Methods for pragmatic randomized clinical trials of pain therapies: IMMPACT statement.

ABSTRACT: Pragmatic, randomized, controlled trials hold the potential to directly inform clinical decision making and health policy regarding the treatment of people experiencing pain. Pragmatic trials are designed to replicate or are embedded within routine clinical care and are increasingly valued to bridge the gap between trial research and clinical practice, especially in multidimensional conditions, such as pain and in nonpharmacological intervention research. To maximize the potential of pragmatic trials in pain research, the careful consideration of each methodological decision is required. Trials aligned with routine practice pose several challenges, such as determining and enrolling appropriate study participants, deciding on the appropriate level of flexibility in treatment delivery, integrating information on concomitant treatments and adherence, and choosing comparator conditions and outcome measures. Ensuring data quality in real-world clinical settings is another challenging goal. Furthermore, current trials in the field would benefit from analysis methods that allow for a differentiated understanding of effects across patient subgroups and improved reporting of methods and context, which is required to assess the generalizability of findings. At the same time, a range of novel methodological approaches provide opportunities for enhanced efficiency and relevance of pragmatic trials to stakeholders and clinical decision making. In this study, best-practice considerations for these and other concerns in pragmatic trials of pain treatments are offered and a number of promising solutions discussed. The basis of these recommendations was an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) meeting organized by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks.

Performance of Urinalysis Parameters in Predicting Urinary Tract Infection: Does One Size Fit all?

In a multi-hospital cohort study of 3392 patients, positive urinalysis parameters had poor positive predictive value for diagnosing urinary tract infection (UTI). Combined urinalysis parameters (pyuria or nitrite) performed better than pyuria alone for ruling out UTI. However, performance of all urinalysis parameters was poor in older women.

Central nervous system medication use around hospitalization.

BACKGROUND: Central nervous system (CNS) medication use is common among older adults, yet the impact of hospitalizations on use remains unclear. This study details CNS medication use, discontinuations, and user profiles during hospitalization periods. METHODS: Retrospective cohort study using electronic health records on patients ≥65 years, from three hospitals (2018-2020), and prescribed a CNS medication around hospitalization (90 days prior to 90 days after). Latent class transitions analysis (LCTA) examined profiles of CNS medication class users across four time points (90 days prior, admission, discharge, 90 days after hospitalization). RESULTS: Among 4666 patients (mean age 74.3 ± 9.3 years; 63% female; 70% White; mean length of stay 4.6 ± 5.6 days (median 3.0 [2.0, 6.0]), the most commonly prescribed CNS medications were antidepressants (56%) and opioids (49%). Overall, 74% (n = 3446) of patients were persistent users of a CNS medication across all four time points; 7% (n = 388) had discontinuations during hospitalization, but of these, 64% (216/388) had new starts or restarts within 90 days after hospitalization. LCTA identified three profile groups: (1) low CNS medication users, 54%-60% of patients; (2) mental health medication users, 30%-36%; and (3) acute/chronic pain medication users, 9%-10%. Probability of staying in same group across the four time points was high (0.88-1.00). Transitioning to the low CNS medication use group was highest from admission to discharge (probability of 9% for pain medication users, 5% for mental health medication users). Female gender increased (OR 2.4, 95% CI 1.3-4.3), while chronic kidney disease lowered (OR 0.5, 0.2-0.9) the odds of transitioning to the low CNS medication use profile between admission and discharge. CONCLUSIONS: CNS medication use stays consistent around hospitalization, with discontinuation more likely between admission and discharge, especially among pain medication users. Further research on patient outcomes is needed to understand the benefits and harms of hospital deprescribing, particularly for medications requiring gradual tapering.

Systematic Literature Review of Health-Related Quality-of-Life Measures for Caregivers of Older Adult Trauma Patients.

INTRODUCTION: As the older adult population increases, hospitals treat more older adults with injuries. After leaving, these patients suffer from decreased mobility and independence, relying on care from others. Family members often assume this responsibility, mostly informally and unpaid. Caregivers of other older adult populations have increased stress and decreased caregiver-related quality of life (CRQoL). Validated CRQoL measures are essential to capture their unique experiences. Our objective was to review existing CRQoL measures and their validity in caregivers of older adult trauma patients. METHODS: A professional librarian searched published literature from the inception of databases through August 12, 2022 in MEDLINE (via PubMed), Embase (via Elsevier), and CINAHL Complete (via EBSCO). We identified 1063 unique studies of CRQoL in caregivers for adults with injury and performed a systematic review following COnsensus-based Standards for the selection of health Measurement Instruments guidelines for CRQoL measures. RESULTS: From the 66 studies included, we identified 54 health-related quality-of-life measures and 60 domains capturing caregiver-centered concerns. The majority (83%) of measures included six or fewer CRQoL content domains. Six measures were used in caregivers of older adults with single-system injuries. There were no validated CRQoL measures among caregivers of older adult trauma patients with multisystem injuries. CONCLUSIONS: While many measures exist to assess healthcare-related quality of life, few, if any, adequately assess concerns among caregivers of older adult trauma patients. We found that CRQoL domains, including mental health, emotional health, social functioning, and relationships, are most commonly assessed among caregivers. Future measures should focus on reliability and validity in this specific population to guide interventions.

New approaches for understanding the potential role of microbes in Alzheimer's disease.

Alzheimer's disease (AD) involves a complex pathological process that evolves over years, and its etiology is understood as a classic example of gene-environment interaction. The notion that exposure to microbial organisms may play some role in AD pathology has been proposed and debated for decades. New evidence from model organisms and -omic studies, as well as epidemiological data from the recent COVID-19 pandemic and widespread use of vaccines, offers new insights into the "germ hypothesis" of AD. To review new evidence and identify key research questions, the Duke/University of North Carolina (Duke/UNC) Alzheimer's Disease Research Center hosted a virtual symposium and workshop: "New Approaches for Understanding the Potential Role of Microbes in Alzheimer's disease." Discussion centered around the antimicrobial protection hypothesis of amyloid accumulation, and other mechanisms by which microbes could influence AD pathology including immune cell activation, changes in blood-brain barrier, or direct neurotoxicity. This summary of proceedings reviews the content presented in the symposium and provides a summary of major topics and key questions discussed in the workshop.

A Phase 2 Clinical Trial to Evaluate the Safety, Reactogenicity, and Immunogenicity of Different Prime-Boost Vaccination Schedules of 2013 and 2017 A(H7N9) Inactivated Influenza Virus Vaccines Administered with and without AS03 Adjuvant in Healthy US Adults.

INTRODUCTION: A surge of human influenza A(H7N9) cases began in 2016 in China due to an antigenically distinct lineage. Data are needed about the safety and immunogenicity of 2013 and 2017 A(H7N9) inactivated influenza vaccines (IIVs) and the effects of AS03 adjuvant, prime-boost interval, and priming effects of 2013 and 2017 A(H7N9) IIVs. METHODS: Healthy adults (n=180), ages 19-50 years, were enrolled into this partially-blinded, randomized, multi-center Phase 2 clinical trial. Participants were randomly assigned to 1 of 6 vaccination groups evaluating homologous versus heterologous prime-boost strategies with two different boost intervals (21 versus 120 days) and two dosages (3.75 or 15 µg of hemagglutinin) administered with or without AS03 adjuvant. Reactogenicity, safety, and immunogenicity measured by hemagglutination inhibition (HAI) and neutralizing antibody titers were assessed. RESULTS: Two doses of A(H7N9) IIV were well tolerated, and no safety issues were identified. Although most participants had injection site and systemic reactogenicity, these symptoms were mostly mild to moderate in severity; injection site reactogenicity was greater in vaccination groups receiving adjuvant. Immune responses were greater after an adjuvanted second dose, and with a longer interval between prime and boost. The highest HAI GMT (95%CI) observed against the 2017 A(H7N9) strain was 133.4 (83.6, 212.6) among participants who received homologous, adjuvanted 3.75 ug+AS03/2017 doses with delayed boost interval. CONCLUSIONS: Administering AS03 adjuvant with the second H7N9 IIV dose and extending the boost interval to 4 months resulted in higher peak antibody responses. These observations can broadly inform strategic approaches for pandemic preparedness. (NCT03589807).

Bacteremia From a Presumed Urinary Source in Hospitalized Adults With Asymptomatic Bacteriuria.

Importance: Guidelines recommend withholding antibiotics in asymptomatic bacteriuria (ASB), including among patients with altered mental status (AMS) and no systemic signs of infection. However, ASB treatment remains common. Objectives: To determine prevalence and factors associated with bacteremia from a presumed urinary source in inpatients with ASB with or without AMS and estimate antibiotics avoided if a 2% risk of bacteremia were used as a threshold to prompt empiric antibiotic treatment of ASB. Design, Setting, and Participants: This cohort study assessed patients hospitalized to nonintensive care with ASB (no immune compromise or concomitant infections) in 68 Michigan hospitals from July 1, 2017, to June 30, 2022. Data were analyzed from August 2022 to January 2023. Main Outcomes and Measures: The primary outcome was prevalence of bacteremia from a presumed urinary source (ie, positive blood culture with matching organisms within 3 days of urine culture). To determine factors associated with bacteremia, we used multivariable logistic regression models. We estimated each patient's risk of bacteremia and determined what percentage of patients empirically treated with antibiotics had less than 2% estimated risk of bacteremia. Results: Of 11 590 hospitalized patients with ASB (median [IQR] age, 78.2 [67.7-86.6] years; 8595 female patients [74.2%]; 2235 African American or Black patients [19.3%], 184 Hispanic patients [1.6%], and 8897 White patients [76.8%]), 8364 (72.2%) received antimicrobial treatment for UTI, and 161 (1.4%) had bacteremia from a presumed urinary source. Only 17 of 2126 patients with AMS but no systemic signs of infection (0.7%) developed bacteremia. On multivariable analysis, male sex (adjusted odds ratio [aOR], 1.45; 95% CI, 1.02-2.05), hypotension (aOR, 1.86; 95% CI, 1.18-2.93), 2 or more systemic inflammatory response criteria (aOR, 1.72; 95% CI, 1.21-2.46), urinary retention (aOR, 1.87; 95% CI, 1.18-2.96), fatigue (aOR, 1.53; 95% CI, 1.08-2.17), log of serum leukocytosis (aOR, 3.38; 95% CI, 2.48-4.61), and pyuria (aOR, 3.31; 95% CI, 2.10-5.21) were associated with bacteremia. No single factor was associated with more than 2% risk of bacteremia. If 2% or higher risk of bacteremia were used as a cutoff for empiric antibiotics, antibiotic exposure would have been avoided in 78.4% (6323 of 8064) of empirically treated patients with low risk of bacteremia. Conclusions and Relevance: In patients with ASB, bacteremia from a presumed urinary source was rare, occurring in less than 1% of patients with AMS. A personalized, risk-based approach to empiric therapy could decrease unnecessary ASB treatment.

Proposing the "Continuum of UTI" for a Nuanced Approach to Diagnosis and Management of Urinary Tract Infections.

PURPOSE: Patients with suspected UTIs are categorized into 3 clinical phenotypes based on current guidelines: no UTI, asymptomatic bacteriuria (ASB), or UTI. However, all patients may not fit neatly into these groups. Our objective was to characterize clinical presentations of patients who receive urine tests using the "continuum of UTI" approach. MATERIALS AND METHODS: This was a retrospective cohort study of a random sample of adult noncatheterized inpatient and emergency department encounters with paired urinalysis and urine cultures from 5 hospitals in 3 states between January 01, 2017, and December 31, 2019. Trained abstractors collected clinical (eg, symptom) and demographic data. A focus group discussion with multidisciplinary experts was conducted to define the continuum of UTI, a 5-level classification scheme that includes 2 new categories: lower urinary tract symptoms/other urologic symptoms and bacteriuria of unclear significance. The newly defined continuum of UTI categories were compared to the current UTI classification scheme. RESULTS: Of 220,531 encounters, 3392 randomly selected encounters were reviewed. Based on the current classification scheme, 32.1% (n = 704) had ASB and 53% (n = 1614) did not have a UTI. When applying the continuum of UTI categories, 68% of patients (n = 478) with ASB were reclassified as bacteriuria of unclear significance and 29% of patients (n = 467) with "no UTI" were reclassified to lower urinary tract symptoms/other urologic symptoms. CONCLUSIONS: Our data suggest the need to reframe our conceptual model of UTI vs ASB to reflect the full spectrum of clinical presentations, acknowledge the diagnostic uncertainty faced by frontline clinicians, and promote a nuanced approach to diagnosis and management of UTIs.

Immunogenicity and safety of varying dosages of a fifth-wave influenza A/H7N9 inactivated vaccine given with and without AS03 adjuvant in healthy adults.

BACKGROUND: Human infections with the avian influenza A(H7N9) virus were first reported in China in 2013 and continued to occur in annual waves. In the 2016/2017 fifth wave, Yangtze River Delta (YRD) lineage viruses, which differed antigenically from those of earlier waves, predominated. METHODS: In this phase 2 double-blinded trial we randomized 720 adults ≥ 19 years of age to receive two injections of a YRD lineage inactivated A/Hong Kong/125/2017 fifth-wave H7N9 vaccine, given 21 days apart, at doses of 3.75, 7.5, and 15 µg of hemagglutinin (HA) with AS03A adjuvant and at doses of 15 and 45 µg of HA without adjuvant. RESULTS: Two doses of adjuvanted vaccine were required to induce HA inhibition (HI) antibody titers ≥ 40 in most participants. After two doses of the 15 µg H7N9 formulation, given with or without AS03 adjuvant, the proportion achieving a HI titer ≥ 40 against the vaccine strain at 21 days after the second vaccination was 65 % (95 % CI, 57 %-73 %) and 0 % (95 % CI, 0 %-4%), respectively. Among those who received two doses of the 15 µg adjuvanted formulation the proportion with HI titer ≥ 40 at 21 days after the second vaccination was 76 % (95 % CI, 66 %-84 %) in those 19-64 years of age and 49 % (95 % CI, 37 %-62 %) in those ≥ 65 years of age. Responses to the adjuvanted vaccine formulations did not vary by HA content. Antibody responses declined over time and responses against drifted H7N9 strains were diminished. Overall, the vaccines were well tolerated but, as expected, adjuvanted vaccines were associated with more frequent solicited systemic and local adverse events. CONCLUSIONS: AS03 adjuvant improved the immune responses to an inactivated fifth-wave H7N9 influenza vaccine, particularly in younger adults, but invoked lower responses to drifted H7N9 strains. These findings may inform future influenza pandemic preparedness strategies.

Medication use quality and safety in older adults: 2022 update.

Improving the quality of medication use and medication safety are important priorities for healthcare providers who care for older adults. The objective of this article was to identify four exemplary articles with this focus in 2022. We selected high-quality studies from an OVID search and hand searching of major high impact journals that advanced the field of research forward. The chosen articles cover domains related to deprescribing, medication safety, and optimizing medication use. The MedSafer Study, a cluster randomized clinical trial in Canada, evaluated whether patient specific deprescribing reports generated by electronic decision support software resulted in reduced adverse drug events in the 30 days post hospital discharge in older adults (domain: deprescribing). The second study, a retrospective cohort study using data from Premier Healthcare Database, examined in-hospital adverse clinical events associated with perioperative gabapentin use among older adults undergoing major surgery (domain: medication safety). The third study used an open-label parallel controlled trial in 39 Australian aged-care facilities to examine the effectiveness of a pharmacist-led intervention to reduce medication-induced deterioration and adverse reactions (domain: optimizing medication use). Lastly, the fourth study engaged experts in a Delphi method process to develop a consensus list of clinically important prescribing cascades that adversely affect older persons' health to aid clinicians to identify, prevent, and manage prescribing cascades (domain: optimizing medication use). Collectively, this review succinctly highlights pertinent topics related to promoting safe use of medications and promotes awareness of optimizing older adults' medication regimens.

Immunogenicity of adjuvanted versus high-dose inactivated influenza vaccines in older adults: a randomized clinical trial.

BACKGROUND: Adjuvanted inactivated influenza vaccine (aIIV) and high-dose inactivated influenza vaccine (HD-IIV) are U.S.-licensed for adults aged ≥ 65 years. This study compared serum hemagglutination inhibition (HAI) antibody titers for the A(H3N2) and A(H1N1)pdm09 and B strains after trivalent aIIV3 and trivalent HD-IIV3 in an older adult population. RESULTS: The immunogenicity population included 342 participants who received aIIV3 and 338 participants who received HD-IIV3. The proportion of participants that seroconverted to A(H3N2) vaccine strains after allV3 (112 participants [32.8%]) was inferior to the proportion of participants that seroconverted after HD-IIV3 (130 participants [38.5%]) at day 29 after vaccination (difference, - 5.8%; 95%CI, - 12.9% to 1.4%). There were no significant differences between the vaccine groups in percent seroconversion to A(H1N1)pdm09 or B vaccine strains, in percent seropositivity for any of the strains, or in post-vaccination GMT for the A(H1N1)pdm09 strain. The GMTs for the post-vaccination A(H3N2) and B strains were higher after HD-IIV than after aIIV3. CONCLUSIONS: Overall immune responses were similar after aIIV3 and HD-IIV3. For the primary outcome, the aIIV3 seroconversion rate for H3N2 did not meet noninferiority criteria compared with HD-IIV3, but the HD-IIV3 seroconversion rate was not statistically superior to the aIIV3 seroconversion rate. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03183908.

An Analysis of How Herpes Zoster Pain Affects Health-related Quality of Life of Placebo Patients From 3 Randomized Phase III Studies.

OBJECTIVES: Herpes zoster (HZ) is a painful condition caused by the reactivation of the varicella-zoster virus, negatively affecting the lives of patients. In this post hoc analysis, we describe the impact of HZ pain on the health-related quality of life (HRQoL) and activities of daily living (ADL) of immunocompetent individuals 50 years of age and older and in hematopoietic stem cell transplantation (HSCT) recipients age 18 years of age and older. MATERIALS AND METHODS: ZOE-50 (NCT01165177), ZOE-70 (NCT01165229), and ZOE-HSCT (NCT01610414) were phase III, randomized studies conducted in immunocompetent adults 50 years of age and older and 70 years of age and older and in HSCT recipients age 18 years of age and older, respectively. This analysis was performed on patients who experienced an HZ episode in the placebo groups. The impact of varying levels of HZ pain on HRQoL and ADL was analyzed using data from the Zoster Brief Pain Inventory (ZBPI) and the Short Form Health Survey 36 (SF-36) and EQ-5D questionnaires. RESULTS: A total of 520 immunocompetent and 172 HSCT individuals with HZ were included. SF-36 and EQ-5D domain scores showed a significant relationship between increased HZ pain and worsening HRQoL. For every increase of 1 in the ZBPI pain score, the estimated mean decrease (worsening) in score in the ZOE-50/70 and ZOE-HSCT, respectively, was 2.0 and 2.4 for SF-36 Role Physical; 2.1 and 1.8 for SF-36 Social Functioning; and 0.041 and 0.045 for EQ-5D utility. Sleep and General activities were the ADL components most affected. DISCUSSION: Moderate and severe HZ pain had a substantial negative impact on all aspects of HRQoL and ADL. This impact was independent of age and immunosuppression.

Using the COM-B model to identify barriers to and facilitators of evidence-based nurse urine-culture practices.

Our surveys of nurses modeled after the Capability, Opportunity, and Motivation Model of Behavior (COM-B model) revealed that opportunity and motivation factors heavily influence urine-culture practices (behavior), in addition to knowledge (capability). Understanding these barriers is a critical step towards implementing targeted interventions to improving urine-culture practices.

Pragmatic evaluation of events and benefits of lipid lowering in older adults (PREVENTABLE): Trial design and rationale.

Whether initiation of statins could increase survival free of dementia and disability in adults aged ≥75 years is unknown. PREVENTABLE, a double-blind, placebo-controlled randomized pragmatic clinical trial, will compare high-intensity statin therapy (atorvastatin 40 mg) with placebo in 20,000 community-dwelling adults aged ≥75 years without cardiovascular disease, disability, or dementia at baseline. Exclusion criteria include statin use in the prior year or for >5 years and inability to take a statin. Potential participants are identified using computable phenotypes derived from the electronic health record and local referrals from the community. Participants will undergo baseline cognitive testing, with physical testing and a blinded lipid panel if feasible. Cognitive testing and disability screening will be conducted annually. Multiple data sources will be queried for cardiovascular events, dementia, and disability; survival is site-reported and supplemented by a National Death Index search. The primary outcome is survival free of new dementia or persisting disability. Co-secondary outcomes are a composite of cardiovascular death, hospitalization for unstable angina or myocardial infarction, heart failure, stroke, or coronary revascularization; and a composite of mild cognitive impairment or dementia. Ancillary studies will offer mechanistic insights into the effects of statins on key outcomes. Biorepository samples are obtained and stored for future study. These results will inform the benefit of statins for increasing survival free of dementia and disability among older adults. This is a pioneering pragmatic study testing important questions with low participant burden to align with the needs of the growing population of older adults.

Ageing and physical resilience after health stressors.

The objectives of this article are to introduce a conceptual framework for physical resilience in the context of ageing and to discuss key elements and challenges in the design of studies of physical resilience after health stressors. Advancing age is associated with increasing exposure to multiple stressors and declining capacity to respond to health stressors. Resilience is defined broadly as the ability to resist or recover well from the adverse effects of a health stressor. In ageing-related study designs of physical resilience after a health stressor, this dynamic resilience response can be observed as changes in repeated measures of function or health status in various domains important to older adults. Methodologic issues in selecting the study population, defining the stressor, covariates, outcomes, and analytic strategies are highlighted in the context of an ongoing prospective cohort study of physical resilience after total knee replacement surgery. The article concludes with approaches to intervention development to optimize resilience.

Research objectives and general considerations for pragmatic clinical trials of pain treatments: IMMPACT statement.

ABSTRACT: Many questions regarding the clinical management of people experiencing pain and related health policy decision-making may best be answered by pragmatic controlled trials. To generate clinically relevant and widely applicable findings, such trials aim to reproduce elements of routine clinical care or are embedded within clinical workflows. In contrast with traditional efficacy trials, pragmatic trials are intended to address a broader set of external validity questions critical for stakeholders (clinicians, healthcare leaders, policymakers, insurers, and patients) in considering the adoption and use of evidence-based treatments in daily clinical care. This article summarizes methodological considerations for pragmatic trials, mainly concerning methods of fundamental importance to the internal validity of trials. The relationship between these methods and common pragmatic trials methods and goals is considered, recognizing that the resulting trial designs are highly dependent on the specific research question under investigation. The basis of this statement was an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) systematic review of methods and a consensus meeting. The meeting was organized by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership. The consensus process was informed by expert presentations, panel and consensus discussions, and a preparatory systematic review. In the context of pragmatic trials of pain treatments, we present fundamental considerations for the planning phase of pragmatic trials, including the specification of trial objectives, the selection of adequate designs, and methods to enhance internal validity while maintaining the ability to answer pragmatic research questions.

Population Pharmacokinetics of Piperacillin/Tazobactam Across the Adult Lifespan.

BACKGROUND AND OBJECTIVE: Piperacillin/tazobactam is one of the most frequently used antimicrobials in older adults. Using an opportunistic study design, we evaluated the pharmacokinetics of piperacillin/tazobactam as a probe drug to evaluate changes in antibacterial drug exposure and dosing requirements, including in older adults. METHODS: A total of 121 adult patients were included. The population pharmacokinetic models that best characterized the observed plasma concentrations of piperacillin and tazobactam were one-compartment structural models with zero-order input and linear elimination. RESULTS: Among all potential covariates, estimated creatinine clearance had the most substantial impact on the elimination clearance for both piperacillin and tazobactam. After accounting for renal function and body size, there was no remaining impact of frailty on the pharmacokinetics of piperacillin and tazobactam. Monte Carlo simulations indicated that renal function had a greater impact on the therapeutic target attainment than age, although these covariates were highly correlated. Frailty, using the Canadian Study of Health and Aging Clinical Frailty Scale, was assessed in 60 patients who were ≥ 65 years of age. CONCLUSIONS: The simulations suggested that adults ≤ 50 years of age infected with organisms with higher minimum inhibitory concentrations may benefit from continuous piperacillin/tazobactam infusions (12 g/day of piperacillin component) or extended infusions of 4 g every 8 hours. However, for a target of 50% fT + minimum inhibitory concentration, dosing based on renal function is generally preferable to dosing by age, and simulations suggested that patients with creatinine clearance ≥ 120 mL/min may benefit from infusions of 4 g every 8 hours for organisms with higher minimum inhibitory concentrations.

Safety and Immunogenicity of Influenza A/H5N8 Virus Vaccine in Healthy Adults: Durability and Cross-reactivity of Antibody Responses.

BACKGROUND: Influenza A/H5N8 viruses infect poultry and wild birds in many countries. In 2021, the first human A/H5N8 cases were reported. METHODS: We conducted a phase I, cohort-randomized, double-blind, controlled trial of inactivated influenza A/H5N8 vaccine (clade 2.3.4.4c) administered with or without adjuvant. Cohort 1 subjects received either two doses of AS03-adjuvanted vaccine containing 3.75 µg or 15 µg hemagglutinin (HA); two doses of 15 µg HA unadjuvanted vaccine; or one dose of AS03-adjuvanted vaccine (3.75 µg or 15 µg HA), followed by one dose of non-adjuvanted vaccine (same HA content). Cohort 2 subjects received two doses of MF59-adjuvanted vaccine containing 3.75 µg or 15 µg HA, or 15 µg HA of non-adjuvanted vaccine. Subjects were followed for 13 months for safety and immunogenicity. RESULTS: We enrolled 386 adult subjects in good health. Solicited adverse events were generally mild and more common among subjects who received adjuvanted vaccines. Antibody responses (hemagglutination inhibition or microneutralization assays) were highest in the two-dose AS03 group, followed by the one-dose AS03 group, the MF59 groups, and the non-adjuvanted groups. Antibody levels returned to baseline 12 months after the second vaccination in all groups except the 15 µg AS03-adjuvanted group. Cross-reactive antibodies to clade 2.3.4.4b strains isolated from recent human cases were demonstrated in a subset of both 15 µg adjuvanted groups. CONCLUSIONS: Two doses of influenza A/H5N8 vaccine were well-tolerated. Immunogenicity improved with receipt of two doses of adjuvanted vaccine and higher antigen content. (Funded by the National Institute of Allergy and Infectious Diseases.

Optimizing reflex urine cultures: Using a population-specific approach to diagnostic stewardship.

BACKGROUND: Clinicians and laboratories routinely use urinalysis (UA) parameters to determine whether antimicrobial treatment and/or urine cultures are needed. Yet the performance of individual UA parameters and common thresholds for action are not well defined and may vary across different patient populations. METHODS: In this retrospective cohort study, we included all encounters with UAs ordered 24 hours prior to a urine culture between 2015 and 2020 at 3 North Carolina hospitals. We evaluated the performance of relevant UA parameters as potential outcome predictors, including sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV). We also combined 18 different UA criteria and used receiver operating curves to identify the 5 best-performing models for predicting significant bacteriuria (≥100,000 colony-forming units of bacteria/mL). RESULTS: In 221,933 encounters during the 6-year study period, no single UA parameter had both high sensitivity and high specificity in predicting bacteriuria. Absence of leukocyte esterase and pyuria had a high NPV for significant bacteriuria. Combined UA parameters did not perform better than pyuria alone with regard to NPV. The high NPV ≥0.90 of pyuria was maintained among most patient subgroups except females aged ≥65 years and patients with indwelling catheters. CONCLUSION: When used as a part of a diagnostic workup, UA parameters should be leveraged for their NPV instead of sensitivity. Because many laboratories and hospitals use reflex urine culture algorithms, their workflow should include clinical decision support and or education to target symptomatic patients and focus on populations where absence of pyuria has high NPV.