Prediabetes is increasing in prevalence and is associated with risk of developing diabetes, heart disease, stroke, and retinopathy. Clinicians have limited tools to facilitate prediabetes discussions within primary care visits. 1) Develop a Patient and Stakeholder Advisory Committee (PASAC) to design, evaluate, and revise a prediabetes shared decision aid, and 2) evaluate the feasibility and experience of implementing the tool within primary care practice. A prediabetes decision aid (double-sided infographic with decision questions) was created by a PASAC that included patients, primary care clinicians, diabetes educators, endocrinologists, and pharmacists. Five clinicians within 3 primary care practices tested the prediabetes tool with 50 adult patients with prediabetes. Patients completed 2 surveys immediately after the office visit and 6 weeks later. Clinicians and PASAC members completed a postintervention survey. The prediabetes shared decision aid was created through a deliberative process over 3 PASAC meetings. Ninety-six percent of patients felt the tool prepared them to decide on a diabetes prevention plan, and 100% of clinicians would use the tool again and felt the tool did not extend visit length. It was feasible to cocreate a prediabetes shared decision aid within a PASAC and implement the tool within a primary care setting. Patients and clinicians reported a prediabetes discussion, which may mitigate rates of progression to diabetes and associated complications. Future research should evaluate which of the intervention components most effectively promotes discussion of prediabetes within a primary care setting.
Despite widespread recognition that adherence to clinical preventive guidelines improves patient outcomes, clinicians struggle to implement guideline changes in a timely manner. Multiple factors influence guideline adoption and effective implementation. However, few studies evaluate their collective and inter-related effects. This qualitative study provides a comprehensive picture of the interplay between multiple factors on uptake of new or changed preventive guidelines. Semistructured interviews conducted in 2018 with a diverse sample of clinicians and practice leaders sought to understand patient, clinician, practice, health system, environment, and guideline factors of influence. An immersion-crystallization approach was used to identify emergent themes. Interviewees expressed motivation to adhere to guidelines but also valued sharing decisions with patients. Personal biases and fears affected both clinician and patient guideline adoption. Practices facilitated implementation through workflow optimization and encouraging a culture of evidence-based practice while a key health system function was to maintain electronic health record alerts. More traditional environmental factors, such as insurance coverage or transportation, were less of a barrier to guideline adoption and implementation than the influence of media and specialists. Various specific guideline characteristics also affected ease of adoption and implementation. Different settings expressed greater health system, practice, or clinician-centric approaches to guideline implementation. Guideline uptake is influenced by a complex interplay of multiple levels of factors including the patient, clinician, practice, health system, environment, and guideline levels. Comprehensively understanding all levels of influence for each specific clinical setting may help to determine the optimal intervention(s) for improving uptake of evidence-based guidelines.
Direct-to-consumer prescription drug advertising is prevalent and affects patient care. Previous research that examined its effect on the patient-provider relationship predates many changes in the advertising and medical landscape that have occurred in the last decade, such as the rise in online promotion and the push for value-based medicine. We conducted a nationally representative mail-push-to-web survey of 1744 US adults in 2017 to explore how patients view the effects of direct-to-consumer prescription drug advertising on patient-provider interactions. Most respondents (76%) said they were likely to ask a health care provider about advertised drugs; 26% said they had already done so. Among the 26% of respondents who talked to a health care provider about a specific prescription drug they saw advertised, 16% said they received a prescription for the advertised drug. Few respondents (5%) reported that advertising had caused conflict with a health care provider, 16% said it had caused them to question their provider’s advice, and 23% said they were likely to look for a different provider if their provider refused to prescribe a requested brand name drug. These results suggest that direct-to-consumer advertising is driving some patients to discuss specific products with their health care providers but that most patients do not believe advertising has a negative influence on the patient-provider interaction itself.
Thyroid disorders are among the most commonly treated conditions by the United States health care system. The number of patients reporting thyroid hormone use has increased in recent years, but it is unknown if there have been differential increases in the number of treated individuals within different demographic groups. Previous research has also not evaluated how expenditures for different thyroid hormone medications have changed in recent years. Using data from the 1997 through 2016 Medical Expenditure Panel Survey, we calculated the proportion of adults reporting thyroid hormone prescriptions by 3 demographic variables (age, sex, and race) and determined expenditures from thyroid hormone prescriptions by medication type (overall, generic, Synthroid or Cytomel, and other brand). Between 1997 and 2016, the proportion of adults who reported thyroid hormone use increased from 4.1% (95% CI, 3.7–4.4) to 8.0% (95% CI, 7.5–8.5). Most of the growth in thyroid hormone use occurred among adults aged >65, and use was also more common among females and non-Hispanic whites. Expenditures from thyroid hormones increased from $1.1 billion (95% CI, 0.9–1.3) in 1997 to $3.2 billion dollars (95% CI, 2.9–3.6) in 2016. Generic thyroid hormone prescriptions comprised 18.1% of all thyroid hormone prescriptions in 2004 (95% CI, 15.8–20.4) and 80.8% of all thyroid hormone prescriptions (95% CI, 78.4–83.2) in 2016. Thyroid hormone use nearly doubled over the last 20 years, and increased use was associated with being older, female, and non-Hispanic white. During the same time period, thyroid hormone expenditures almost tripled.
Inhaled corticosteroid (ICS)–based therapy is often used for patients with chronic obstructive pulmonary disease (COPD). However, this approach is under scrutiny because of ICS overuse in patients for whom it is not recommended and because of concerns about adverse events, particularly pneumonia, with long-term ICS use. Evidence suggests ICS may be beneficial in specific patients, namely, those with high blood eosinophil counts (eg, ≥300 cells/µL) or who are at a high risk of exacerbations. According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2020 ABCD assessment tool, these patients belong in group D. For these patients, recommended initial treatment includes ICS in combination with long-acting β2-agonists (LABAs) when blood eosinophil counts are ≥300 cells/µL or LABA + long-acting muscarinic antagonist (LAMA) when patients are highly symptomatic, that is, with greater dyspnea and/or exercise limitation. Follow-up treatments for patients with persistent dyspnea and/or exacerbations may include LABA + ICS, LABA + LAMA, or LABA + LAMA + ICS, with use of ICS being guided by blood eosinophil counts. In this review, differences in the inflammatory mechanism underlying COPD and asthma and the role of ICS treatment in COPD are summarized. Furthermore, findings from recent clinical trials where use of ICS-based dual or triple therapy in COPD was compared with LABA + LAMA therapy and trials in which ICS withdrawal was evaluated in patients with COPD are reviewed. Finally, a step-by-step guide for ICS withdrawal in patients who are unlikely to benefit from this treatment is proposed. A video of the author discussing the overall takeaway of the review article could be downloaded from the link provided: https://www.youtube.com/watch?v=Uq7Sr5jqPDI.
Cervical spondylotic myelopathy (CSM) is a neurologic condition that develops insidiously over time as degenerative changes of the spine result in compression of the cord and nearby structures. It is the most common form of spinal cord injury in adults; yet, its diagnosis is often delayed. The purpose of this article is to review the pathophysiology, natural history, diagnosis, and management of CSM with a focus on the recommended timeline for physicians suspecting CSM to refer patients to a spine surgeon. Various processes underlie spondylotic changes of the canal and are separated into static and dynamic factors. Not all patients with evidence of cord compression will present with symptoms, and the progression of disease varies by patient. The hallmark symptoms of CSM include decreased hand dexterity and gait instability as well as sensory and motor dysfunction. magnetic resonance imaging is the imaging modality of choice in patients with suspected CSM, but computed tomography myelography may be used in patients with contraindications. Patients with mild CSM may be treated surgically or nonoperatively, whereas those with moderate-severe disease are treated operatively. Due to the long-term disability that may result from a delay in diagnosis and management, prompt referral to a spine surgeon is recommended for any patient suspected of having CSM. This review provides information and guidelines for practitioners to develop an actionable awareness of CSM.
There are approximately 1 million transgender and gender-diverse adults in the United States. Despite increased awareness and acceptance, they frequently encounter medical settings that are not welcoming and/or health care providers who are not knowledgeable about their health needs. Use of correct terminology, following best practices for name and pronoun use, and knowledge of gender-affirming interventions can create office environments that are welcoming to transgender clients. Health disparities faced by transgender patients that impact access to care include higher rates of mental health issues, substance use disorders, violence, and poverty. Transgender women are at greater risk for HIV acquisition and are less likely to achieve viral suppression compared with cisgender (nontransgender) individuals. Medical providers can facilitate HIV prevention efforts by offering pre- and postexposure prophylaxis to transgender patients at risk for HIV infection. Improving health outcomes requires attention to cultural competency and an understanding of lived experiences and priorities of transgender people.
Patient identification is an important step for advance care planning (ACP) discussions. We conducted a scoping review to identify prognostic indices potentially useful for initiating ACP. We included studies that developed and/or validated a multivariable prognostic index for all-cause mortality between 6 months and 5 years in community-dwelling adults. PubMed was searched in October 2018 for articles meeting our search criteria. If a systematic review was identified from the search, we checked for additional eligible articles in its references. We abstracted data on population studied, discrimination, calibration, where to find the index, and variables included. Each index was further assessed for clinical usability. We identified 18 articles with a total of 17 unique prognostic indices after screening 9154 titles. The majority of indices (88%) had c-statistics greater than or equal to 0.70. Only 1 index was externally validated. Ten indices, 8 developed in the United States and 2 in the United Kingdom, were considered clinically usable. Of the 17 unique prognostic indices, 10 may be useful for implementation in the primary care setting to identify patients who may benefit from ACP discussions. An index classified as "clinically usable" may not be easy to use because of a large number of variables that are not routinely collected and the need to program the index into the electronic medical record.
This article is meant as a personal reflection on my unexpected retirement, and includes memories and thoughts about my career with the Indian Health Service near the border with Mexico, serving the Tohono O’odham tribe.
The intracellular lifestyle of bacteria is widely acknowledged to be an important mechanism in chronic and recurring infection. Among the Staphylococcus genus, only Staphylococcus aureus and Staphylococcus pseudintermedius have been clearly identified as intracellular in nonprofessional phagocytic cells (NPPCs), for which the mechanism is mainly fibronectin-binding dependent. Here, we used bioinformatics tools to search for possible new fibronectin-binding proteins (FnBP-like) in other Staphylococcus species. We found a protein in Staphylococcus delphini called Staphylococcus delphini surface protein Y (SdsY). This protein shares 68% identity with the Staphylococcus pseudintermedius surface protein D (SpsD), 36% identity with S. aureus FnBPA, and 39% identity with S. aureus FnBPB. The SdsY protein possesses the typical structure of FnBP-like proteins, including an N-terminal signal sequence, an A domain, a characteristic repeated pattern, and an LPXTG cell wall anchor motif. The level of adhesion to immobilized fibronectin was significantly higher in all S. delphini strains tested than in the fibronectin-binding-deficient S. aureus DU5883 strain. By using a model of human osteoblast infection, the level of internalization of all strains tested was significantly higher than with the invasive-incompetent S. aureus DU5883. These findings were confirmed by phenotype restoration after transformation of DU5883 by a plasmid expression vector encoding the SdsY repeats. Additionally, using fibronectin-depleted serum and murine osteoblast cell lines deficient for the β1 integrin, the involvement of fibronectin and β1 integrin was demonstrated in S. delphini internalization. The present study demonstrates that additional staphylococcal species are able to invade NPPCs and proposes a method to identify FnBP-like proteins.
Phagocytosis is the key mechanism for host control of Pseudomonas aeruginosa, a motile Gram-negative, opportunistic bacterial pathogen which frequently undergoes adaptation and selection for traits that are advantageous for survival. One such clinically relevant adaptation is the loss of bacterial motility, observed within chronic infections, that is associated with increased antibiotic tolerance and phagocytic resistance. Previous studies using phagocytes from a leukocyte adhesion deficiency type 1 (LAD-I) patient identified CD18 as a putative cell surface receptor for uptake of live P. aeruginosa. However, how bacterial motility alters direct engagement with CD18-containing integrins remains unknown. Here we demonstrate, with the use of motile and isogenic nonmotile deletion mutants of two independent strains of P. aeruginosa and with CRISPR-generated CD18-deficient cell lines in human monocytes and murine neutrophils, that CD18 expression facilitates the uptake of both motile and nonmotile P. aeruginosa. However, unexpectedly, mechanistic studies revealed that CD18 expression was dispensable for the initial attachment of the bacteria to the host cells, which was validated with ectopic expression of complement receptor 3 (CR3) by CHO cells. Our data support that surface N-linked glycan chains (N-glycans) likely facilitate the initial interaction of bacteria with monocytes and cooperate with CD18 integrins in trans to promote internalization of bacteria. Moreover, talin-1 and kindlin-3 proteins promote uptake, but not binding, of P. aeruginosa by murine neutrophils, which supports a role for CD18 integrin signaling in this process. These findings provide novel insights into the cellular determinants for phagocytic recognition and uptake of P. aeruginosa.
Bovine digital dermatitis (BDD), an infectious disease of the bovine foot with a predominant treponemal etiology, is a leading cause of lameness in dairy and beef herds worldwide. BDD is poorly responsive to antimicrobial therapy and exhibits a relapsing clinical course; an effective vaccine is therefore urgently sought. Using a reverse vaccinology approach, the present study surveyed the genomes of the three BDD-associated Treponema phylogroups for putative β-barrel outer membrane proteins and considered their potential as vaccine candidates. Selection criteria included the presence of a signal peptidase I cleavage site, a predicted β-barrel fold, and cross-phylogroup homology. Four candidate genes were overexpressed in Escherichia coli BL21(DE3), refolded, and purified. Consistent with their classification as β-barrel OMPs, circular-dichroism spectroscopy revealed the adoption of a predominantly β-sheet secondary structure. These recombinant proteins, when screened for their ability to adhere to immobilized extracellular matrix (ECM) components, exhibited a diverse range of ligand specificities. All four proteins specifically and dose dependently adhered to bovine fibrinogen. One recombinant protein was identified as a candidate diagnostic antigen (disease specificity, 75%). Finally, when adjuvanted with aluminum hydroxide and administered to BDD-naive calves using a prime-boost vaccination protocol, these proteins were immunogenic, eliciting specific IgG antibodies. In summary, we present the description of four putative treponemal β-barrel OMPs that exhibit the characteristics of multispecific adhesins. The observed interactions with fibrinogen may be critical to host colonization and it is hypothesized that vaccination-induced antibody blockade of these interactions will impede treponemal virulence and thus be of therapeutic value.
Programmed death-ligand 1 (PD-L1/B7-H1) serves as a cosignaling molecule in cell-mediated immune responses and contributes to chronicity of inflammation and the escape of tumor cells from immunosurveillance. Here, we investigated the molecular mechanisms leading to PD-L1 upregulation in human oral carcinoma cells and in primary human gingival keratinocytes in response to infection with Porphyromonas gingivalis (P. gingivalis), a keystone pathogen for the development of periodontitis. The bacterial cell wall component peptidoglycan uses bacterial outer membrane vesicles to be taken up by cells. Internalized peptidoglycan triggers cytosolic receptors to induce PD-L1 expression in a myeloid differentiation primary response 88 (Myd88)-independent and receptor-interacting serine/threonine-protein kinase 2 (RIP2)-dependent fashion. Interference with the kinase activity of RIP2 or mitogen-activated protein (MAP) kinases interferes with inducible PD-L1 expression.
Mycoplasma gallisepticum is the primary etiological agent of chronic respiratory disease in chickens. Live attenuated vaccines are most commonly used in the field to control the disease, but current vaccines have some limitations. Vaxsafe MG (strain ts-304) is a new vaccine candidate that is efficacious at a lower dose than the current commercial vaccine strain ts-11, from which it is derived. In this study, the transcriptional profiles of the trachea of unvaccinated chickens and chickens vaccinated with strain ts-304 were compared 2 weeks after challenge with M. gallisepticum strain Ap3AS during the chronic stage of infection. After challenge, genes, gene ontologies, pathways, and protein classes involved in inflammation, cytokine production and signaling, and cell proliferation were upregulated, while those involved in formation and motor movement of cilia, formation of intercellular junctional complexes, and formation of the cytoskeleton were downregulated in the unvaccinated birds compared to the vaccinated birds, reflecting immune dysregulation and the pathological changes induced in the trachea by infection with M. gallisepticum. Vaccination appears to protect the structural and functional integrity of the tracheal mucosa 2 weeks after infection with M. gallisepticum.
Gamma interferon (IFN-)-induced innate immune responses play important roles in the inhibition of Toxoplasma gondii infection. It has been reported that IFN- stimulates non-acidification-dependent growth restriction of T. gondii in HeLa cells, but the mechanism remains unclear. Here, we found that -aminobutyric acid (GABA) receptor-associated protein-like 2 (GABARAPL2) plays a critical role in parasite restriction in IFN--treated HeLa cells. GABARAPL2 is recruited to membrane structures surrounding parasitophorous vacuoles (PV). Autophagy adaptors are required for the proper localization and function of GABARAPL2 in the IFN- -induced immune response. These findings provide further understanding of a noncanonical autophagy pathway responsible for IFN--dependent inhibition of T. gondii growth in human HeLa cells and demonstrate the critical role of GABARAPL2 in this response.
Brucella spp. are facultative intracellular bacteria notorious for their ability to induce a chronic, and often lifelong, infection known as brucellosis. To date, no licensed vaccine exists for prevention of human disease, and mechanisms underlying chronic illness and immune evasion remain elusive. We and others have observed that B cell-deficient mice challenged with Brucella display reduced bacterial burden following infection, but the underlying mechanism has not been clearly defined. Here, we show that at 1 month postinfection, B cell deficiency alone enhanced resistance to splenic infection ~100-fold; however, combined B and T cell deficiency did not impact bacterial burden, indicating that B cells only enhance susceptibility to infection when T cells are present. Therefore, we investigated whether B cells inhibit T cell-mediated protection against Brucella. Using B and T cell-deficient Rag1–/– animals as recipients, we demonstrate that adoptive transfer of CD4+ T cells alone confers marked protection against Brucella melitensis that is abrogated by cotransfer of B cells. Interestingly, depletion of CD4+ T cells from B cell-deficient, but not wild-type, mice enhanced susceptibility to infection, further confirming that CD4+ T cell-mediated immunity against Brucella is inhibited by B cells. In addition, we found that the ability of B cells to suppress CD4+ T cell-mediated immunity and modulate CD4+ T cell effector responses during infection was major histocompatibility complex class II (MHCII)-dependent. Collectively, these findings indicate that B cells modulate CD4+ T cell function through an MHCII-dependent mechanism which enhances susceptibility to Brucella infection.
Antimicrobial peptides play an important role in host defense against Vibrio cholerae. Generally, the V. cholerae O1 classical biotype is polymyxin B (PB) sensitive and El Tor is relatively resistant. Detection of classical biotype traits like the production of classical cholera toxin and PB sensitivity in El Tor strains has been reported in recent years, including in the devastating Yemen cholera outbreak during 2016-2018. To investigate the factor(s) responsible for the shift in the trend of sensitivity to PB, we studied the two-component system encoded by carRS, regulating the lipid A modification of El Tor vibrios, and found that only carR contains a single nucleotide polymorphism (SNP) in recently emerged PB-sensitive strains. We designated the two alleles present in PB-resistant and -sensitive strains carRr and carRs alleles, respectively, and replaced the carRs allele of a sensitive strain with the carRr allele, using an allelic-exchange approach. The sensitive strain then became resistant. The PB-resistant strain N16961 was made susceptible to PB in a similar fashion. Our in silico CarR protein models suggested that the D89N substitution in the more stable CarRs protein brings the two structural domains of CarR closer, constricting the DNA binding cleft. This probably reduces the expression of the carR-regulated almEFG operon, inducing PB susceptibility. Expression of almEFG in PB-sensitive strains was found to be downregulated under natural culturing conditions. In addition, the expression of carR and almEG decreased in all strains with increased concentrations of extracellular Ca2+ but increased with a rise in pH. The downregulation of almEFG in CarRs strains confirmed that the G265A mutation is responsible for the emergence of PB-sensitive El Tor strains.
A Yersinia pestis mutant synthesizing an adjuvant form of lipid A (monophosphoryl lipid A, MPLA) displayed increased biogenesis of bacterial outer membrane vesicles (OMVs). To enhance the immunogenicity of the OMVs, we constructed an Asd-based balanced-lethal host-vector system that oversynthesized the LcrV antigen of Y. pestis, raised the amounts of LcrV enclosed in OMVs by the type II secretion system, and eliminated harmful factors like plasminogen activator (Pla) and murine toxin from the OMVs. Vaccination with OMVs containing MPLA and increased amounts of LcrV with diminished toxicity afforded complete protection in mice against subcutaneous challenge with 8 x 105 CFU (80,000 50% lethal dose [LD50]) and intranasal challenge with 5 x 103 CFU (50 LD50) of virulent Y. pestis. This protection was significantly superior to that resulting from vaccination with LcrV/alhydrogel or rF1-V/alhydrogel. At week 4 postimmunization, the OMV-immunized mice showed more robust titers of antibodies against LcrV, Y. pestis whole-cell lysate (YPL), and F1 antigen and more balanced IgG1:IgG2a/IgG2b-derived Th1 and Th2 responses than LcrV-immunized mice. Moreover, potent adaptive and innate immune responses were stimulated in the OMV-immunized mice. Our findings demonstrate that self-adjuvanting Y. pestis OMVs provide a novel plague vaccine candidate and that the rational design of OMVs could serve as a robust approach for vaccine development.
Peptidoglycan, the sugar-amino acid polymer that composes the bacterial cell wall, requires a significant expenditure of energy to synthesize and is highly immunogenic. To minimize the loss of an energetically expensive metabolite and avoid host detection, bacteria often recycle their peptidoglycan, transporting its components back into the cytoplasm, where they can be used for subsequent rounds of new synthesis. The peptidoglycan-recycling substrate binding protein (SBP) MppA, which is responsible for recycling peptidoglycan fragments in Escherichia coli, has not been annotated for most intracellular pathogens. One such pathogen, Chlamydia trachomatis, has a limited capacity to synthesize amino acids de novo and therefore must obtain oligopeptides from its host cell for growth. Bioinformatics analysis suggests that the putative C. trachomatis oligopeptide transporter OppABCDF (OppABCDFCt) encodes multiple SBPs (OppA1Ct, OppA2Ct, and OppA3Ct). Intracellular pathogens often encode multiple SBPs, while only one, OppA, is encoded in the E. coli opp operon. We hypothesized that the putative OppABCDF transporter of C. trachomatis functions in both oligopeptide transport and peptidoglycan recycling. We coexpressed the putative SBP genes (oppA1Ct, oppA2Ct, oppA3Ct) along with oppBCDFCt in an E. coli mutant lacking the Opp transporter and determined that all three chlamydial OppA subunits supported oligopeptide transport. We also demonstrated the in vivo functionality of the chlamydial Opp transporter in C. trachomatis. Importantly, we found that one chlamydial SBP, OppA3Ct, possessed dual substrate recognition properties and is capable of transporting peptidoglycan fragments (tri-diaminopimelic acid) in E. coli and in C. trachomatis. These findings suggest that Chlamydia evolved an oligopeptide transporter to facilitate the acquisition of oligopeptides for growth while simultaneously reducing the accumulation of immunostimulatory peptidoglycan fragments in the host cell cytosol. The latter property reflects bacterial pathoadaptation that dampens the host innate immune response to Chlamydia infection.
Staphylococcus aureus is a noted human and animal pathogen. Despite decades of research on this important bacterium, there are still many unanswered questions regarding the pathogenic mechanisms it uses to infect the mammalian host. This can be attributed to it possessing a plethora of virulence factors and complex virulence factor and metabolic regulation. PurR, the purine biosynthesis regulator, was recently also shown to regulate virulence factors in S. aureus, and mutations in purR result in derepression of fibronectin binding proteins (FnBPs) and extracellular toxins, required for a so-called hypervirulent phenotype. Here, we show that hypervirulent strains containing purR mutations can be attenuated with the addition of purine biosynthesis mutations, implicating the necessity for de novo purine biosynthesis in this phenotype and indicating that S. aureus in the mammalian host experiences purine limitation. Using cell culture, we showed that while purR mutants are not altered in epithelial cell binding, compared to that of wild-type (WT) S. aureus, purR mutants have enhanced invasion of these nonprofessional phagocytes, consistent with the requirement of FnBPs for invasion of these cells. This correlates with purR mutants having increased transcription of fnb genes, resulting in higher levels of surface-exposed FnBPs to promote invasion. These data provide important contributions to our understanding of how the pathogenesis of S. aureus is affected by sensing of purine levels during infection of the mammalian host.
Nutrient acquisition is a central challenge for all organisms. For the fungal pathogen Candida albicans, utilization of amino acids has been shown to be critical for survival, immune evasion, and escape, while the importance of catabolism of host-derived proteins and peptides in vivo is less well understood. Stp1 and Stp2 are paralogous transcription factors (TFs) regulated by the
The translocated actin recruiting phosphoprotein (Tarp) is a multidomain type III secreted effector used by Chlamydia trachomatis. In aggregate, existing data suggest a role of this effector in initiating new infections. As new genetic tools began to emerge to study chlamydial genes in vivo, we speculated as to what degree Tarp function contributes to Chlamydia’s ability to parasitize mammalian host cells. To address this question, we generated a complete tarP deletion mutant using the fluorescence-reported allelic exchange mutagenesis (FRAEM) technique and complemented the mutant in trans with wild-type tarP or mutant tarP alleles engineered to harbor in-frame domain deletions. We provide evidence for the significant role of Tarp in C. trachomatis invasion of host cells. Complementation studies indicate that the C-terminal filamentous actin (F-actin)-binding domains are responsible for Tarp-mediated invasion efficiency. Wild-type C. trachomatis entry into HeLa cells resulted in host cell shape changes, whereas the tarP mutant did not. Finally, using a novel cis complementation approach, C. trachomatis lacking tarP demonstrated significant attenuation in a murine genital tract infection model. Together, these data provide definitive genetic evidence for the critical role of the Tarp F-actin-binding domains in host cell invasion and for the Tarp effector as a bona fide C. trachomatis virulence factor.
Legionella pneumophila, the etiological agent of Legionnaires’ disease, employs an arsenal of hundreds of Dot/Icm-translocated effector proteins to facilitate replication within eukaryotic phagocytes. Several effectors, called metaeffectors, function to regulate the activity of other Dot/Icm-translocated effectors during infection. The metaeffector Lpg2505 is essential for L. pneumophila intracellular replication only when its cognate effector, SidI, is present. SidI is a cytotoxic effector that interacts with the host translation factor eEF1A and potently inhibits eukaryotic protein translation by an unknown mechanism. Here, we evaluated the impact of Lpg2505 on SidI-mediated phenotypes and investigated the mechanism of SidI function. We determined that Lpg2505 binds with nanomolar affinity to SidI and suppresses SidI-mediated inhibition of protein translation. SidI binding to eEF1A and Lpg2505 is not mutually exclusive, and the proteins bind distinct regions of SidI. We also discovered that SidI possesses GDP-dependent glycosyl hydrolase activity and that this activity is regulated by Lpg2505. We have therefore renamed Lpg2505 MesI (
Implanted medical device-associated infections pose significant health risks, as they are often the result of bacterial biofilm formation. Staphylococcus aureus is a leading cause of biofilm-associated infections which persist due to mechanisms of device surface adhesion, biofilm accumulation, and reprogramming of host innate immune responses. We found that the S. aureus fibronectin binding protein A (FnBPA) is required for normal biofilm development in mammalian serum and that the SaeRS two-component system is required for functional FnBPA activity in serum. Furthermore, serum-developed biofilms deficient in FnBPA were more susceptible to macrophage invasion, and in a model of biofilm-associated implant infection, we found that FnBPA is crucial for the establishment of infection. Together, these findings show that S. aureus FnBPA plays an important role in physical biofilm development and represents a potential therapeutic target for the prevention and treatment of device-associated infections.
Efficient delivery of antigenic cargo to trigger protective immune responses is critical to the success of vaccination. Genetically engineered microorganisms, including virus, bacteria, and protozoa, can be modified to carry and deliver heterologous antigens to the host immune system. The biological vectors can induce a broad range of immune responses and enhance heterologous antigen-specific immunological outcomes. The protozoan genus Eimeria is widespread in domestic animals, causing serious coccidiosis. Eimeria parasites with strong immunogenicity are potent coccidiosis vaccine candidates and offer a valuable model of live vaccines against infectious diseases in animals. Eimeria parasites can also function as a vaccine vector. Herein, we review recent advances in design and application of recombinant Eimeria as a vaccine vector, which has been a topic of ongoing research in our laboratory. By recapitulating the establishment of an Eimeria transfection platform and its application, it will help lay the foundation for the future development of effective parasite-based vaccine delivery vectors and beyond.
Glaesserella (Haemophilus) parasuis is a commensal bacterium of the upper respiratory tract in pigs and also the causative agent of Glässer’s disease, which causes significant morbidity and mortality in pigs worldwide. Isolates are characterized into 15 serovars by their capsular polysaccharide, which has shown a correlation with isolate pathogenicity. To investigate the role the capsule plays in G. parasuis virulence and host interaction, a capsule mutant of the serovar 5 strain HS069 was generated (HS069cap) through allelic exchange following natural transformation. HS069cap was unable to cause signs of systemic disease during a pig challenge study and had increased sensitivity to complement killing and phagocytosis by alveolar macrophages. Compared with the parent strain, HS069cap produced more robust biofilm and adhered equivalently to 3D4/31 cells; however, it was unable to persistently colonize the nasal cavity of inoculated pigs, with all pigs clearing HS069cap by 5 days postchallenge. Our results indicate the importance of the capsular polysaccharide to G. parasuis virulence as well as nasal colonization in pigs.
Localized skin lesions are characteristic of cutaneous leishmaniasis (CL); however, Leishmania (Viannia) species, which are responsible for most CL cases in the Americas, can spread systemically, sometimes resulting in mucosal disease. Detection of Leishmania has been documented in healthy mucosal tissues (conjunctiva, tonsils, and nasal mucosa) and healthy skin of CL patients and in individuals with asymptomatic infection in areas of endemicity of L. (V.) panamensis and L. (V.) braziliensis transmission. However, the conditions and mechanisms that favor parasite persistence in healthy mucosal tissues are unknown. In this descriptive study, we compared the cell populations of the nasal mucosa (NM) of healthy donors and patients with active CL and explored the immune gene expression signatures related to molecular detection of Leishmania in this tissue in the absence of clinical signs or symptoms of mucosal disease. The cellular composition and gene expression profiles of NM samples from active CL patients were similar to those of healthy volunteers, with a predominance of epithelial over immune cells, and within the CD45+ cell population, a higher frequency of CD66b+ followed by CD14+ and CD3+ cells. In CL patients with molecular evidence of Leishmania persistence in the NM, genes characteristic of an anti-inflammatory and tissue repair responses (IL4R, IL5RA, POSTN, and SATB1) were overexpressed relative to NM samples from CL patients in which Leishmania was not detected. Here, we report the first immunological description of subclinically infected NM tissues of CL patients and provide evidence of a local anti-inflammatory environment favoring parasite persistence in the NM.
Endothelial activation and microvascular dysfunction are key pathogenic processes in severe malaria. We evaluated the early role of these processes in experimentally induced Plasmodium falciparum and P. vivax infection. Participants were enrolled in induced blood-stage malaria clinical trials. Plasma osteoprotegerin, angiopoietin-2, and von Willebrand Factor (vWF) levels were measured as biomarkers of endothelial activation. Microvascular function was assessed using peripheral arterial tonometry and near-infrared spectroscopy, and the endothelial glycocalyx was assessed by sublingual videomicroscopy and measurement of biomarkers of degradation. Forty-five healthy, malaria-naive participants were recruited from 5 studies. Osteoprotegerin and vWF levels increased in participants following inoculation with P. vivax (n = 16) or P. falciparum (n = 15), with the angiopoietin-2 level also increasing in participants following inoculation with P. falciparum. For both species, the most pronounced increase was seen in osteoprotegerin. This was particularly marked in participants inoculated with P. vivax, where the osteoprotegerin level correlated with the levels of parasitemia and the malaria clinical score. There were no changes in measures of endothelial glycocalyx or microvascular function. Plasma biomarkers of endothelial activation increased in early P. falciparum and P. vivax infection and preceded changes in the endothelial glycocalyx or microvascular function. The more pronounced increase in osteoprotegerin suggests that this biomarker may play a role in disease pathogenesis.
LuxS/AI-2 is an important quorum sensing system which affects the growth, biofilm formation, virulence, and metabolism of bacteria. LuxS is encoded by the luxS gene, but how this gene is associated with a diverse array of physiological activities in Edwardsiella piscicida (E. piscicida) is not known. Here, we constructed an luxS gene mutant strain, the luxS strain, to identify how LuxS/AI-2 affects pathogenicity. The results showed that LuxS was not found in the luxS gene mutant strain, and this gene deletion decreased E. piscicida growth compared to that of the wild-type strain. Meanwhile, the wild-type strain significantly increased penetration and motility in mucin compared to levels with the luxS strain. The 50% lethal dose (LD50) of the E. piscicida luxS strain for zebrafish was significantly higher than that of the wild-type strain, which suggested that the luxS gene deletion could attenuate the strain’s virulence. The AI-2 activities of EIB202 were 56-fold higher than those in the luxS strain, suggesting that the luxS gene promotes AI-2 production. Transcriptome results demonstrated that between cells infected with the luxS strain and those infected with the wild-type strain 46 genes were significantly differentially regulated, which included 34 upregulated genes and 12 downregulated genes. Among these genes, the largest number were closely related to cell immunity and signaling systems. In addition, the biofilm formation ability of EIB202 was significantly higher than that of the luxS strain. The supernatant of EIB202 increased the biofilm formation ability of the luxS strain, which suggested that the luxS gene and its product LuxS enhanced biofilm formation in E. piscicida. All results indicate that the LuxS/AI-2 quorum sensing system in E. piscicida promotes its pathogenicity through increasing a diverse array of physiological activities.
The spirochete Borrelia burgdorferi sensu lato is the causative agent of Lyme disease (LD). The spirochetes produce the CspZ protein that binds to a complement regulator, factor H (FH). Such binding downregulates activation of host complement to facilitate spirochete evasion of complement killing. However, vaccination with CspZ does not protect against LD infection. In this study, we demonstrated that immunization with CspZ-YA, a CspZ mutant protein with no FH-binding activity, protected mice from infection by several spirochete genotypes introduced via tick feeding. We found that the sera from CspZ-YA-vaccinated mice more efficiently eliminated spirochetes and blocked CspZ FH-binding activity than sera from CspZ-immunized mice. We also found that vaccination with CspZ, but not CspZ-YA, triggered the production of anti-FH antibodies, justifying CspZ-YA as an LD vaccine candidate. The mechanistic and efficacy information derived from this study provides insights into the development of a CspZ-based LD vaccine.
As the technical ability for genetic diagnosis continues to improve, an increasing number of diagnoses are made in infancy or as early as the neonatal period. Many of these diagnoses are known to be associated with developmental delay and intellectual disability, features that would not be clinically detectable at the time of diagnosis. Others may be associated with cognitive impairment, but the incidence and severity are yet to be fully described. These neonates and infants with genetic diagnoses therefore represent an emerging group of patients who are at high risk for neurodevelopmental disabilities. Although there are well-established developmental supports for high-risk infants, particularly preterm infants, after discharge from the NICU, programs specifically for infants with genetic diagnoses are rare. And although previous research has demonstrated the positive effect of early developmental interventions on outcomes among preterm infants, the impact of such supports for infants with genetic disorders who may be born term, remains to be understood. We therefore review the literature regarding existing developmental assessment and intervention approaches for children with genetic disorders, evaluating these in the context of current developmental supports postdischarge for preterm infants. Further research into the role of developmental support programs for early assessment and intervention in high-risk neonates diagnosed with rare genetic disorders is needed.
To determine if in utero selective serotonin reuptake inhibitor (SSRI) or selective serotonin norepinephrine inhibitor (SNRI) exposure is associated with developmental vulnerability in kindergarten among children whose mothers were diagnosed with prenatal mood or anxiety disorder. Linkable administrative data were used to create a population-based cohort of 266 479 mother-child dyads of children born in Manitoba, Canada, between 1996 and 2014, with follow-up through 2015. The sample was restricted to mothers who had a mood or anxiety disorder diagnosis between 90 days before conception (N = 13 818). Exposed women had ≥2 SSRI or SNRI dispensations during pregnancy (n = 2055); unexposed mothers did not have a dispensation of an SSRI or SNRI during pregnancy (n = 10 017). The Early Development Instrument (EDI) was used to assess developmental health in kindergarten children. The EDI is a 104-component kindergarten teacher-administered questionnaire, encompassing 5 developmental domains. Of the 3048 children included in the study who met inclusion criteria and had an EDI, 21.43% of children in the exposed group were assessed as vulnerable on 2 or more domains versus 16.16% of children in the unexposed group (adjusted odds ratio = 1.43; 95% confidence interval 1.08–1.90). Children in the exposed group also had a significant risk of being vulnerable in language and/or cognition (adjusted odds ratio = 1.40; 95% confidence interval 1.03–1.90). Exposure to SSRIs or SNRIs during pregnancy was associated with an increased risk of developmental vulnerability and an increased risk of deficits in language and/or cognition. Replication of results is necessary before clinical implications can be reached.
There is a dearth of evidence regarding the association of use of electronic cigarettes (e-cigarettes) with certain product characteristics and adolescent and young adult risk of unhealthy tobacco use patterns (eg, frequency of combustible cigarette smoking), which is needed to inform the regulation of e-cigarettes. Data were collected via an online survey of participants in the Southern California Children’s Health Study from 2015 to 2016 (baseline) and 2016 to 2017 (follow-up) (N = 1312). We evaluated the association of binary categories of 3 nonmutually exclusive characteristics of the e-cigarette used most frequently with the number of cigarettes smoked in the past 30 days at 1-year follow-up. Product characteristics included device (vape pen and/or modifiable electronic cigarette [mod]), use of nicotine in electronic liquid (e-liquid; yes or no), and use for dripping (directly dripping e-liquid onto the device; yes or no). Relative to never e-cigarette users, past-30-day e-cigarette use was associated with greater frequency of past-30-day cigarette smoking at follow-up. Among baseline past-30-day e-cigarette users, participants who used mods (versus vape pens) smoked >6 times as many cigarettes at follow-up (mean: 20.8 vs 1.3 cigarettes; rate ratio = 6.33; 95% confidence interval: 1.64–24.5) after adjustment for sociodemographic characteristics, baseline frequency of cigarette smoking, and number of days of e-cigarette use. After adjustment for device, neither nicotine e-liquid nor dripping were associated with frequency of cigarette smoking. Baseline mod users (versus vape pen users) smoked more cigarettes in the past 30 days at follow-up. Regulation of e-cigarette device type warrants consideration as a strategy to reduce cigarette smoking among adolescents and young adults who vape.
We describe an atypical pediatric case of immunoglobulin A vasculitis (IgAV), also referred to as Henoch-Schönlein purpura, in which formation of spontaneous hematoma of the paraspinal muscles developed. Spontaneous or unprovoked hematomas rarely occur in IgAV. These manifestations have not been described specifically in the pediatric literature as coinciding with IgAV. These findings are alarming for nonaccidental trauma, particularly in a patient without underlying blood dyscrasia. Our objective for this report is to highlight the possible association of muscular hematoma formation with IgAV and to help providers consider this association when trauma and hemophilia has been ruled out.
Causal analysis is a core function of safety programs. Although established protocols exist for conducting root cause analysis for serious safety events, there is limited guidance for apparent cause analysis (ACA) in health care. At our institution, through a novel facilitated ACA approach, we aim to improve safety culture and provide a clear approach to address precursor safety events and near-miss safety events. We define facilitated ACA as limited investigation (scope and duration) of a safety event that resulted in little to no harm. These investigations require fewer resources and focus on preventive strategies. Our facilitated ACA model, with an operational algorithm and structured process, was developed and implemented at our tertiary-care, freestanding, urban pediatric hospital in 2018. Sixty-four ACAs were completed, and 83% were identified with the algorithm. Process measures, including time from event reporting to ACA launch (median 3 days; interquartile range 2–6 days), are tracked. Patient safety consultants averaged 5 hours to complete a facilitated ACA. A median of 3 disciplines or departments participated in each facilitated ACA. Through an iterative process, we implemented a structured process for facilitated ACA, and the model’s strength includes (1) right event, (2) right team, (3) right analysis, and (4) right action plans. This novel facilitated ACA model may support organizational cause analysis and improve safety culture with higher-reliability processes.
Standing orders are an effective way to increase vaccination rates, yet little is known about how pediatricians use this strategy for childhood immunizations. We assessed current use of, barriers to using, and factors associated with use of standing orders for vaccination among pediatricians. Internet and mail survey from June 2017 to September 2017 among a nationally representative sample of pediatricians. In the principal component analysis of barrier items, we identified 2 factors: physician responsibility and concerns about office processes. A multivariable analysis that included barrier scales and physician and/or practice characteristics was used to identify factors associated with use of standing orders. The response rate was 79% (372 of 471); 59% of respondents reported using standing orders. The most commonly identified barriers among nonusers were concern that patients may mistakenly receive the wrong vaccine (68%), concern that patients prefer to speak with the physician about a vaccine before receiving it (62%), and belief that it is important for the physician to be the person who recommends a vaccine to patients (57%). These 3 items also made up the physician responsibility barrier factor. Respondents with higher physician responsibility scores were less likely to use standing orders (risk ratio: 0.59 [95% confidence interval: 0.53–0.66] per point increase). System-level decision-making about vaccines, suburban or rural location, and lower concerns about office processes scores were each associated with use of standing orders in the bivariate, but not the multivariable, analysis. Among pediatricians, use of standing orders for vaccination is far from universal. Interventions to increase use of standing orders should address physicians’ attitudinal barriers as well as organizational factors.
Peanut allergy is one of the most common food allergies in children, with increasing prevalence over time. The dual-allergen exposure hypothesis now supports transcutaneous sensitization to peanut as a likely pathophysiologic mechanism for peanut allergy development. As a result, there is emerging evidence that early peanut introduction has a role in peanut allergy prevention. Current first-line diagnostic tests for peanut allergy have limited specificity, which may be enhanced with emerging tools such as component-resolved diagnostics. Although management of peanut allergy includes avoidance and carrying an epinephrine autoinjector, risk of fatal anaphylaxis is extremely low, and there is minimal risk related to cutaneous or inhalational exposure. Quality of life in children with peanut allergy requires significant focus. Moving forward, oral and epicutaneous immunotherapy are emerging and exciting tools that may have a role to play in desensitization to peanut.
Early diagnosis of cerebral palsy (CP) is critical in obtaining evidence-based interventions when plasticity is greatest. In 2017, international guidelines for early detection of CP were published on the basis of a systematic review of evidence. Our study aim was to reduce the age at CP diagnosis throughout a network of 5 diverse US high-risk infant follow-up programs through consistent implementation of these guidelines. The study leveraged plan-do-study-act and Lean methodologies. The primary outcome was age at CP diagnosis. Data were acquired during the corresponding 9-month baseline and quarterly throughout study. Balancing measures were clinic no-show rates and parent perception of the diagnosis visit. Clinic teams conducted strengths, weaknesses, opportunities, and threats analyses, process flow evaluations, standardized assessments training, and parent questionnaires. Performance of a 3- to 4-month clinic visit was a critical process step because it included a Hammersmith Infant Neurologic Examination, a General Movements Assessment, and standardized assessments of motor function. The age at CP diagnosis decreased from a weighted average of 19.5 (95% confidence interval 16.2 to 22.8) to 9.5 months (95% confidence interval 4.5 to 14.6), with P = .008; 3- to 4-month visits per site increased from the median (interquartile range) 14 (5.2–73.7) to 54 (34.5–152.0), with P < .001; and no-show rates were not different. Parent questionnaires revealed positive provider perception with improvement opportunities for information content and understandability. Large-scale implementation of international guidelines for early detection of CP is feasible in diverse high-risk infant follow-up clinics. The initiative was received positively by families and without adversely affecting clinic operational flow. Additional parent support and education are necessary.
Several studies have investigated the association of breastfeeding status with offspring mortality in Africa, but most studies were from one center only or had limited statistical power to draw robust conclusions. Data came from 75 nationally representative cross-sectional Demographic and Health Surveys in 35 countries in sub-Saharan Africa conducted between 2000 and 2016. Our study relied on 217 112 individuals aged 4 days to 23 months for breastfeeding pattern analysis, 161 322 individuals aged 6 to 23 months for breastfeeding history analysis, and 104 427 individuals aged 12 to 23 months for breastfeeding duration analysis. Compared with children aged 4 days to 23 months exclusively breastfed in the first 3 days of life, those not breastfed had a high risk of mortality at <2 years of age (odds ratio [OR] = 13.45; 95% confidence interval [CI] = 11.43–15.83). Young children who were predominantly breastfed or partially breastfed had moderately increased risk of mortality at <2 years of age (OR = 1.11, 95% CI = 1.03–1.21 for predominant pattern; OR = 1.12, 95% CI = 0.99–1.27 for partial pattern). Compared with children aged 6 to 23 months who were breastfed within the first 6 months of life, those not breastfed had a high risk of mortality (OR = 5.65; 95% CI = 4.27–7.47). Compared with children aged 12 to 23 months who were breastfed for ≥6 months, those who were breastfed for shorter periods had a higher risk of mortality (OR = 2.78, 95% CI = 1.45–5.32 for duration of <3 months; OR = 5.28, 95% CI = 3.24–8.61 for those who were not breastfed). Our findings support exclusive breastfeeding during the first 6 months of life and continued breastfeeding up to 2 years of age recommended by the World Health Organization for reducing mortality of children <2 years old in sub-Saharan Africa.
A 16-year-old girl presented to her primary care physician with a one-month history of decreased appetite and abdominal pain. She had normal bowel movements and no vomiting, but her periumbilical pain limited her ability to finish most meals. She had gradual weight loss over the previous 2 years, and during the previous 4 years, she intermittently received counseling for depression after the loss of her mother. Her initial physical examination and laboratory evaluation were unremarkable. She was referred to a nutritionist, adolescent medicine, and pediatric gastroenterology. Her presentation evolved over time, which ultimately led to a definitive diagnosis.
Systemic sclerosis sine scleroderma (ssSSc) is a rare variant of systemic sclerosis, with only one pediatric case reported in the medical literature to date. Pulmonary arterial hypertension as the presenting feature of ssSSc is extremely rare, even in adults, and so far has never been reported in children. We report, for the first time, a case of pediatric ssSSc in a 3-year-old girl, who presented with interstitial lung disease and pulmonary hypertension. The patient was prescribed early aggressive pulmonary vasodilators combined with anti-inflammatory medications. The clinical response was good, and her current condition at 12 years of age is remarkable, considering the high mortality rates reported in adults. We underscore the importance of early aggressive treatment in future cases of similar presentation.
To describe (1) the developmental trajectories of peer victimization from 6 to 17 years of age and (2) the early childhood behaviors and family characteristics associated with the trajectories. We used data from 1760 children enrolled in the Quebec Longitudinal Study of Child Development, a population-based birth cohort. Participants self-reported peer victimization at ages 6, 7, 8, 10, 12, 13, 15, and 17 years. Participants’ behavior and family characteristics were measured repeatedly between ages 5 months and 5 years. We identified 4 trajectories of peer victimization from 6 to 17 years of age: low (32.9%), moderate-emerging (29.8%), childhood-limited (26.2%), and high-chronic (11.1%). Compared with children in the low peer victimization trajectory, children in the other 3 trajectories were more likely to exhibit externalizing behaviors in early childhood, and those in the high-chronic and moderate-emerging trajectories were more likely to be male. Paternal history of antisocial behavior was associated with moderate-emerging (odds ratio [OR] = 1.54; 95% confidence interval [CI] = 1.09–2.19) and high-chronic (OR = 1.93; 95% CI = 1.25–2.99) relative to low peer victimization. Living in a nonintact family in early childhood was associated with childhood-limited (OR = 1.48; 95% CI = 1.11–1.97) and high-chronic (OR = 1.59; 95% CI = 1.09–2.31) relative to low peer victimization. Early childhood externalizing behaviors and family vulnerabilities were associated with the development of peer victimization. Some children entered the cascade of persistent peer victimization at the beginning of primary school. Support to these children and their families early in life should be an important component of peer victimization preventive interventions.
Although autodialer centralized reminder and recall (C-R/R) from state immunization information systems (IISs) has been shown to raise childhood vaccination rates, its impact on human papillomavirus (HPV) vaccination rates is unclear. In a 4-arm pragmatic randomized controlled trial across 2 states, we randomly selected practices representative of the specialty (pediatrics, family medicine, and health center) where children received care. Within each practice, patients 11 to 17.9 years old who had not completed their HPV vaccine series (NY: N = 30 616 in 123 practices; CO: N = 31 502 in 80 practices) were randomly assigned to receive 0, 1, 2, or 3 IIS C-R/R autodialer messages per vaccine dose. We assessed HPV vaccine receipt via the IIS, calculated intervention costs, and compared HPV vaccine series initiation and completion rates across study arms. In New York, HPV vaccine initiation rates ranged from 37.0% to 37.4%, and completion rates were between 29.1% and 30.1%, with no significant differences across study arms. In Colorado, HPV vaccine initiation rates ranged from 31.2% to 33.5% and were slightly higher for 1 reminder compared with none, but vaccine completion rates, ranging from 27.0% to 27.8%, were similar. On adjusted analyses in Colorado, vaccine initiation rates were slightly higher for 1 and 3 C-R/R messages (adjusted risk ratios 1.07 and 1.04, respectively); completion rates were slightly higher for 1 and 3 C-R/R messages (adjusted risk ratios 1.02 and 1.03, respectively). IIS-based C-R/R for HPV vaccination did not improve HPV vaccination rates in New York and increased vaccination rates slightly in Colorado.
Children born very preterm (VPT) are at an increased risk of developing mental health (MH) disorders. Our aim for this study was to assess rates of MH disorders in children born VPT and term at 13 years of age and stability of MH disorders between ages 7 and 13 years by using a diagnostic measure. Participants were from the Victorian Infant Brain Study longitudinal cohort and included 125 children born VPT (<30 weeks’ gestational age and/or <1250 g) and 49 children born term (≥37 weeks’ gestational age) and their families. Participants were followed-up at both 7 and 13 years, and the Development and Well-Being Assessment was administered to assess for MH disorders. Compared with term peers, 13-year-olds born VPT were more likely to meet criteria for any MH disorder (odds ratio 5.9; 95% confidence interval 1.71–20.03). Anxiety was the most common disorder in both groups (VPT = 14%; term = 4%), whereas attention-deficit/hyperactivity disorder carried the greatest differential elevated risk (odds ratio 5.6; 95% confidence interval 0.71–43.80). Overall rates of MH disorders remained stable between 7 and 13 years, although at an individual level, many participants shifted in or out of diagnostic categories over time. Children born VPT show higher rates of MH disorders than their term peers, with changing trajectories over time. Findings highlight the importance of early identification and ongoing assessment to support those with MH disorders in this population.