reported by non-participating organizations included: administrative (100%); medical doctor or advanced practice practitioner (67%); and registered nurse, medical assistant, or licensed nursing assistant (67%). Vaccine partners reported similar staffing requirements. Estimated additional monthly funding needs were $3,750 for non-participating organizations and $1,680 for vaccine-partners. CONCLUSIONS: A minority of NH healthcare facilities established public JYNNEOS vaccination clinics. The primary barrier was insufficient staffing; additional resources and funding needs were modest. Success of the next emergency vaccination campaign depends on sustained advocacy, resources, and partnership.

Dynamic antibody responses to the Mycobacterium tuberculosis proteome.

Considerable effort has been directed toward controlling tuberculosis, which kills almost two million people yearly. High on the research agenda is the discovery of biomarkers of active tuberculosis (TB) for diagnosis and for monitoring treatment outcome. Rational biomarker discovery requires understanding host-pathogen interactions leading to biomarker expression. Here we report a systems immunology approach integrating clinical data and bacterial metabolic and regulatory information with high-throughput detection in human serum of antibodies to the entire Mycobacterium tuberculosis proteome. Sera from worldwide TB suspects recognized approximately 10% of the bacterial proteome. This result defines the M. tuberculosis immunoproteome, which is rich in membrane-associated and extracellular proteins. Additional analyses revealed that during active tuberculosis (i) antibody responses focused on an approximately 0.5% of the proteome enriched for extracellular proteins, (ii) relative target preference varied among patients, and (iii) responses correlated with bacillary burden. These results indicate that the B cell response tracks the evolution of infection and the pathogen burden and replicative state and suggest functions associated with B cell-rich foci seen in tuberculous lung granulomas. Our integrated proteome-scale approach is applicable to other chronic infections characterized by diverse antibody target recognition.

6-month versus 36-month isoniazid preventive treatment for tuberculosis in adults with HIV infection in Botswana: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: In accordance with WHO guidelines, people with HIV infection in Botswana receive daily isoniazid preventive therapy against tuberculosis without obtaining a tuberculin skin test, but duration of prophylaxis is restricted to 6 months. We aimed to assess effectiveness of extended isoniazid therapy. METHODS: In our randomised, double-blind, placebo-controlled trial we enrolled adults infected with HIV aged 18 years or older at government HIV-care clinics in Botswana. Exclusion criteria included current illness such as cough and an abnormal chest radiograph without antecedent tuberculosis or pneumonia. Eligible individuals were randomly allocated (1:1) to receive 6 months' open-label isoniazid followed by 30 months' masked placebo (control group) or 6 months' open-label isoniazid followed by 30 months' masked isoniazid (continued isoniazid group) on the basis of a computer-generated randomisation list with permuted blocks of ten at each clinic. Antiretroviral therapy was provided if participants had CD4-positive lymphocyte counts of fewer than 200 cells per µL. We used Cox regression analysis and the log-rank test to compare incident tuberculosis in the groups. Cox regression models were used to estimate the effect of antiretroviral therapy. The trial is registered at ClinicalTrials.gov, number NCT00164281. FINDINGS: Between Nov 26, 2004, and July 3, 2009, we recorded 34 (3·4%) cases of incident tuberculosis in 989 participants allocated to the control group and 20 (2·0%) in 1006 allocated to the continued isoniazid group (incidence 1·26% per year vs 0·72%; hazard ratio 0·57, 95% CI 0·33-0·99, p=0·047). Tuberculosis incidence in those individuals receiving placebo escalated approximately 200 days after completion of open-label isoniazid. Participants who were tuberculin skin test positive (ie, ≥5 mm induration) at enrolment received a substantial benefit from continued isoniazid treatment (0·26, 0·09-0·80, p=0·02), whereas participants who were tuberculin skin test-negative received no significant benefit (0·75, 0·38-1·46, p=0·40). By study completion, 946 (47%) of 1995 participants had initiated antiretroviral therapy. Tuberculosis incidence was reduced by 50% in those receiving 360 days of antiretroviral therapy compared with participants receiving no antiretroviral therapy (adjusted hazard ratio 0·50, 95% CI 0·26-0·97). Severe adverse events and death were much the same in the control and continued isoniazid groups. INTERPRETATION: In a tuberculosis-endemic setting, 36 months' isoniazid prophylaxis was more effective for prevention of tuberculosis than was 6-month prophylaxis in individuals with HIV infection, and chiefly benefited those who were tuberculin skin test positive. FUNDING: US Centers for Disease Control and Prevention and US Agency for International Development.

Ensuring Equitable COVID-19 Vaccine Allocation in New Hampshire: The First Eight Months toward a New Era.

The global coronavirus disease 2019 (COVID-19) pandemic has been exacerbated by social vulnerabilities and racial disparities, resulting in disproportionate morbidity and mortality that require continued attention to strategies that ensure equitable vaccine allocation. The State of New Hampshire (NH) developed a transparent framework to guide COVID-19 vaccine allocation plans, of which one key component was the allocation of 10% of vaccine supply to disproportionately impacted and highly vulnerable populations, predominantly identified through a national vulnerability index. The process, operational approaches, ethical challenges, and unanticipated consequences resulted in many valuable lessons learned. Equitable allocation of this limited and critical pandemic countermeasure required public understanding and engagement, which was achieved through a publicly available framework that was flexible, resourced using public funds, and widely communicated. Broad partnerships were also critical to addressing disparities in the delivery of vaccine. The lessons learned and described here will facilitate more nimble and equitable jurisdictional responses in future public health emergencies.

Creation of State Antibiogram and Subsequent Launch of Public Health-Coordinated Antibiotic Stewardship in New Hampshire: Small State, Big Collaboration.

BACKGROUND: An antibiogram is a summary of antibiotic susceptibility patterns for selected bacterial pathogens and antibiotics. The New Hampshire Department of Health and Human Services' Division of Public Health Services (DPHS) sought to create an annual state antibiogram to monitor statewide antibiotic resistance trends, guide appropriate empiric antibiotic prescribing, and inform future statewide antibiotic stewardship. METHODS: Through legislative authority, DPHS required hospital laboratories to report antibiogram data annually. DPHS convened an advisory group of infectious disease and pharmacy stakeholders and experts to develop a standardized reporting form for bacteria and antibiotic susceptibility, which was disseminated to all 26 hospitals in New Hampshire. We combined the reported data into a statewide antibiogram, and we created clinical messaging to highlight findings and promote rational antibiotic prescribing among health care providers. RESULTS: All hospital laboratories in New Hampshire submitted annual antibiogram data for 2016 and 2017, including more than 30 000 and 20 000 bacterial isolates recovered from urine and nonurine cultures, respectively, each year. The advisory group created clinical messages for appropriate treatment of common infectious syndromes, including uncomplicated urinary tract infections, community-acquired pneumonia, skin and soft-tissue infections, intra-abdominal infections, and health care-associated gram-negative aerobic infections. The statewide antibiograms and clinical messaging were widely disseminated. CONCLUSIONS: The small size of New Hampshire, a centralized public health structure, and close working relationships with hospitals and clinical partners allowed for efficient creation and dissemination of an annual statewide antibiogram, which has fostered public health-clinical partnerships and built a foundation for future state-coordinated antibiotic stewardship. This process serves as a model for other jurisdictions that are considering antibiogram development.

Serial T-SPOT.TB responses in Tanzanian adolescents: Transient, persistent and irregular conversions.

BACKGROUND: Prospective studies of interferon-gamma release assays (IGRA) on healthy subjects in tuberculosis-endemic regions have not examined the long-term variability of serial assays. This issue is relevant to the interpretation of tuberculosis (TB) vaccine trials based on prevention of infection. METHODS: T-SPOT.TB assays were performed manually on healthy adolescents during a tuberculosis vaccine trial in Tanzania at 5 intervals over 3 years. Assay results were defined as negative, positive, borderline or invalid. Subsequently, microtiter plates were analyzed by an automated reader to obtain quantitative counts of spot forming cells (SFCs) for the present analysis. RESULTS: 3387 T-SPOT.TB samples were analyzed from 928 adolescents; manual and automated assay results were 97% concordant. Based on the quantitative results 143 (15%) participants were prevalent IGRA-positives at baseline, were ineligible for further study. Among the remaining IGRA-negative participants, the annual rate of IGRA conversion was 2·9%. Among 43 IGRA converters with repeat assays 12 (28%) were persistent converters, 16 (37%) were transient converters, and 15 (35%) comprised a new category defined as irregular converters (≥2 different subsequent results). ESAT-6 and CFP-10 responses were higher in prevalent than incident positives: 53 vs 36 for CFP-10 (p < 0·007); 44 vs 34 for ESAT-6 (p = 0·12). CONCLUSIONS: Definitions of IGRA conversion, reversion, and persistence depend critically on the frequency of testing. Multiple shifts in categories among adolescents in a TB-endemic country may represent multiple infections, variable host responses in subclinical infection, or assay variation. These findings should to be considered in the design and interpretation of TB vaccine trials based on prevention of infection. Household contact studies could determine whether even transient IGRA conversion might represent exposure to an active case of M. tuberculosis disease.

The bacteraemia of disseminated tuberculosis among HIV-infected patients with prolonged fever in Tanzania.

BACKGROUND: Disseminated tuberculosis (TB) is a common cause of death among human immunodeficiency virus (HIV)-infected patients in developing countries. Blood culture offers a potential means to diagnose disseminated TB, but optimal blood culture methods have not been studied. METHODS: Two hundred and fifty-eight HIV-infected patients hospitalized in Tanzania with ≥2 weeks fever or cough had diagnostic studies for TB: 3 sputum samples for acid-fast bacilli smear and culture; 40 ml of blood for culture, randomized 1:1 to 40 ml × 1, or 20 ml × 2 collected 12-24 h apart. Blood was processed using automated MB BacT(®) broth and manual Isolator(®) lysis-centrifugation agar. Mortality was assessed at 2 months. RESULTS: TB was confirmed in 83 (32%) of 258 patients: by sputum only in 42 (51%, median CD4 = 72 cells/µl), blood only in 15 (18%, median CD4 = 44 cells/µl), and in sputum and blood in 26 (31%, median CD4 = 12 cells/µl). Blood was positive in 21 (16%) for 40 ml × 1 vs 20 (15%) for 20 ml × 1 (p = 0.83) vs 20 (16%) for 20 ml × 2 (p = 0.97). MB BacT was positive in 31 (76%) and Isolator was positive in 20 (49%) of 41 samples (p = 0.01). The mean colony-forming units/ml was 8 (range 3-14). Twenty-one (51%) patients with disseminated TB died; median survival was 6 days (range 0-58). CONCLUSIONS: Disseminated TB in HIV is characterized by persistent bacteraemia, delayed microbiological detection, and high mortality. Twenty millilitres of blood processed by automated broth is the optimal culture method to detect disseminated TB. Empiric TB therapy is warranted for HIV-infected patients from TB-endemic countries with prolonged cough or fever.

Last mile research: a conceptual map.

Background: The term 'last mile' has been used across disciplines to refer to populations who are farthest away, most difficult to reach, or last to benefit from a program or service. However, last mile research lacks a shared understanding around its conceptualization.Objectives: This project used a concept mapping process to answer the questions: what is last mile research in global health and, how can it be used to make positive change for health equity in the last mile?Methods: Between July and December 2019, a five-stage concept mapping exercise was undertaken using online concept mapping software and an in-person consensus meeting. The stages were: establishment of an expert group and focus prompt; idea generation; sorting and rating; initial analysis and final consensus meeting.Results: A group of 15 health researchers with experience working with populations in last mile contexts and who were based at the Matariki Network institutions of Queen's University, CAN and Dartmouth College, USA took part. The resulting concept map had 64 unique idea statements and the process resulted in a map with five clusters. These included: (1) Last mile populations; (2) Research methods and approaches; (3) Structural and systemic factors; (4) Health system factors, and (5) Broader environmental factors. Central to the map were the ideas of equity, human rights, health systems, and contextual sensitivity.Conclusion: This is the first time 'last mile research' has been the focus of a formal concept mapping exercise. The resulting map showed consensus about who last mile populations are, how research should be undertaken in the last mile and why last mile health disparities exist. The map can be used to inform research training programs, however, repeating this process with researchers and members from different last mile populations would also add further insight.

Outbreak of skin infections in college football team members due to an unusual strain of community-acquired methicillin-susceptible Staphylococcus aureus.

We report a skin and soft-tissue infection outbreak among football team members due to a USA300 methicillin-susceptible Staphylococcus aureus (MRSA) strain with genes coding for Panton-Valentine leukocidin and the arginine catabolic mobile element. We postulate that the strain is a community-associated USA300 MRSA strain that lost methicillin resistance but retained important virulence factors.

Mycobacterium tuberculosis bloodstream infection prevalence, diagnosis, and mortality risk in seriously ill adults with HIV: a systematic review and meta-analysis of individual patient data.

BACKGROUND: The clinical and epidemiological significance of HIV-associated Mycobacterium tuberculosis bloodstream infection (BSI) is incompletely understood. We hypothesised that M tuberculosis BSI prevalence has been underestimated, that it independently predicts death, and that sputum Xpert MTB/RIF has suboptimal diagnostic yield for M tuberculosis BSI. METHODS: We did a systematic review and individual patient data (IPD) meta-analysis of studies performing routine mycobacterial blood culture in a prospectively defined patient population of people with HIV aged 13 years or older. Studies were identified through searching PubMed and Scopus up to Nov 10, 2018, without language or date restrictions and through manual review of reference lists. Risk of bias in the included studies was assessed with an adapted QUADAS-2 framework. IPD were requested for all identified studies and subject to harmonised inclusion criteria: age 13 years or older, HIV positivity, available CD4 cell count, a valid mycobacterial blood culture result (excluding patients with missing data from lost or contaminated blood cultures), and meeting WHO definitions for suspected tuberculosis (presence of screening symptom). Predicted probabilities of M tuberculosis BSI from mixed-effects modelling were used to estimate prevalence. Estimates of diagnostic yield of sputum testing with Xpert (or culture if Xpert was unavailable) and of urine lipoarabinomannan (LAM) testing for M tuberculosis BSI were obtained by two-level random-effect meta-analysis. Estimates of mortality associated with M tuberculosis BSI were obtained by mixed-effect Cox proportional-hazard modelling and of effect of treatment delay on mortality by propensity-score analysis. This study is registered with PROSPERO, number 42016050022. FINDINGS: We identified 23 datasets for inclusion (20 published and three unpublished at time of search) and obtained IPD from 20, representing 96·2% of eligible IPD. Risk of bias for the included studies was assessed to be generally low except for on the patient selection domain, which was moderate in most studies. 5751 patients met harmonised IPD-level inclusion criteria. Technical factors such as number of blood cultures done, timing of blood cultures relative to blood sampling, and patient factors such as inpatient setting and CD4 cell count, explained significant heterogeneity between primary studies. The predicted probability of M tuberculosis BSI in hospital inpatients with HIV-associated tuberculosis, WHO danger signs, and a CD4 count of 76 cells per µL (the median for the cohort) was 45% (95% CI 38-52). The diagnostic yield of sputum in patients with M tuberculosis BSI was 77% (95% CI 63-87), increasing to 89% (80-94) when combined with urine LAM testing. Presence of M tuberculosis BSI compared with its absence in patients with HIV-associated tuberculosis increased risk of death before 30 days (adjusted hazard ratio 2·48, 95% CI 2·05-3·08) but not after 30 days (1·25, 0·84-2·49). In a propensity-score matched cohort of participants with HIV-associated tuberculosis (n=630), mortality increased in patients with M tuberculosis BSI who had a delay in anti-tuberculosis treatment of longer than 4 days compared with those who had no delay (odds ratio 3·15, 95% CI 1·16-8·84). INTERPRETATION: In critically ill adults with HIV-tuberculosis, M tuberculosis BSI is a frequent manifestation of tuberculosis and predicts mortality within 30 days. Improved diagnostic yield in patients with M tuberculosis BSI could be achieved through combined use of sputum Xpert and urine LAM. Anti-tuberculosis treatment delay might increase the risk of mortality in these patients. FUNDING: This study was supported by Wellcome fellowships 109105Z/15/A and 105165/Z/14/A.

Kinetics of pertussis immune responses to tetanus-diphtheria-acellular pertussis vaccine in health care personnel: implications for outbreak control.

We assessed the kinetics of the humoral immune response to pertussis antigens following vaccination of health care personnel with adult tetanus-diphtheria-acellular pertussis vaccine (Tdap). By 2 weeks after vaccination, 88%-94% of subjects demonstrated a booster response. This brisk response of adults to Tdap supports a role for vaccination in pertussis outbreak control.