Rheumatic heart disease in Indigenous young peoples.

Indigenous children and young peoples live with an inequitable burden of acute rheumatic fever and rheumatic heart disease. In this Review, we focus on the epidemiological burden and lived experience of these conditions for Indigenous young peoples in Australia, New Zealand, and Canada. We outline the direct and indirect drivers of rheumatic heart disease risk and their mitigation. Specifically, we identify the opportunities and limitations of predominantly biomedical approaches to the primary, secondary, and tertiary prevention of disease among Indigenous peoples. We explain why these biomedical approaches must be coupled with decolonising approaches to address the underlying cause of disease. Initiatives underway to reduce acute rheumatic fever and rheumatic heart disease in Australia, New Zealand, and Canada are reviewed to identify how an Indigenous rights-based approach could contribute to elimination of rheumatic heart disease and global disease control goals.

Evaluation of Homology-Independent CRISPR-Cas9 Off-Target Assessment Methods.

The ability to alter genomes specifically by CRISPR-Cas gene editing has revolutionized biological research, biotechnology, and medicine. Broad therapeutic application of this technology, however, will require thorough preclinical assessment of off-target editing by homology-based prediction coupled with reliable methods for detecting off-target editing. Several off-target site nomination assays exist, but careful comparison is needed to ascertain their relative strengths and weaknesses. In this study, HEK293T cells were treated with Streptococcus pyogenes Cas9 and eight guide RNAs with varying levels of predicted promiscuity in order to compare the performance of three homology-independent off-target nomination methods: the cell-based assay, GUIDE-seq, and the biochemical assays CIRCLE-seq and SITE-seq. The three methods were benchmarked by sequencing 75,000 homology-nominated sites using hybrid capture followed by high-throughput sequencing, providing the most comprehensive assessment of such methods to date. The three methods performed similarly in nominating sequence-confirmed off-target sites, but with large differences in the total number of sites nominated. When combined with homology-dependent nomination methods and confirmation by sequencing, all three off-target nomination methods provide a comprehensive assessment of off-target activity. GUIDE-seq's low false-positive rate and the high correlation of its signal with observed editing highlight its suitability for nominating off-target sites for ex vivo CRISPR-Cas therapies.

Impact of infection on risk of Parkinson's disease: a quantitative assessment of case-control and cohort studies.

Identifying modifiable risk factors for Parkinson's disease (PD) to help prevent this disease has attracted increasing interest in recent years for the limited effective drugs at present. Despite many studies indicated that infection acts as a risk factor for PD, there is no quantitative assessment of the impact of viral and bacterial infections on the risk of developing PD. The present study performed a meta-analysis on the basis of 38 datasets from 13 studies covering 287,773 PD cases and 7,102,901 controls to ascertain the association between PD and infection and the differences in the strength of the viral and bacterial infections. The overall meta-analytic results indicated that individuals with infection had a 20% increased risk of PD compared with controls (OR 1.20, 95%CI 1.07-1.32). The subgroup analysis according to the type of infection found that bacterial infection had a significant impact on increased risk of PD (OR 1.40, 95%CI 1.32-1.48). The present analysis indicated that infection could increase the risk of developing PD, and physician should be aware of the risk of developing PD in subjects with infection.

Clinical Mimics: An Emergency Medicine-Focused Review of Streptococcal Pharyngitis Mimics.

BACKGROUND: Pharyngitis is a common disease in the emergency department (ED). Despite a relatively low incidence of complications, there are many dangerous conditions that can mimic this disease and are essential for the emergency physician to consider. OBJECTIVE: This article provides a review of the evaluation and management of group A ß-hemolytic Streptococcal (GABHS) pharyngitis, as well as important medical conditions that can mimic this disease. DISCUSSION: GABHS pharyngitis often presents with fever, sore throat, tonsillar exudates, and anterior cervical lymphadenopathy. History and physical examination are insufficient for the diagnosis. The Centor criteria or McIsaac score can help risk stratify patients for subsequent testing or treatment. Antibiotics may reduce symptom duration and suppurative complications, but the effect is small. Rheumatic fever is uncommon in developed countries, and shared decision making is recommended if antibiotics are used for this indication. Oral analgesics and topical anesthetics are important for symptom management. Physicians should consider alternate diagnoses that may mimic GABHS pharyngitis, which can include epiglottitis, infectious mononucleosis, Kawasaki disease, acute retroviral syndrome, Lemierre's syndrome, Ludwig's angina, peritonsillar abscess, retropharyngeal abscess, and viral pharyngitis. A focused history and physical examination can help differentiate these conditions. CONCLUSIONS: GABHS may present similarly to other benign and potentially deadly diseases. Diagnosis and treatment of pharyngitis should be based on clinical evaluation. Consideration of pharyngitis mimics is important in the evaluation and management of ED patients.

Rheumatic Heart Disease in the Twenty-First Century.

Rheumatic heart disease (RHD) is a chronic valvular disease resulting after severe or repetitive episodes of acute rheumatic fever (ARF), an autoimmune response to group A Streptococcus infection. RHD has been almost eliminated with improved social and health infrastructure in affluent countries while it remains a neglected disease with major cause of morbidity and mortality in many low- and middle-income countries, and resource-limited regions of high-income countries. Despite our evolving understanding of the pathogenesis of RHD, there have not been any significant advances to prevent or halt progression of disease in recent history. Long-term penicillin-based treatment and surgery remain the backbone of a RHD control program in the absence of an effective vaccine. The advent of echocardiographic screening algorithms has improved the accuracy of diagnosing RHD and has shed light on the enormous burden of disease. Encouragingly, this has led to a rekindled commitment from researchers in the most affected countries to advocate and take bold actions to end this disease of social inequality.

Invasive group a streptococcal disease: epidemiology, pathogenesis and management.

Invasive group A streptococcal infections are uncommon, although serious, infections with high case fatality rates. Periodic resurgences in invasive group A streptococcal infections in industrialized countries have been reported from the 1980s onwards, with current estimates of incidence in these countries of approximately 3-4 per 100 000 population. Infants, pregnant women and the elderly are at increased risk of invasive group A streptococcal infection. The group A streptococcus has an array of virulence factors that underpin its invasive capacity and, in approximately 10% of cases, superantigen toxins produced by the bacteria stimulate a large proportion of T cells, leading to streptococcal toxic shock syndrome. Given the rapid clinical progression, effective management of invasive group A streptococcal infections hinges on early recognition of the disease and prompt initiation of supportive care (often intensive care) together with antibacterial therapy. In cases of toxic shock syndrome, it is often difficult to distinguish between streptococcal and staphylococcal infection before cultures become available and so antibacterial choice must include coverage of both of these organisms. In addition, clindamycin is an important adjunctive antibacterial because of its anti-toxin effects and excellent tissue penetration. Early institution of intravenous immunoglobulin therapy should be considered in cases of toxic shock syndrome and severe invasive infection, including necrotizing fasciitis. Early surgical debridement of necrotic tissue is also an important part of management in cases of necrotizing fasciitis.

Direct economic effect following mupirocin therapy failure among patients with uncomplicated skin and skin-structure infections in a large population-based cohort.

The goal of the study was to derive initial costs associated with failure of initial mupirocin therapy among patients diagnosed with uncomplicated skin and skin-structure infections (uSSSIs). A retrospective observational analysis of medical, pharmacy, and enrollment records was conducted using data from the National Managed Care Benchmark Database. Patients were classified as failing treatment with mupirocin if they either filled a second antibiotic commonly used to treat uSSSIs five to 30 days after their index mupirocin prescription fill or experienced a uSSSI-related hospitalization within 30 days after the index mupirocin prescription fill. Among 12,650 failure episodes, 11,867 (93.8%) required a second antibiotic contributing a mean cost of $62 per prescription. Approximately 4,782 (37.8%) had an associated outpatient encounter resulting in a mean cost of $221 per encounter. Nine percent of failures required a hospitalization with a mean cost of $6,597 per hospitalization. These medical, hospital, and pharmacy costs translated into an expected cost of $735.45 per mupirocin failure among patients with uSSSIs. The management of uSSSIs is costly in terms of health care resource use and direct health care expenditures when initial therapy with mupirocin fails.

Measuring the quality of care for group A streptococcal pharyngitis in 5 US health plans.

BACKGROUND: There is a high degree of professional consensus that children diagnosed with pharyngitis should only receive antibiotics if they have a positive test for group A streptococcus (GAS). OBJECTIVES: To develop and test the validity of a quality of care performance measure that examines GAS testing rates in children diagnosed with pharyngitis and prescribed an antibiotic. DESIGN: The measure developed examines the annual rate of GAS testing in children aged 2 to 18 years with an episode of pharyngitis who were prescribed antibiotics. The measure was tested for feasibility of implementation and validity in 5 health plans in the United States. Health plan administrative data were used to identify episodes of pharyngitis using International Classification of Diseases, Ninth Revision (ICD-9) codes 462, 463, and 034.0. Pharmacy data (National Drug Codes) were used to determine if antibiotics were prescribed for the pharyngitis episode. Laboratory claims data (Current Procedural Terminology codes) were used to determine whether a GAS test was performed. Rates of GAS testing in children with pharyngitis who received antibiotics were calculated for each health plan. Medical record abstractions were performed on a random sample (n = 465) of cases to assess percent agreement with laboratory claims data for GAS testing. Sensitivity of the administrative data for accurately identifying when GAS tests were performed was also assessed. RESULTS: Of the 120 158 children aged 2 to 18 years who had at least 1 episode of pharyngitis during the measurement year, 51 172 (43%) received antibiotics. Group A streptococcal testing rates for patients who were prescribed antibiotics varied widely among the participating health plans (59%-83% of cases; P<.05). Percent agreement between administrative and medical records data for GAS tests was 86%. The sensitivity of the administrative data for accurately identifying when GAS tests were performed was 85%. CONCLUSIONS: This quality measure is feasible to implement at the health plan level and validly assesses GAS testing rates using administrative data. The participating health plans are not performing GAS tests as indicated by current expert practice guidelines in a substantial proportion of cases. Improvements in adhering to these guidelines are warranted given the current levels of antibiotic overuse and antibiotic resistance nationally.

Assessment of the interaction of human complement regulatory proteins with group A Streptococcus. Identification of a high-affinity group A Streptococcus binding site in FHL-1.

Group A Streptococcus (GAS), the most frequent bacterial cause of suppurative infections in humans, expresses on the cell surface M proteins with capacity to bind factor H, FHL-1 and C4b binding protein (C4BP). This has been interpreted as a mechanism developed by this pathogen to decrease phagocytosis by macrophages and polymorphonuclear cells. We report the analysis of the capacity to bind factor H, FHL-1 and C4BP of 69 clinical isolates from 19 different serotypes. We show that strains binding complement regulators (30/69) belong to specific M serotypes. Of these, M18 strains are relatively frequent and interact with all three complement regulators simultaneously. However, the most virulent M1 and M3 strains did not bind complement regulators in our assays. The relevance of the interaction between complement regulators and S. pyogenes was analyzed using different approaches with the conclusion that under physiological conditions only FHL-1 and C4BP bind to streptococci. We show that FHL-1 presents a higher binding affinity for S. pyogenes than factor H because it carries a hydrophobic, high-affinity, GAS binding site in addition to the heparin binding site in SCR7. Using synthetic peptides we provide evidence that the high-affinity GAS binding site in FHL-1 involves the hydrophobic tail (Ser-Phe-Thr-Leu) that distinguishes FHL-1 from factor H.

Antimicrobial therapy issues facing pediatricians.

In the field of infectious diseases, the emergence of new pathogens or old diseases in newly recognized forms; changing virulence of pathogens; changing patterns of antimicrobial susceptibility; new diagnostic techniques, drugs or vaccines; changing concepts of chemoprophylaxis; controversies about medical vs. surgical techniques; and the challenge of care of children with infectious diseases within new guidelines of managed care are recently identified areas of change. The increased resistance of Streptococcus pneumoniae to many commonly used antimicrobials and the increased proportion of beta-lactamase-producing nontypable Haemophilus influenzae and Moraxella catarrhalis concern many practitioners. The decreased antibiotic susceptibility of S. pneumoniae is a relatively new phenomenon in the United States. Optimal therapy for mild, moderate or severe pneumococcal disease is dependent on current local susceptibility patterns. Group A streptococci are uniformly susceptible to readily achieved concentrations of all penicillins and cephalosporins. However, recent clusters of cases of rheumatic fever, increased recognition of toxic shock syndrome and bacteremic and localized severe pneumococcal disease have increased concern about the changing ecology of the Streptococcus and the implications for therapy. Finally recognition that many children with acute bacterial otitis media have resolution of disease without use of antimicrobial agents has led to more rigorous study designs for evaluating new drugs.(ABSTRACT TRUNCATED AT 250 WORDS)

Portadores faringeos de streptococcus pyogenes en escolares de diferente nivel socio-económico / Pharyngeal carries of streptococcus pyogenes in school children of different socioeconomic levels

Se estudiaron 196 niños, 103 varones y 93 hembras, en edades comprendidas entre 7 y 14 años, de dos niveles socieconómicos; el nivel alto, representado por 100 niños de un grupo educativo ubicado en la urbanización Prados del Este y el bajo, representado por 96 niños de una unidad escolar ubicada en la urbanización Prado de María. Se demostró la presencia de Streptococcus pyogenes en 11(11,0%) niños del nivel socieconomico alto. La mayor incidencia del Streptococcus pyogenes en la faringe de niños con bajo nivel socieconómico podría explicarse por razones epidemiológicas relacionadas con el hacinamiento del grupo familiar al cual pertenecen estos niños esto determinaria un mayor contacto interpersonal y, por lo tanto, estarían repetida y frecuentemente, expuestos a la adquisición del microorganismo

Prevalencia del streptococcus pyogenes y su relación con la fiebre reumática / Prevalence of Streptococcus pyogenes and its relation to rheumatic fever

La fiebre reumática es una enfermedad de la infancia y de la adolescencia, alcanza su mayor frecuencia entre los cuatro y los nueve años de edad; su incidencia es muy alta en la segunda década de la vida y declina rápidamente a partir de los 20 años. El objetivo del presente estudio fué determinar la presencia de Streptococcus pyogenes en niños de dos guarderías de diferente nivel socio-económico y establecer un programa de vigilancia en ambas. Para ello, se procesaron 42 cultivos de exudado faríngeo de la guardería del Centro de Estudios de Atención Primaria de la Salud y 39 de la guardería CENDI, Coyoacán. Obteniéndose un 14% de positividad en la primera por un 11% de la segunda. Estos resultados son discutivos en el presente trabajo. Finalmente al implantar este to de programas se le debe dar un énfasis especial a los portadores ya que son la fuente de infección a otras personas.