Immunogenicity of Conjugated and Polysaccharide Pneumococcal Vaccines Administered During Pregnancy or Postpartum to Women With HIV.

BACKGROUND: Pneumococcal vaccination is recommended in people with HIV, prioritizing PCV. We compared the immunogenicity of PCV-10 and PPV-23 administered antepartum or postpartum. METHODS: This double-blind study randomized 346 pregnant women with HIV on antiretrovirals to PCV-10, PPV-23, or placebo at 14-34 weeks gestational age. Women who received placebo antepartum were randomized at 24 weeks postpartum to PCV-10 or PPV-23. Antibodies against 7 serotypes common to both vaccines and 1 serotype only in PPV-23 were measured by ELISA/chemiluminescence; B- and T-cell responses to serotype 1 by FLUOROSPOT; and plasma cytokines/chemokines by chemiluminescence. RESULTS: Antibody responses were higher after postpartum versus antepartum vaccination. PCV-10 generated lower antibody levels than PPV-23 against 4 and higher against 1 of 7 common serotypes. Additional factors associated with high postvaccination antibody concentrations were high prevaccination antibody concentrations and CD4+ cells; low CD8+ cells and plasma HIV RNA; and several plasma cytokines/chemokines. Serotype 1 B- and T-cell memory did not increase after vaccination. CONCLUSIONS: Antepartum immunization generated suboptimal antibody responses, suggesting that postpartum booster doses may be beneficial and warrant further studies. Considering that PCV-10 and PPV-23 had similar immunogenicity, but PPV-23 covered more serotypes, use of PPV-23 may be prioritized in women with HIV on antiretroviral therapy. CLINICAL TRAILS REGISTRATION: NCT02717494.

Effect of Maternal Immunization With 10-Valent Pneumococcus Conjugate Vaccine (PCV-10), 23-Valent Pneumococcus Polysaccharide Vaccine, or Placebo on the Immunogenicity of PCV-10 in Human Immunodeficiency Virus-Exposed Uninfected Infants: A Randomized Clinical Trial.

BACKGROUND: The effect of pneumococcal vaccination of mothers with human immunodeficiency virus (HIV) on infant responses to childhood vaccination has not been studied. We compared the immunogenicity of 10-valent pneumococcus conjugate vaccine (PCV-10) in HIV-exposed uninfected infants born to mothers who received PCV-10, 23-valent pneumococcus polysaccharide vaccine (PPV-23), or placebo during pregnancy. METHODS: Antibody levels against 7 serotypes were measured at birth, before the first and second doses of PCV-10m and after completion of the 2-dose regimen in 347 infants, including 112 born to mothers who received PPV-23, 112 who received PCV-10, and 119 who received placebo during pregnancy. Seroprotection was defined by antibody levels ≥0.35 µg/mL. RESULTS: At birth and at 8 weeks of life, antibody levels were similar in infants born to PCV-10 or PPV-23 recipients and higher than in those born to placebo recipient. After the last dose of PCV-10, infants in the maternal PCV-10 group had significantly lower antibody levels against 5 serotypes than those in the maternal PPV-23 group and against 3 serotypes than those in the maternal placebo group, and they did not have higher antibody levels against any serotype. The seroprotection rate against 7 serotypes was 50% in infants in the maternal PCV-10 group, compared with 71% in both of the maternal PPV-23 and placebo groups (P < .001). CONCLUSIONS: Administration of PCV-10 during pregnancy was associated with decreased antibody responses to PCV-10 and seroprotection rates in infants. Considering that PCV-10 and PPV-23 had similar immunogenicity in pregnant women with HIV and that administration of PPV-23 did not affect the immunogenicity of PCV-10 in infants, PPV-23 in pregnancy may be preferred over PCV-10.

Pandemic Response Requires Research Samples: A U.S. Safety-Net Hospital's Experience and Call for National Action.

Biorepositories provide a critical resource for gaining knowledge of emerging infectious diseases and offer a mechanism to rapidly respond to outbreaks; the emergence of the novel coronavirus, SARS-CoV-2, has proved their importance. During the COVID-19 pandemic, the absence of centralized, national biorepository efforts meant that the onus fell on individual institutions to establish sample repositories. As a safety-net hospital, Boston Medical Center (BMC) recognized the importance of creating a COVID-19 biorepository to both support critical science at BMC and ensure representation in research for its urban patient population, most of whom are from underserved communities. This article offers a realistic overview of the authors' experience in establishing this biorepository at the onset of the COVID-19 pandemic during the height of the first surge of cases in Boston, Massachusetts, with the hope that the challenges and solutions described are useful to other institutions. Going forward, funders, policymakers, and infectious disease and public health communities must support biorepository implementation as an essential element of future pandemic preparedness.

Twenty-Year Public Health Impact of 7- and 13-Valent Pneumococcal Conjugate Vaccines in US Children.

Pneumococcal conjugate vaccines (PCVs) have been used in the United States since 2000. To assess the cumulative 20-year effect of PCVs on invasive pneumococcal disease (IPD) incidence among children <5 years of age, we analyzed Active Bacterial Core Surveillance data, conducted a literature review, and modeled expected and observed disease. We found that PCVs have averted >282,000 cases of IPD, including ≈16,000 meningitis, ≈172,000 bacteremia, and ≈55,000 bacteremic pneumonia cases. In addition, vaccination has prevented 97 million healthcare visits for otitis media, 438,914-706,345 hospitalizations for pneumonia, and 2,780 total deaths. IPD cases declined 91%, from 15,707 in 1997 to 1,382 in 2019. Average annual visits for otitis media declined 41%, from 78 visits/100 children before PCV introduction to 46 visits/100 children after PCV13 introduction. Annual pneumonia hospitalizations declined 66%-79%, from 110,000-175,000 in 1997 to 37,000 in 2019. These findings confirm the substantial benefits of PCVs for preventing IPD in children.

Gradual decline in outpatient antibiotic prescriptions in paediatrics: A data warehouse-based 11-year cohort study.

AIM: To describe trends in antibiotic (AB) prescriptions in children in primary care over 11 years, using a large data warehouse. METHODS: A retrospective cohort study assessed outpatient AB prescriptions 2007-2017, using the Massachusetts Health Disparities Repository. The evolution of paediatric outpatient AB prescriptions was assessed using time-series analyses through annual per cent change (APC) for the population and for children with or without comorbid condition. RESULTS: About 25 000 children were followed in primary care with 31 248 AB prescriptions reported in the data warehouse. The youngest children had more AB prescriptions. Penicillins were prescribed most frequently (46%), then macrolides (28%). One third of children had comorbid conditions, receiving significantly more antibiotics (30.3 vs 21.0 AB/100 child-years, relative risk: 1.43, 95% CI: 1.40, 1.46). Overall AB prescription decreased over the period (APC = -5.34%, 95% CI: -7.10, -3.54), with similar trends for penicillins (APC = -5.49; 95% CI: -8.27, -2.62) and macrolides (APC = -6.46; 95% CI: -8.37, -4.58); antibiotic prescribing declined more in children with comorbid conditions. CONCLUSION: Outpatient AB prescribing decline was gradual and consistent in paediatrics over the period. Prescription differences persisted between age groups, conditions and indication. The availability of routine care data through data warehouse fosters the surveillance automation, providing inexpensive fast tools to design appropriate antimicrobial stewardship.

Multisystem Inflammatory Syndrome in an Adult With COVID-19-A Trial of Anakinra: A Case Report.

COVID-19 disease has been a pandemic caused by a ß-coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A life-threatening multisystem inflammatory syndrome (MIS), secondary to SARS-CoV-2 virus infection, sharing common features with Kawasaki disease shock syndrome, staphylococcal/streptococcal shock syndrome, and macrophage activation syndrome in pediatric patients has been described. A total of 27 cases in adults (MIS-A) with a similar presentation have been reported so far. Here we describe the case of a 21-year-old man admitted with abdominal pain, diarrhea, tachycardia, and low blood pressure. He had elevated troponin, ferritin, and interleukin-2 receptor levels and had evidence of myocarditis. He tested positive for SARS-CoV-2 IgG antibody, and a diagnosis of MIS-A was made. Our case adds to the scant literature on this topic, and to our knowledge, it is the first case where anakinra was administered. He recovered well. MIS-A should be considered when young adults present with multiorgan dysfunction.

Decline in Pneumococcal Disease Attenuated in Older Adults and Those With Comorbidities Following Universal Childhood PCV13 Immunization.

BACKGROUND: Following introduction of 7-valent pneumococcal conjugate vaccine (PCV7) in the United States, epidemiology of pneumococcal disease shifted such that disease incidence in the elderly exceeded that in children. We evaluated the impact of replacing PCV7 with PCV13 on disease burden in adults and identified age/risk-specific subgroups with the highest remaining disease burden. METHODS: A retrospective design and data from two US healthcare claims repositories were used. Study population included adults aged ≥18 years and was stratified by age (18-49, 50-64, 65-74, ≥75) and risk profile (healthy, at-risk, high-risk). Rate ratios comparing invasive pneumococcal disease (IPD), all-cause hospitalized pneumonia (ACHP), and pneumococcal pneumonia requiring hospitalization among at-risk and high-risk adults vs healthy counterparts were estimated for 2007-2010 (pre-PCV13), 2011-2012 (peri-PCV13), and 2013-2015 (post-PCV13). RESULTS: Across study periods, IPD and ACHP rates increased with age (2-27 times higher in persons ≥75 vs 18-49) and comorbidity (4-20 times higher in high-risk vs healthy). From pre- to post-PCV13 period, IPD rates declined 5%-48% and ACHP rates declined 4%-19% across age and risk groups (ACHP did not decline in persons ≥75). Decline in IPD and ACHP was attenuated among older adults and those with comorbidities. Accordingly, rate ratios among at-risk and high-risk persons (vs healthy counterparts) increased during the peri- and post-PCV13 periods compared with the pre-PCV13 period. CONCLUSIONS: The switch to PCV13 was associated with large declines in pneumococcal disease among US adults. However, the decline was attenuated with increasing age (and, for ACHP, was absent in persons ≥75) and in those with comorbidities.

Effectiveness of 13-Valent Pneumococcal Conjugate Vaccine Against Invasive Disease Caused by Serotype 3 in Children: A Systematic Review and Meta-analysis of Observational Studies.

The 13-valent pneumococcal conjugate vaccine (PCV13) is the only licensed PCV with serotype 3 polysaccharide in its formulation. Postlicensure PCV13 effectiveness studies against serotype 3 invasive pneumococcal disease (IPD) in children have shown inconsistent results.  We performed a systematic review and meta-analysis of observational studies to assess PCV13 vaccine effectiveness (VE) for serotype 3 IPD in children. We systematically searched PubMed, Embase, and the Cochrane library for studies published before 14 August 2017. We identified 4 published studies and 2 conference posters that provided PCV13 VE estimates stratified by serotype. The pooled PCV13 VE against serotype 3 IPD from the random-effects meta-analysis was 63.5% (95% confidence interval [CI], 37.3%-89.7%). A sensitivity analysis including conference posters gave a pooled VE estimate of 72.4% (95% CI, 56.7%-88.0%). The pooled data from case-control studies with similar methodologies and high quality support direct PCV13 protection against serotype 3 IPD in children.

Deconstructing Pneumococcal Progression from Colonization to Disease.

Despite advances in treatment and prevention, the pneumococcus continues to be a dominant cause of severe pneumonia and sepsis and of otitis media, sinusitis, and nonbacteremic pneumonia. Lewnard and colleagues (Infect Immun 86:e00727-17, 2018, https://doi.org/10.1128/IAI.00727-17) used a unique data set of nasopharyngeal and middle ear fluid samples to provide further insight into the progression of nasopharyngeal pneumococcal colonization to disease. They report the comparative rate of progression from colonization to otitis media by serotype, providing insight into how conjugate vaccines that do not reduce the overall prevalence of pneumococci in the nasopharynx dramatically impact the incidence of acute and complex otitis media.

Capacity of Pneumococci to Activate Macrophage Nuclear Factor κB: Influence on Necroptosis and Pneumonia Severity.

During pneumococcal pneumonia, antibacterial defense requires the orchestrated expression of innate immunity mediators, initiated by alveolar macrophages and dependent on transcription driven by nuclear factor κB (NF-κB). Such immune pressure may select for pneumococci, which avoid or subvert macrophage NF-κB activation. Analyzing pneumococci collected from children in Massachusetts, we found that the activation of macrophage NF-κB by Streptococcus pneumoniae is highly diverse, with a preponderance of low NF-κB activators that associate particularly with complicated pneumonia. Low NF-κB activators cause more severe lung infections in mice, and they drive macrophages toward an alternate and detrimental cell fate of necroptosis. Both outcomes can be reversed by activation of macrophages with pneumococci that are high NF-κB activators. These results suggest that low NF-κB activation is a virulence property of pneumococci and that the appropriate activation of macrophages, including NF-κB, may hold promise as an adjunct therapeutic avenue for pneumococcal pneumonia.

Rates and costs of invasive pneumococcal disease and pneumonia in persons with underlying medical conditions.

BACKGROUND: The presence of certain underlying medical conditions is known to increase the risk of pneumococcal disease in persons of all ages and across a wide spectrum of conditions, as demonstrated in two recent evaluations. Corresponding estimates of attributable economic costs have not been well characterized. We thus undertook a retrospective evaluation to estimate rates and costs of pneumococcal disease among children and adults with and without underlying medical conditions in the United States. METHODS: Data were obtained from three independent healthcare claims repositories. The study population included all persons enrolled in participating health plans during 2007-2010, and was stratified into subgroups based on age and risk profile: healthy; at-risk, due to selected comorbid conditions; and high-risk, due to selected immunocompromising conditions. At-risk and high-risk conditions, as well as episodes of invasive pneumococcal disease (IPD) and all-cause pneumonia (PNE), were identified via diagnosis, procedure, and drug codes. Rates and healthcare costs of IPD and PNE (2010US$) among at-risk and high-risk persons were compared with those from age-stratified healthy counterparts using incidence rate ratios (IRR) and cost ratios. RESULTS: Rates of IPD and PNE were consistently higher among at-risk persons (IRR = 4.1 [95 % CI 3.9-4.3] and 4.5 [4.49-4.53]) and high-risk persons (IRR = 10.3 [9.7-11.0] and 8.2 [8.2-8.3]) of all ages versus their healthy counterparts. Rates were notably high for at-risk persons with ≥2 conditions (IRR = 9.0 [8.4-9.7] and 10.3 [10.3-10.4]), as well as those with asthma (IRR = 3.4 [3.0-3.8] and 4.5 [4.47-4.53]) or diabetes (IRR = 4.3 [4.0-4.6] and 4.7 [4.6-4.7]). Healthcare costs totaled $21.7 million per 100,000 at-risk person-years and $58.5 million per 100,000 high-risk person-years, which were 8.7 [8.5-8.8] and 23.4 [22.9-23.8] times higher than corresponding costs for healthy persons. CONCLUSIONS: Rates and costs of IPD and PNE are substantially higher among persons with certain chronic and immunocompromising conditions versus those without any such conditions. Rates and costs for persons with asthma and diabetes were especially increased, and rates and costs for individuals with ≥2 at-risk conditions approached those among persons with high-risk conditions.

Antibody to a conserved antigenic target is protective against diverse prokaryotic and eukaryotic pathogens.

Microbial capsular antigens are effective vaccines but are chemically and immunologically diverse, resulting in a major barrier to their use against multiple pathogens. A ß-(1→6)-linked poly-N-acetyl-d-glucosamine (PNAG) surface capsule is synthesized by four proteins encoded in genetic loci designated intercellular adhesion in Staphylococcus aureus or polyglucosamine in selected Gram-negative bacterial pathogens. We report that many microbial pathogens lacking an identifiable intercellular adhesion or polyglucosamine locus produce PNAG, including Gram-positive, Gram-negative, and fungal pathogens, as well as protozoa, e.g., Trichomonas vaginalis, Plasmodium berghei, and sporozoites and blood-stage forms of Plasmodium falciparum. Natural antibody to PNAG is common in humans and animals and binds primarily to the highly acetylated glycoform of PNAG but is not protective against infection due to lack of deposition of complement opsonins. Polyclonal animal antibody raised to deacetylated glycoforms of PNAG and a fully human IgG1 monoclonal antibody that both bind to native and deacetylated glycoforms of PNAG mediated complement-dependent opsonic or bactericidal killing and protected mice against local and/or systemic infections by Streptococcus pyogenes, Streptococcus pneumoniae, Listeria monocytogenes, Neisseria meningitidis serogroup B, Candida albicans, and P. berghei ANKA, and against colonic pathology in a model of infectious colitis. PNAG is also a capsular polysaccharide for Neisseria gonorrhoeae and nontypable Hemophilus influenzae, and protects cells from environmental stress. Vaccination targeting PNAG could contribute to immunity against serious and diverse prokaryotic and eukaryotic pathogens, and the conserved production of PNAG suggests that it is a critical factor in microbial biology.

Stability of the pneumococcal population structure in Massachusetts as PCV13 was introduced.

BACKGROUND: The success of 7-valent pneumococcal conjugate vaccination (PCV-7) introduced to the US childhood immunization schedule in 2000 was partially offset by increases in invasive pneumococcal disease (IPD) and pneumococcal carriage due to non-vaccine serotypes, in particular 19A, in the years that followed. A 13-valent conjugate vaccine (PCV-13) was introduced in 2010. As part of an ongoing study of the response of the Massachusetts pneumococcal population to conjugate vaccination, we report the findings from the samples collected in 2011, as PCV-13 was introduced. METHODS: We used multilocus sequence typing (MLST) to analyze 367 pneumococcal isolates carried by Massachusetts children (aged 3 months-7 years) collected during the winter of 2010-11 and used eBURST software to compare the pneumococcal population structure with that found in previous years. RESULTS: One hundred and four distinct sequence types (STs) were found, including 24 that had not been previously recorded. Comparison with a similar sample collected in 2009 revealed no significant overall difference in the ST composition (p = 0.39, classification index). However, we describe clonal dynamics within the important replacement serotypes 19A, 15B/C, and 6C, and clonal expansion of ST 433 and ST 432, which are respectively serotype 22F and 21 clones. CONCLUSIONS: While little overall change in serotypes or STs was evident, multiple changes in the frequency of individual STs and or serotypes may plausibly be ascribed to the introduction of PCV-13. This 2011 sample documents the initial impact of PCV-13 and will be important for comparison with future studies of the evolution of the pneumococcal population in Massachusetts.

Rates of pneumonia among children and adults with chronic medical conditions in Germany.

BACKGROUND: The objective of this study is to evaluate rates of all-cause pneumonia among "at-risk" and "high-risk" children and adults in Germany-in comparison with age-stratified healthy counterparts-during the period following the 2006 recommendation for universal immunization of infants with pneumococcal conjugate vaccine. METHODS: Retrospective cohort design and healthcare claims information for 3.4 M persons in Germany (2009-2012) were employed. Study population was stratified by age and risk profile (healthy, "at-risk" [with chronic medical conditions], and "high-risk" [immunocompromised]). At-risk and high-risk conditions, as well as episodes of all-cause pneumonia, were identified via diagnosis, procedure, and drug codes. RESULTS AND DISCUSSION: Rates of all-cause pneumonia were 1.7 (95 % CI 1.7-1.8) to 2.5 (2.4-2.5) times higher among children and adults with at-risk conditions versus healthy counterparts, and 1.8 (1.8-1.9) to 4.1 (4.0-4.2) times higher among children and adults with high-risk conditions. Rates of all-cause pneumonia among at-risk persons increased in a graded and monotonic fashion with increasing numbers of conditions (i.e., risk stacking). CONCLUSIONS: An increased risk for all-cause pneumonia in German children and adults with a spectrum of medical conditions persists in the era of widespread pneumococcal vaccination, and pneumonia risk in persons with ≥2 at-risk conditions is comparable or higher than those with high-risk conditions.

Risk of pneumococcal disease in children with chronic medical conditions in the era of pneumococcal conjugate vaccine.

BACKGROUND: In the current era of universal immunization of young children with pneumococcal conjugate vaccine, it is unclear whether the high risk ratios for pneumococcal disease previously attributed to specified chronic conditions have persisted. In addition, further analysis of pneumococcal disease risk may clarify whether certain chronic conditions that currently are not specified as significantly increasing the risk of pneumococcal disease should be so considered. METHODS: We conducted a retrospective cohort analysis utilizing healthcare claims data from the period 2007-2010 to compare rates of pneumococcal disease among children <5 and 5-17 years of age with high-risk and at-risk conditions to rates among children without these conditions in the same age group. Risk profiles and manifestations of pneumococcal infection were ascertained from diagnosis, procedure, and drug codes. RESULTS: Among at-risk children, rate ratios for invasive pneumococcal disease (vs children without at-risk/high-risk conditions) were 1.8 (95% confidence interval [CI], 1.4-2.3) in children <5 years of age and 3.3 (95% CI, 2.4-4.4) in children 5-17 years of age. Corresponding rate ratios for high-risk children were 11.2 (95% CI, 7.0-17.9) and 40.1 (95% CI, 28.8-56.0). Rate ratios increased in asthmatic children with increasing disease severity and in all at-risk children by the number of concurrent at-risk conditions. Rate ratios for pneumococcal pneumonia and all-cause pneumonia demonstrated similar patterns. CONCLUSIONS: Children with high-risk and at-risk conditions continue to demonstrate an increased burden of pneumococcal disease. Pneumococcal disease rates are high among asthmatic children with moderate and severe disease and children with multiple at-risk conditions.

Modelling the population-level benefits and cost-effectiveness of cell-based quadrivalent influenza vaccine for children and adolescents aged 6 months to 17 years in the US.

BACKGROUND: Cell-based quadrivalent influenza vaccines (QIVc) can increase effectiveness against seasonal influenza by avoiding mismatch from egg adaption of vaccine viruses. This study evaluates the population-level cost-effectiveness and impacts on health outcomes of QIVc versus an egg-based vaccine (QIVe) in children aged 6 months to 17 years in the US. RESEARCH DESIGN AND METHODS: A dynamic age-structured susceptible-exposed-infected-recovered model was used to simulate influenza transmission in low and high incidence seasons for two scenarios: 1. QIVe for 6 months-17 year-olds, QIVc for 18-64 year-olds, and adjuvanted QIV (aQIV) for ≥ 65 year-olds, and 2. QIVc for 6 months-64 year-olds, and aQIV for ≥ 65 year-olds. Probabilistic sensitivity analysis was performed to account for uncertainty in parameter estimates. Cost-effectiveness was evaluated as incremental cost-effectiveness ratios (ICERs). RESULTS: Extension of QIVc to children resulted in 3-4% reductions in cases (1,656,271), hospitalizations (16,688), and deaths (2,126) at a population level in a high incidence season, and 65% reductions (cases: 2,856,384; hospitalizations: 31667; deaths: 4,163) in a low incidence season. Use of QIVc would be cost-saving, with ICERs of -$16,427/QALY and -$8,100/QALY from a payer perspective and -$22,669/QALY and -$15,015/QALY from a societal perspective, for low and high incidence seasons respectively. Cost savings were estimated at approximately $468 million and $1.366 billion for high and low incidence seasons, respectively. CONCLUSION: Use of QIVc instead of QIVe in children > 6 months of age in the US would reduce the disease burden and be cost-saving from both a payer and societal perspective.

Relative vaccine effectiveness of MF59-adjuvanted vs high-dose trivalent inactivated influenza vaccines for prevention of test-confirmed influenza hospitalizations during the 2017-2020 influenza seasons.

OBJECTIVES: This study evaluated relative vaccine effectiveness (rVE) of MF59-adjuvanted trivalent inactivated influenza vaccine (aTIV) vs high-dose trivalent inactivated influenza vaccine (HD-TIV) for prevention of test-confirmed influenza emergency department visits and/or inpatient admissions ("ED/IP") and for IP admissions alone pooled across the 2017-2020 influenza seasons. Exploratory individual season analyses were also performed. METHODS: This retrospective test-negative design study included United States (US) adults age ≥65 years vaccinated with aTIV or HD-TIV who presented to an ED or IP setting with acute respiratory or febrile illness during the 2017-2020 influenza seasons. Test-positive cases and test-negative controls were grouped by vaccine received. The rVE of aTIV vs HD-TIV was evaluated using a combination of inverse probability of treatment weighting and logistic regression to adjust for potential confounders. RESULTS: Pooled analyses over the three seasons found no significant differences in the rVE of aTIV vs HD-TIV for prevention of test-confirmed influenza ED/IP (-2.5% [-19.6, 12.2]) visits and admissions or IP admissions alone (-1.6% [-22.5, 15.7]). The exploratory individual season analyses also showed no significant differences. CONCLUSIONS: Evidence from the 2017-2020 influenza seasons indicates aTIV and HD-TIV are comparable for prevention of test-confirmed influenza ED/IP visits in US adults age ≥65 years.