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"The Sombre Aspect of the Entire Landscape" - Epidemiology and the Faroe Islands

Klass, Perri; Ratner, Adam J
PMID: 35333484
ISSN: 1533-4406
CID: 5200682

Vaccinating Children against Covid-19 - The Lessons of Measles

Klass, Perri; Ratner, Adam J
PMID: 33471977
ISSN: 1533-4406
CID: 4765042

Multisystem Inflammatory Syndrome in U.S. Children and Adolescents

Feldstein, Leora R; Rose, Erica B; Horwitz, Steven M; Collins, Jennifer P; Newhams, Margaret M; Son, Mary Beth F; Newburger, Jane W; Kleinman, Lawrence C; Heidemann, Sabrina M; Martin, Amarilis A; Singh, Aalok R; Li, Simon; Tarquinio, Keiko M; Jaggi, Preeti; Oster, Matthew E; Zackai, Sheemon P; Gillen, Jennifer; Ratner, Adam J; Walsh, Rowan F; Fitzgerald, Julie C; Keenaghan, Michael A; Alharash, Hussam; Doymaz, Sule; Clouser, Katharine N; Giuliano, John S; Gupta, Anjali; Parker, Robert M; Maddux, Aline B; Havalad, Vinod; Ramsingh, Stacy; Bukulmez, Hulya; Bradford, Tamara T; Smith, Lincoln S; Tenforde, Mark W; Carroll, Christopher L; Riggs, Becky J; Gertz, Shira J; Daube, Ariel; Lansell, Amanda; Coronado Munoz, Alvaro; Hobbs, Charlotte V; Marohn, Kimberly L; Halasa, Natasha B; Patel, Manish M; Randolph, Adrienne G
BACKGROUND:Understanding the epidemiology and clinical course of multisystem inflammatory syndrome in children (MIS-C) and its temporal association with coronavirus disease 2019 (Covid-19) is important, given the clinical and public health implications of the syndrome. METHODS:We conducted targeted surveillance for MIS-C from March 15 to May 20, 2020, in pediatric health centers across the United States. The case definition included six criteria: serious illness leading to hospitalization, an age of less than 21 years, fever that lasted for at least 24 hours, laboratory evidence of inflammation, multisystem organ involvement, and evidence of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) based on reverse-transcriptase polymerase chain reaction (RT-PCR), antibody testing, or exposure to persons with Covid-19 in the past month. Clinicians abstracted the data onto standardized forms. RESULTS:We report on 186 patients with MIS-C in 26 states. The median age was 8.3 years, 115 patients (62%) were male, 135 (73%) had previously been healthy, 131 (70%) were positive for SARS-CoV-2 by RT-PCR or antibody testing, and 164 (88%) were hospitalized after April 16, 2020. Organ-system involvement included the gastrointestinal system in 171 patients (92%), cardiovascular in 149 (80%), hematologic in 142 (76%), mucocutaneous in 137 (74%), and respiratory in 131 (70%). The median duration of hospitalization was 7 days (interquartile range, 4 to 10); 148 patients (80%) received intensive care, 37 (20%) received mechanical ventilation, 90 (48%) received vasoactive support, and 4 (2%) died. Coronary-artery aneurysms (z scores ≥2.5) were documented in 15 patients (8%), and Kawasaki's disease-like features were documented in 74 (40%). Most patients (171 [92%]) had elevations in at least four biomarkers indicating inflammation. The use of immunomodulating therapies was common: intravenous immune globulin was used in 144 (77%), glucocorticoids in 91 (49%), and interleukin-6 or 1RA inhibitors in 38 (20%). CONCLUSIONS:Multisystem inflammatory syndrome in children associated with SARS-CoV-2 led to serious and life-threatening illness in previously healthy children and adolescents. (Funded by the Centers for Disease Control and Prevention.).
PMID: 32598831
ISSN: 1533-4406
CID: 4503892

A group B Streptococcus indexed transposon mutant library to accelerate genetic research on an important perinatal pathogen

Bhavana, Venkata H; Hillebrand, Gideon H; Gopalakrishna, Kathyayini P; Rapp, Rebekah A; Ratner, Adam J; Tettelin, Hervé; Hooven, Thomas A
Group B Streptococcus (GBS) is a significant global cause of serious infections, most of which affect pregnant women, newborns, and infants. Studying GBS genetic mutant strains is a valuable approach for learning more about how these infections are caused and is a key step toward developing more effective preventative and treatment strategies. In this resource report, we describe a newly created library of defined GBS genetic mutants, containing over 1,900 genetic variants, each with a unique disruption to its chromosome. An indexed library of this scale is unprecedented in the GBS field; it includes strains with mutations in hundreds of genes whose potential functions in human disease remain unknown. We have made this resource freely available to the broader research community through deposition in a publicly funded bacterial maintenance and distribution repository.
PMID: 37933989
ISSN: 2165-0497
CID: 5620302

Cefiderocol Red Wine Urine Syndrome in Pediatric Patients: A Multicenter Case Series

Shapiro, Kate; Ungar, Stephanie P; Krugman, Jessica; McGarrity, Orlagh; Cross, Shane J; Indrakumar, Bairavi; Hatcher, James; Ratner, Adam J; Wolf, Joshua
Cefiderocol is a novel cephalosporin antibiotic with activity against multidrug-resistant gram-negative bacteria and limited pediatric experience. This case series describes 3 immunocompromised children receiving blood transfusion who developed benign red or purple urine with administration of cefiderocol. Interaction with iron from blood products is a possible mechanism. It is important to recognize this phenomenon and distinguish it from hematuria to avoid unnecessary diagnostic testing.
PMID: 37922468
ISSN: 1532-0987
CID: 5607072

Genomic Analysis of Group B Streptococcus Carriage Isolates From Botswana Reveals Distinct Local Epidemiology and Identifies Novel Strains

Hanze Villavicencio, Karen L.; Job, Megan J.; Burghard, Anne Claire; Taffet, Allison; Banda, Francis M.; Vurayai, Moses; Mokomane, Margaret; Arscott-Mills, Tonya; Mazhani, Tiny; Nchingane, Seeletso; Thomas, Brady; Steenhoff, Andrew P.; Ratner, Adam J.
In pregnant people colonized with group B Streptococcus (GBS) in Botswana, we report the presence/expansion of sequence types 223 and 109, a low rate of erythromycin resistance, and 3 novel sequence types. These data highlight the importance of local epidemiologic studies of GBS, a significant source of neonatal disease.
ISSN: 2328-8957
CID: 5614972

Capsule production promotes Group B Streptococcus intestinal colonization

Vaz, Michelle J; Dongas, Sophia; Ratner, Adam J
Late-onset disease is the most common clinical presentation of Group B Streptococcus (GBS) infection during infancy, and gastrointestinal (GI) colonization is an important precursor. Previously, we described a murine model of postnatal GBS GI colonization that resulted in sustained colonization and progression to invasive disease. Capsular polysaccharide is an important GBS virulence factor. Vaccines based on a subset of capsular serotypes are in clinical trials. However, little is known regarding the role of specific GBS capsular serotypes in GI colonization. We examined the role of GBS capsule in GI colonization using capsule-producing and acapsular strains derived from GBS strain A909 (serotype Ia) in a murine model. Using isogenic GBS strains differing only in capsular serotypes, we explored the role of specific serotypes in GI colonization by determining competitive indices during cocolonization. We found that GBS A909 colonizes the murine GI tract without causing invasive disease. In monocolonization experiments, there was colonization persistence with the capsule-producing strain (100%) compared to the acapsular mutant strain (13%). In cocolonization experiments, the capsule-producing strain outcompeted its isogenic acapsular mutant, with a geometric mean competitive index of 8, 95% confidence interval (CI) [1.7, 38.9] in the colon at 7 days post-colonization. A909 expressing its native serotype Ia capsule outcompeted an isogenic mutant that expresses serotype III capsule, with a geometric mean competitive index of 2.5, 95% CI [1.2, 5.1] in the colon at 7 days post-colonization. Thus, polysaccharide capsule production enhances GBS GI colonization in vivo. In an A909 genetic background, the production of a serotype Ia capsule provides a competitive advantage over an isogenic strain producing type III capsule. The murine model is a valuable tool to understand the role of GBS capsule types in GI colonization. IMPORTANCE The establishment of GBS intestinal colonization is believed to be a critical precursor to late-onset disease in neonates, which has a significant impact on neurodevelopment outcomes in this population. Our prior work described a murine model of postnatal Group B Streptococcus (GBS) acquisition and invasive disease. Using this model, we explored the importance of GBS polysaccharide capsule production on gastrointestinal colonization. We found that the expression of capsule (compared to isogenic acapsular strains) provides an advantage in intestinal colonization and, importantly, that capsule type Ia has an advantage over capsule type III in a GBS A909 strain background. We speculate that specific serotypes may differ in colonization fitness, which may play a role in serotype distribution in neonatal disease.
PMID: 37732775
ISSN: 2165-0497
CID: 5614072

Characterization of tigurilysin, a novel human CD59-specific cholesterol-dependent cytolysin, reveals a role for host specificity in augmenting toxin activity

Shahi, Ifrah; Dongas, Sophia A; Ilmain, Juliana K; Torres, Victor J; Ratner, Adam J
Cholesterol-dependent cytolysins (CDCs) are a large family of pore-forming toxins, produced by numerous Gram-positive pathogens. CDCs depend on host membrane cholesterol for pore formation; some CDCs also require surface-associated human CD59 (hCD59) for binding, conferring specificity for human cells. We purified a recombinant version of a putative CDC encoded in the genome of Streptococcus oralis subsp. tigurinus, tigurilysin (TGY), and used CRISPR/Cas9 to construct hCD59 knockout (KO) HeLa and JEG-3 cell lines. Cell viability assays with TGY on wild-type and hCD59 KO cells showed that TGY is a hCD59-dependent CDC. Two variants of TGY exist among S. oralis subsp. tigurinus genomes, only one of which is functional. We discovered that a single amino acid change between these two TGY variants determines its activity. Flow cytometry and oligomerization Western blots revealed that the single amino acid difference between the two TGY isoforms disrupts host cell binding and oligomerization. Furthermore, experiments with hCD59 KO cells and cholesterol-depleted cells demonstrated that TGY is fully dependent on both hCD59 and cholesterol for activity, unlike other known hCD59-dependent CDCs. Using full-length CDCs and toxin constructs differing only in the binding domain, we determined that having hCD59 dependence leads to increased lysis efficiency, conferring a potential advantage to organisms producing hCD59-dependent CDCs.
PMID: 37702594
ISSN: 1465-2080
CID: 5593542

Vaginal carriage of Haemophilus influenzae in a non-pregnant reproductive-age population

Limaye, Meghana A; Brubaker, Sara; Randis, Tara M; Ratner, Adam J
BACKGROUND:Haemophilus influenzae (Hi) is an emerging cause of early onset neonatal sepsis, but mechanisms of transmission are not well understood. We aimed to determine the prevalence of vaginal carriage of Hi in reproductive age women and to examine behavioral and demographic characteristics associated with its carriage. METHODS:) value < 35 were defined as positive. Sanger sequencing confirmed the presence of hpd. Behavioral and demographic characteristics associated with vaginal carriage of Hi were examined. RESULTS:415 samples were available. 315 (75.9%) had sufficient bacterial DNA and were included. 14 (4.4%) were positive for hpd. There were no demographic or behavioral differences between the women with Hi vaginal carriage and those without. There was no difference in history of bacterial vaginosis, vaginal microbiome community state type, or presence of Group B Streptococcus in women with and without vaginal carriage of Hi. CONCLUSION:Hi was present in vaginal lavage specimens of 4.4% of this cohort. Hi presence was unrelated to clinical or demographic characteristics, though the relatively small number of positive samples may have limited power to detect such differences.
PMID: 37208594
ISSN: 1471-2180
CID: 5503682

Maternity care provider acceptance of a future Group B Streptococcus vaccine - A qualitative study in three countries

Geoghegan, Sarah; Acosta, Francia; Stephens, Laura C; Gillan, Hanah; Valera, Sandra; Drew, Richard J; Eogan, Maeve; Ratner, Adam J; Steenhoff, Andrew P; Butler, Karina M; Feemster, Kristen A
INTRODUCTION/BACKGROUND:There are vaccines in clinical trials that target the bacterium Group B Streptococcus (GBS). When approved, GBS vaccines will be intended for administration to pregnant women to prevent infection in their infants. The success of any vaccine will depend on its' uptake in the population. Experience with prior maternal vaccines, e.g. influenza, Tdap and COVID-19 vaccines, teaches us that acceptance of vaccines, especially if novel, is challenging for pregnant women, and that provider recommendation is a key driver of vaccine uptake. METHODS:This study investigated attitudes of maternity care providers towards the introduction of a GBS vaccine in three countries (the United States (US), Ireland, and the Dominican Republic (DR)) with different GBS prevalence and prevention practices. Semi-structured interviews with maternity care providers were transcribed and coded for themes. The constant comparative method, and inductive theory building were used to develop conclusions. RESULTS:Thirty-eight obstetricians, 18 general practitioners and 14 midwives participated. There was variability in provider attitudes towards a hypothetical GBS vaccine. Responses ranged from enthusiasm to doubts over the need for a vaccine. Attitudes were influenced by perceived additional benefits of a vaccine over current strategy and confidence in the safety of vaccines during pregnancy. Knowledge, experience and approaches to GBS prevention differed geographically and according to provider type, and influenced how participants assessed the risks and benefits of a GBS vaccine. CONCLUSION/CONCLUSIONS:Maternity care providers are engaged in the topic of GBS management and there is opportunity to leverage attitudes and beliefs that will support a strong recommendation for a GBS vaccine. However, knowledge of GBS, and of the limitations of current prevention strategies vary among providers in different regions, and between different provider types. Targeted educational efforts with antenatal providers should focus on highlighting safety data the potential benefits of vaccination over current strategies.
PMID: 36803900
ISSN: 1873-2518
CID: 5448102