Twice-Yearly Depemokimab in Severe Asthma with an Eosinophilic Phenotype.

BACKGROUND: Depemokimab is an ultra-long-acting biologic therapy with enhanced binding affinity for interleukin-5 that may enable effective 6-month dosing intervals. METHODS: In these phase 3A, randomized, placebo-controlled replicate trials, we evaluated the efficacy and safety of depemokimab in patients with severe asthma and an eosinophilic phenotype characterized by a high eosinophil count (≥300 cells per microliter in the previous 12 months or ≥150 cells per microliter at screening) and a history of exacerbations despite the receipt of medium- or high-dose inhaled glucocorticoids. Patients were randomly assigned in a 2:1 ratio to receive either depemokimab (at a dose of 100 mg subcutaneously) or placebo at weeks 0 and 26, plus standard care. The primary end point was the annualized rate of exacerbations at 52 weeks. Secondary end points, which were analyzed in a hierarchical manner to adjust for multiplicity, included the change from baseline in the score on the St. George's Respiratory Questionnaire (SGRQ), the forced expiratory volume in 1 second, and asthma symptom reports at 52 weeks. RESULTS: Across the two trials, 792 patients underwent randomization and 762 were included in the full analysis; 502 were assigned to receive depemokimab and 260 to receive placebo. The annualized rate of exacerbations was 0.46 (95% confidence interval [CI]), 0.36 to 0.58) with depemokimab and 1.11 (95% CI, 0.86 to 1.43) with placebo (rate ratio, 0.42; 95% CI, 0.30 to 0.59; P<0.001) in SWIFT-1 and 0.56 (95% CI, 0.44 to 0.70) with depemokimab and 1.08 (95% CI, 0.83 to 1.41) with placebo (rate ratio, 0.52; 95% CI, 0.36 to 0.73; P<0.001) in SWIFT-2. No significant between-group difference in the change from baseline in the SGRQ score was observed in either trial, so no statistical inference was drawn on subsequent secondary end points. The proportion of patients with any adverse event was similar in the two groups in both trials. CONCLUSIONS: Depemokimab reduced the annualized rate of exacerbations among patients with severe asthma with an eosinophilic phenotype. (Funded by GSK; SWIFT-1 and SWIFT-2 ClinicalTrials.gov numbers, NCT04719832 and NCT04718103.).

Small Animal Models to Study Herpes Simplex Virus Infections.

Herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2) are two of the most prevalent human viruses worldwide. They are known to cause a variety of diseases including genital herpes, meningitis, encephalitis, cold sores and herpes stromal keratitis. The seropositive rate for HSV-1 is around 90%, whereas for HSV-2 it remains around 20-25% for the general adult population. The infections caused by these viruses remain difficult to study because a large proportion of infected individuals are asymptomatic. Furthermore, given the neurotropic characteristics of the virus, studies aimed at understanding the complex pathogenesis in humans is difficult. As a result, animal models have been developed to understand several characteristics of HSV biology, pathogenesis, disease and host responses to infection. These models are also commonly used as the first evaluation of new drugs and vaccines. There are several well-established animal models to study infection with HSV, including mice, guinea pigs and rabbits. Variables within the animal models depend on the species of animal, route of infection, viral strain, dosage, etc. This review aims at summarizing the most commonly used animal models to study HSV pathogenesis and therapies.

Development of neffy, an Epinephrine Nasal Spray, for Severe Allergic Reactions.

Epinephrine autoinjectors (EAIs) are used for the treatment of severe allergic reactions in a community setting; however, their utility is limited by low prescription fulfillment rates, failure to carry, and failure to use due to fear of needles. Given that delayed administration of epinephrine is associated with increased morbidity/mortality, there has been a growing interest in developing needle-free, easy-to-use delivery devices. neffy (epinephrine nasal spray) consists of three Food and Drug Administration (FDA)-approved components: epinephrine, Intravail A3 (absorption enhancer), and a Unit Dose Spray (UDS). neffy's development pathway was established in conjunction with the FDA and the European Medicines Agency and included multiple clinical trials to evaluate pharmacokinetic and pharmacodynamic responses under a variety of conditions, such as self-administration and allergic and infectious rhinitis, as well as an animal anaphylaxis model of severe hypotension, where neffy demonstrated a pharmacokinetic profile that is within the range of approved injection products and a pharmacodynamic response that is as good or better than injections. The increased pulse rate (PR) and blood pressure (BP) observed even one minute following the administration of neffy confirm the activation of α and ß adrenergic receptors, which are the key components of epinephrine's mechanism of action. The results suggest that neffy will provide a safe and effective needle-free option for the treatment of severe allergic reactions, including anaphylaxis.

A chimeric haemagglutinin-based universal influenza virus vaccine boosts human cellular immune responses directed towards the conserved haemagglutinin stalk domain and the viral nucleoprotein.

BACKGROUND: The development of a universal influenza virus vaccine, to protect against both seasonal and pandemic influenza A viruses, is a long-standing public health goal. The conserved stalk domain of haemagglutinin (HA) is a promising vaccine target. However, the stalk is immunosubdominant. As such, innovative approaches are required to elicit robust immunity against this domain. In a previously reported observer-blind, randomised placebo-controlled phase I trial (NCT03300050), immunisation regimens using chimeric HA (cHA)-based immunogens formulated as inactivated influenza vaccines (IIV) -/+ AS03 adjuvant, or live attenuated influenza vaccines (LAIV), elicited durable HA stalk-specific antibodies with broad reactivity. In this study, we sought to determine if these vaccines could also boost T cell responses against HA stalk, and nucleoprotein (NP). METHODS: We measured interferon-γ (IFN-γ) responses by Enzyme-Linked ImmunoSpot (ELISpot) assay at baseline, seven days post-prime, pre-boost and seven days post-boost following heterologous prime:boost regimens of LAIV and/or adjuvanted/unadjuvanted IIV-cHA vaccines. FINDINGS: Our findings demonstrate that immunisation with adjuvanted cHA-based IIVs boost HA stalk-specific and NP-specific T cell responses in humans. To date, it has been unclear if HA stalk-specific T cells can be boosted in humans by HA-stalk focused universal vaccines. Therefore, our study will provide valuable insights for the design of future studies to determine the precise role of HA stalk-specific T cells in broad protection. INTERPRETATION: Considering that cHA-based vaccines also elicit stalk-specific antibodies, these data support the further clinical advancement of cHA-based universal influenza vaccine candidates. FUNDING: This study was funded in part by the Bill and Melinda Gates Foundation (BMGF).

How Allergists Can Perform an Occupational History in Every Patient.

The occupational history is often neglected in the routine evaluation of new patients with asthma, chronic rhinitis, or dermatologic complaints. Such omissions are inadvertent because work-related conditions are often not prioritized. There also may be lack of awareness of the scope of respiratory or cutaneous allergens capable of inducing occupational asthma (OA) or work-related contact dermatitis. Evidence exists suggesting that the occupational history is often neglected among primary care physicians and specialists. Failure to diagnose OA in a timely fashion by identifying occupational sources of exposure, for example, may result in unnecessary morbidity in workers whose exposure is not modified. In this commentary, we propose a brief intake survey to be administered to all patients coming to an allergy practice to quickly screen for possible work-related respiratory symptoms and another for occupational dermatitis. This would require minimal physician time and could be self-administered at the initial encounter and incorporated into the medical record. A positive response to either survey should trigger a more detailed evaluation by the allergy specialist. More detailed approaches for stepwise clinical evaluation of the worker suspected of OA and contact dermatitis are discussed.

Price Transparency in United States' Health Care: A Narrative Policy Review of the Current State and Way Forward.

Health care price transparency is gaining momentum as a tangible policy intervention that can unleash market principles to increase competition, help begin to decrease U.S. health care expenditures, and provide Americans with access to affordable, high-quality health care. Indeed, pricing reform is required to facilitate patient shopping in health care. In this narrative policy review, we offer a brief history of health care price transparency efforts and an overview of the health care price transparency literature. Further, we highlight the current rules and legislative initiatives aimed at achieving the full potential of health care price transparency. Lastly, we offer key takeaways and highlight suggestions for future policy directions, including the need to ensure hospital and insurance compliance through more appropriate penalties and incentives, importance of reducing regulation to promote financial upside that can be obtained by both patients and providers who actively promote shopping for lower cost, higher quality health care goods and services, and the need for transparent and easily found quality metrics, including outcomes most important to patients, driven by physicians "on the ground" with patient input.

Consistent efficacy and safety of sublingual immunotherapy tablets across allergens and geographic regions.

Background: The clinical development program of the SQ grass, ragweed, tree, and house dust mite (HDM) sublingual immunotherapy (SLIT)-tablets for allergic rhinitis/conjunctivitis (AR/C) included clinical trials conducted in North America, Europe, and Japan. Objective: Data from these trials were analyzed to assess efficacy, immunologic mechanisms, and safety outcomes across allergens and geographic regions. Methods: Thirteen phase III, double-blind, placebo controlled trials in the subjects with AR/C were conducted in North America, Europe (including Russia), and Japan (N = 7763 analyzed). Trials were generally similar with respect to medical practice, target population, eligibility criteria, and efficacy and safety monitoring. Data were analyzed for the approved doses in North America and Europe. Four statistical models were used to enhance comparison of the efficacy end points among the trials. Results: The SLIT-tablets demonstrated consistent efficacy across allergens and regions, regardless of the statistical analysis used. Relative improvement in the primary efficacy end point compared with placebo by using the predefined protocol analysis ranged from 17.9% to 32.8%, 17.5% to 19.3%, 20.6% to 38.3%, and 39.6% with the grass, HDM, ragweed, and tree SLIT-tablets, respectively. The kinetics of specific immunoglobulin E (IgE) and IgG4 responses were similar among the allergens and regions. Local application-site reactions were the most common adverse events for all allergens and in all regions. Most treatment-related adverse events for all allergens and in all regions were mild in severity. The rate of systemic allergic reactions was similar across regions (0%-0.54%). Conclusion: Confirmatory phase III trials for SLIT-tablets in the treatment of AR/C showed consistent efficacy, immunologic, and safety outcomes across allergens and geographic regions.

Assessing the variation and drivers of cost in 1-level lumbar fusion: a time-driven activity-based costing analysis.

BACKGROUND CONTEXT: As value-based health care arrangements gain traction in spine care, understanding the true cost of care becomes critical. Historically, inaccurate cost proxies have been used, including negotiated reimbursement rates or list prices. However, time-driven activity-based costing (TDABC) allows for a more accurate cost assessment, including a better understanding of the primary drivers of cost in 1-level lumbar fusion. PURPOSE: To determine the variation of total hospital cost, differences in characteristics between high-cost and nonhigh-cost patients, and to identify the primary drivers of total hospital cost in a sample of patients undergoing 1-level lumbar fusion. STUDY DESIGN/SETTING: Retrospective, multicenter (one academic medical center, one community-based hospital), observational study. PATIENT SAMPLE: A total of 383 patients undergoing elective 1-level lumbar fusion for degenerative spine conditions between November 2, 2021 and December 2, 2022. OUTCOME MEASURES: Total hospital cost of care (normalized); preoperative, intraoperative, and postoperative cost of care (normalized); ratio of most to least expensive 1-level lumbar fusion. METHODS: Patients undergoing a 1-level lumbar fusion between November 2, 2021 and December 2, 2022 were identified at two hospitals (one quaternary referral academic medical center and one community-based hospital) within our health system. TDABC was used to calculate total hospital cost, which was also broken up into: pre-, intra-, and postoperative timeframes. Operating surgeon and patient characteristics were also collected and compared between high- and nonhigh-cost patients. The correlation of surgical time and cost was determined. Multivariable linear regression was used to determine factors associated with total hospital cost. RESULTS: The most expensive 1-level lumbar fusion was 6.8x more expensive than the least expensive 1-level lumbar fusion, with the intraoperative period accounting for 88% of total cost. On average. the implant cost accounted for 30% of the total, but across the patient sample, the implant cost accounted for a range of 6% to 44% of the total cost. High-cost patients were younger (55 years [SD: 13 years] vs 63 years [SD: 13 years], p=.0002), more likely to have commercial health insurance (24 out of 38 (63%) vs 181 out of 345 (52%), p=.003). There was a poor correlation between time of surgery (ie, incision to close) and total overall cost (ρ: .26, p<.0001). Increase age (RC: -0.003 [95% CI: -0.006 to -0.000007], p=.049) was associated with decreased cost. Surgery by certain surgeons was associated with decreased total cost when accounting for other factors (p<.05). CONCLUSIONS: A large variation exists in the total hospital cost for patients undergoing 1-level lumbar fusion, which is primarily driven by surgeon-level decisions and preferences (eg, implant and technology use). Also, being a "fast" surgeon intraoperatively does not mean your total cost is meaningfully lower. As efforts continue to optimize patient value through ensuring appropriate clinical outcomes while also reducing cost, spine surgeons must use this knowledge to lead, or at least be active participants in, any discussions that could impact patient care.

Post-operative Patient Portal Messaging is Associated With Return to the Emergency Department After Lumbar Spine Surgery.

STUDY DESIGN: Retrospective study. OBJECTIVE: To explore the association between patients undergoing lumbar spine surgery who message their care team via an electronic patient portal (EPP) post-operatively and emergency department (ED) visits within 90 days of surgery. SUMMARY OF BACKGROUND DATA: Secure patient messaging through electronic patient portals has grown over recent years. Despite its frequent utilization by patients to engage with their care team, its association with clinical outcomes remains unknown in spine surgery. METHODS: This study was approved by our Institutional Review Board. Inclusion criteria were adults who underwent single-stage lumbar spine surgery between January 2016-June 2023. Patients with incomplete information, multi-stage surgeries, and those who died within 90 days of surgery were excluded. Patient sociodemographic, surgical, hospital readmission, and patient-provider engagement data were collected. RESULTS: A total of 13,135 patients were included. A total of 1,711 patients (13%) had a post-operative ED visit, and 4,791 patients (36%) used the patient portal to send a message after surgery. Sending a post-operative patient message after undergoing lumbar spine surgery was associated with an increased likelihood of having an ED visit that does not lead to readmission (1.29 (1.10-1.53), P = 0.002). Patients with high school degrees were more likely to have an ED visit without readmission (1.33 (1.08-1.65), P = 0.008). CONCLUSION: Patients at a higher risk of presenting to the ED post-operatively should be identified and may benefit from additional counseling and access to the care team virtually to limit unnecessary healthcare utilization. Focusing on patients who reach out via EPP messaging post-operatively may be a good target patient group to address first. Future research is needed to investigate the possible health literacy and other socioeconomic barriers affecting these patients so that appropriate, more cost-effective resources can be utilized to avoid clinically unnecessary and costly ED visits.

When Do Patients Achieve PROMIS Milestones After Rotator Cuff Repair?

Background: Given the variability of the questions asked, the Patient-Reported Outcomes Measurement Information System (PROMIS) upper extremity (UE) computer adaptive test (CAT) Version 2.0 item bank aids in the evaluation of rotator cuff repair (RCR) rehabilitation by determining when recovery milestones are possible based on the quality of patient responses at certain time points. Purpose: To assess the time point at which patients with RCR were able to achieve specific functional milestones, determined as positive responses to the 5 most frequently asked items on the PROMIS UE CAT Version 2.0. Study Design: Case series; Level of evidence, 4. Methods: The postoperative PROMIS UE CAT Version 2.0 scores of patients who underwent RCR between February 16, 2017, and July 30, 2019, were reviewed with respect to individual PROMIS item, response, and timing of response. A functional milestone was considered achieved if the patient response was "without any difficulty" or "with a little difficulty" to any of the 5 most frequently asked PROMIS items. The percentage of patients in each monthlong postoperative interval who answered with either response was recorded. The logit generalized estimating equations method was used to analyze the association between milestone achievement for each PROMIS item and predictor variables (age, sex, body mass index, smoking status, race, ethnicity, and employment status). Results: A total of 1131 responses from 371 patients were included. The majority of patients attained milestone achievement on 4 of the 5 most frequently asked PROMIS items at time points ranging from 1 to 5 months postoperatively: "Are you able to carry a shopping bag or briefcase?" (by 1 month), "Are you able to put on and take off a coat or jacket?" (by 3 months), "Are you able to pour liquid from a bottle into a glass?" (by 3 months), and "Are you able to carry a heavy object (over 10 pounds/5 kg)?" (by 5 months). For the item "Are you able to put on a shirt or blouse?", the majority of patients did not achieve the milestone by 1 year. Conclusion: These findings support the application of PROMIS UE CAT Version 2.0 milestone achievement in the shared decision-making process and postoperative monitoring, as patients can use this information to determine when they can return to certain activities and providers can apply these standards to identify patients needing additional clinical support.

Preventing Readmissions for Hepatic Encephalopathy.

Hepatic encephalopathy is a strong predictor of hospital readmissions in patients with advanced liver disease. The frequent recurrence of hepatic encephalopathy and subsequent readmissions may lead to nonreversible organ dysfunction, resulting in a significant decrease of patient quality of life and increase of health care burden costs for patients and facilities. Many of these readmissions for hepatic encephalopathy are preventable. Multidisciplinary patient-centered care throughout the continuum is essential in the management of hepatic encephalopathy. Understanding the patient's daily functions and limitations in the outpatient setting is key to correctly identifying the cause of hospital admission.

Human Cytomegalovirus mRNA-1647 Vaccine Candidate Elicits Potent and Broad Neutralization and Higher Antibody-Dependent Cellular Cytotoxicity Responses Than the gB/MF59 Vaccine.

BACKGROUND: MF59-adjuvanted gB subunit (gB/MF59) vaccine demonstrated approximately 50% efficacy against human cytomegalovirus (HCMV) acquisition in multiple clinical trials, suggesting that efforts to improve this vaccine design might yield a vaccine suitable for licensure. METHODS: A messenger RNA (mRNA)-based vaccine candidate encoding HCMV gB and pentameric complex (PC), mRNA-1647, is currently in late-stage efficacy trials. However, its immunogenicity has not been compared to the partially effective gB/MF59 vaccine. We assessed neutralizing and Fc-mediated immunoglobulin G (IgG) effector antibody responses induced by mRNA-1647 in both HCMV-seropositive and -seronegative vaccinees from a first-in-human clinical trial through 1 year following third vaccination using a systems serology approach. Furthermore, we compared peak anti-gB antibody responses in seronegative mRNA-1647 vaccinees to that of seronegative gB/MF59 vaccine recipients. RESULTS: mRNA-1647 vaccination elicited and boosted HCMV-specific IgG responses in seronegative and seropositive vaccinees, respectively, including neutralizing and Fc-mediated effector antibody responses. gB-specific IgG responses were lower than PC-specific IgG responses. gB-specific IgG and antibody-dependent cellular phagocytosis responses were lower than those elicited by gB/MF59. However, mRNA-1647 elicited higher neutralization and antibody-dependent cellular cytotoxicity (ADCC) responses. CONCLUSIONS: Overall, mRNA-1647 vaccination induced polyfunctional and durable HCMV-specific antibody responses, with lower gB-specific IgG responses but higher neutralization and ADCC responses compared to the gB/MF59 vaccine. CLINICAL TRIALS REGISTRATION: NCT03382405 (mRNA-1647) and NCT00133497 (gB/MF59).