Citations

In this review, we discuss the risks and adverse effects reported for the current Food and Drug Association (FDA)-approved biologics used in the management of asthma, including omalizumab, benralizumab, dupilumab, mepolizumab, reslizumab, and tezepelumab. Our review focuses on the risk of hypersensitivity reactions, infection, and malignancy. Where relevant, we have included information regarding the risk of cardiovascular disease and eosinophilia, and we have included specific information regarding vaccine use among patients receiving the above biologics. We also review currently available data regarding the use of biologics in the context of pregnancy. Our goal is to provide a comprehensive resource for providers utilizing these agents, so that they may adequately counsel patients about the risks of therapy and identify adverse events if they occur.

Abstract Human immune system (HIS) mice constructed in various ways are widely used for investigations of human immune responses to pathogens, transplants and immunotherapies. In HIS mice that generate T cells de novo from hematopoietic progenitors, T cell-dependent multisystem autoimmune disease occurs, most rapidly when the human T cells develop in the native NOD.Cg- Prkdcscid Il2rgtm1Wjl (NSG) mouse thymus, where negative selection is abnormal. Disease develops very late when human T cells develop in human fetal thymus grafts, where robust negative selection is observed. We demonstrate here that PD-1+CD4+ peripheral (Tph) helper-like and follicular (Tfh) helper-like T cells developing in HIS mice can induce autoimmune disease. Tfh- like cells were more prominent in HIS mice with a mouse thymus, in which the highest levels of IgG were detected in plasma, compared to those with a human thymus. While circulating IgG and IgM antibodies were autoreactive to multiple mouse antigens, in vivo depletion of B cells and antibodies did not delay the development of autoimmune disease. Conversely, adoptive transfer of enriched Tfh- or Tph-like cells induced disease and autoimmunity-associated B cell phenotypes in recipient mice containing autologous human APCs without T cells. Tfh/Tph cells from mice with a human thymus expanded and induced disease more rapidly than those originating in a murine thymus, implicating HLA-restricted T cell-APC interactions in this process. Since Tfh, Tph, autoantibodies and lymphopenia-induced proliferation (LIP) have all been implicated in various forms of human autoimmune disease, the observations here provide a platform for the further dissection of human autoimmune disease mechanisms and therapies.

Background Recent technologies enable real‐time 3‐dimensional intracardiac echocardiography (ICE) with the advantages of 2‐dimensional ICE and imaging capabilities of transesophageal echocardiography. The purpose of this study is to evaluate the real‐world, multicenter safety and performance of a novel 3‐dimensional ICE system in a variety of cardiac interventions used in standard clinical practice. Methods This prospective, multicenter, observational, single‐arm study enrolled patients who were scheduled for an invasive cardiac procedure involving guidance with ICE and followed until discharge or ≤48 hours postprocedure. Intracardiac imaging was performed with the 3‐dimensional ICE catheter, VeriSight Pro (Philips Inc.). Fluoroscopy was used in all cases and transesophageal echocardiography was used in some cases. The primary safety end point was device‐related adverse events. The primary efficacy end point included technical success, imaging success, and clinical success. Results Between October 2021 and November 2022, 155 patients were enrolled and screened. Percutaneous interventions performed included atrial septal defect/patent foramen ovale closures, left atrial appendage occlusion, catheter ablations, and valve procedures. No adverse events were related to the device or procedure. The technical, imaging, and clinical success rates were 98.7% (95% CI, 95.4%–99.8%), 96.1% (95% CI, 91.8%–98.6%), 94.8% (95% CI, 91.8%–98.6%), respectively. Overall, the VeriSight Pro ICE image quality was assessed to be “acceptable” or greater in relation to reference image modality among 96.2% (149 of 155) of procedures. Conclusions VeriSight ICE imaging is safe and effective in the guidance of a wide variety of percutaneous cardiovascular procedures and has provided successful and high‐quality imaging of cardiac structures.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Pediatric Central Nervous System Cancers provide multidisciplinary diagnostic workup, staging, and treatment recommendations for diffuse high-grade gliomas and medulloblastomas in children and adolescents. This article summarizes the studies and panel discussion that serve as the rationale for comprehensive care recommendations included in the NCCN Guidelines for Pediatric Central Nervous System Cancers.

ABSTRACT The PIM family of serine/threonine kinases (PIM1, PIM2, and PIM3) are involved in the development of cancer and represent promising therapeutic targets. We investigated the therapeutic potential of targeting PIM kinases in diffuse large B‐cell lymphoma (DLBCL), particularly the activated B‐cell‐like (ABC) subtype, using the pan‐PIM inhibitor AZD1208. We demonstrated that PIM1 and PIM2 are more highly expressed in ABC‐ cells than in germinal center B‐cell‐like (GCB) ‐DLBCL cells, and that ABC‐DLBCL cell lines are more sensitive to PIM inhibition with AZD1208. Transcriptome analysis of ABC‐DLBCL cell lines treated with AZD1208 revealed a downregulation of genes involved in NF‐κB signaling, a crucial pathway for ABC‐DLBCL. We also explored synergistic drug combinations using a high‐throughput screen, which identified BCL2 and glutaminase inhibitors as effective partners for AZD1208, particularly in aggressive ABC‐DLBCL and double‐hit cell lines. The combination of AZD1208 with the clinically available BCL2 inhibitor venetoclax was synergistic in most DLBCL cell lines, and this combination induced apoptosis and reduced levels of AKT and MCL1 proteins. In conclusion, our findings suggested that AZD1208, especially when combined with BCL2 inhibitors like venetoclax, holds promise as a treatment strategy for aggressive lymphomas. These combinations may enable lower doses of PIM inhibitors, leading to increased tolerability and improved anti‐tumor activity in clinical settings. The study also highlighted the potential for targeting PIM kinases in combination with other therapies to overcome drug resistance in DLBCL.

Importance High-quality evidence regarding suppressive valacyclovir treatment in herpes zoster ophthalmicus (HZO) is necessary to guide care. Objective To determine whether suppressive valacyclovir compared with placebo delays the occurrence of new or worsening stromal keratitis (SK), endothelial keratitis (EK), iritis, or dendriform epithelial keratitis (DEK) during 12 months of treatment and if treatment benefit persisted at 18 months (secondary end point). Design, Setting, and Participants The Zoster Eye Disease Study (ZEDS) was a randomized clinical trial conducted in 95 sites from November 2017 to June 2024. Immunocompetent, nonpregnant adults with a history of an HZO rash, documented active keratitis or iritis within 1 year, and an estimated glomerular filtration rate of 45 mL/min/1.73 m 2 or greater were eligible. After determined to be eligible, participants were randomized in 4 strata: age at onset (<60 years vs ≥60 years) and disease duration (<6 months vs ≥6 months). Interventions A total of 12 months of double-masked daily valacyclovir, 1000 mg, or placebo. Main Outcomes and Measures The primary outcome was time to first occurrence within 12 months of new or worsening SK, EK, iritis, or DEK. Results A total of 527 participants (median [IQR] age, 60 [50-68] years; 266 female [50.5%]; 266 in the valacyclovir group; 261 in the placebo group) were randomized in 4 strata; 481 completed 12 months, and 460 completed 18 months. Data were analyzed by intention to treat. At 12 months, primary end points occurred in 86 participants (33%) assigned to placebo and 74 (28%) assigned to valacyclovir, and at 18 months in 104 participants (40%) assigned to placebo and 86 (32%) assigned to valacyclovir. The hazard ratio (HR) of the primary end point at 12 months was 0.77 for participants taking valacyclovir vs placebo (HR, 0.77; adjusted 95% CI, 0.56-1.05; P = .09) and 0.73 at the secondary end point at 18 months (HR, 0.73; adjusted 95% CI, 0.55-0.97; P = .03). There was a reduction of multiple other secondary end points at 12 months (HR, 0.70; 95% CI, 0.52-0.95; P = .02) and 18 months (HR, 0.72; 95% CI, 0.55-0.95; P = .02). Conclusions and Relevance Although the primary outcome did not show a benefit of suppressive valacyclovir treatment, secondary study outcomes showed treatment superiority at the 18-month end point and reduced number of multiple episodes of keratitis or iritis at both 12 and 18 months. These results support consideration of 1 year of suppressive valacyclovir treatment for HZO. Trial Registration ClinicalTrials.gov Identifier: NCT03134196

Importance Evidence regarding suppressive valacyclovir treatment on postherpetic neuralgia is necessary to guide care. Objective To test the hypothesis that suppressive treatment with 1000 mg/d of oral valacyclovir for 12 months reduces the prevalence, severity, and duration of postherpetic neuralgia compared with placebo at 12 and 18 months in participants with herpes zoster ophthalmicus (HZO). Design, Setting, and Participants Multicenter, placebo-controlled randomized clinical trial including 527 immunocompetent, nonpregnant adults with history of HZO rash, documented keratitis, or iritis within 1 year and an estimated glomerular filtration rate of 45 mL/min/1.73 m 2 or greater. The study was conducted at 95 participating sites (in Canada, New Zealand, and the US) from November 2017 to June 2024 and participant visits occurred every 3 months. Intervention Treatment with 1000 mg/d of valacyclovir or placebo for 12 months. Main Outcomes and Measures Prevalence of postherpetic neuralgia, severity as determined by pain score (a score of ≥3 on a scale of 1-10), pain duration (≥3 months after HZO onset), and total daily dose of pain medication. Results Of the 527 participants (490 completed 12 months of treatment and 460 completed 18 months), 73 (14%) had postherpetic neuralgia and were analyzed by age at HZO onset (<60 years or ≥60 years) and disease duration (recent [<6 months] or chronic [≥6 months]). Of the 73 participants with postherpetic neuralgia (34 in the valacyclovir group and 39 in the placebo group), the mean age was 62.4 years (SD, 13.6 years), 59% were female, 5% were Black or African American, and 10% were Hispanic. The prevalence of postherpetic neuralgia at 12 months was not reduced by valacyclovir (12/32 [38%]) compared with placebo (14/35 [40%]) (between-group difference, 2.5% [95% CI, −20.8% to 25.8%]; P >.99). The participants who were younger than 60 years at HZO onset and had a chronic disease duration had lower pain scores in the valacyclovir group (mean score, 0.3 [SD, 0.9]) vs the placebo group (mean score, 0.8 [SD, 1.9]) at 12 months ( P = .045) and at 18 months (mean score, 0.2 [SD, 0.9] vs 1.0 [SD, 2.3], respectively; P = .02). There was a decrease in pain duration in the valacyclovir group at 18 months (mean, 13.6 [SD, 11.4] months) vs the placebo group (mean, 18.7 [SD, 29.5] months) (linear mixed-effects model between-group difference, −3.39 months [95% CI, −6.73 to −0.04 months]; P = .046). The total daily dose of neuropathic pain medication was lower in the valacyclovir group (mean, 271.4 [SD, 593.8] mg/d) vs the placebo group (mean, 363.4 [SD, 592.2] mg/d) at 12 months (linear mixed-effects model P = .006) and at 18 months (mean, 209.0 [SD, 412.8] mg/d vs 286.2 [SD, 577.9] mg/d, respectively; linear mixed-effects model P = .01). Conclusions and Relevance One year of suppressive treatment with valacyclovir was associated with a lower dosage of neuropathic pain medication. Participants in the valacyclovir group, who were younger at HZO onset and had a chronic disease duration, had lower pain scores. These secondary outcomes support consideration of 1 year of suppressive treatment with valacyclovir to reduce dosage of pain medications and pain due to HZO. Trial Registration ClinicalTrials.gov Identifier: NCT03134196

Background Mechanical thrombectomy (MT) is established as an effective treatment for large vessel occlusion strokes, but its efficacy and safety for medium vessel occlusions (MeVOs) remain less clear. This study examines the impact of periprocedural embolization to a new vascular territory (ENT) on clinical outcomes in patients with MeVO stroke treated with MT. Methods A multicenter, retrospective analysis was conducted using the MAD-MT (Multicenter Analysis of primary Distal medium vessel occlusions: effect of Mechanical Thrombectomy) registry, including 2122 patients with MeVO stroke w­ho underwent MT between September 2017 and July 2023. ENT was defined as filling defects in previously unaffected territories, excluding embolization near the original occlusion, observed on final angiographic runs after retrieval of the primary thrombus. The associations between ENT, procedural variables, and 90-day clinical outcomes were evaluated, including functional independence (modified Rankin Scale (mRS) scores of 0–2), excellent outcomes (mRS 0–1), mortality, and hemorrhagic complications. Results ENT occurred in 2.9% (63/2122) of patients. Longer onset-to-arterial puncture time (adjusted OR 1.03; 95% CI 1.01 to 1.05; P=0.002) and a greater number of passes (adjusted OR 1.15; 95% CI 1.01 to 1.32; P=0.032) were associated with increased ENT risk, while excellent recanalization (thrombolysis in cerebral infarction (TICI) scale score 2c–3) was associated with reduced ENT risk (adjusted OR 0.41; 95% CI 0.23 to 0.72; P=0.002). ENT was not associated with poorer functional independence, mortality, or hemorrhagic complications. Conclusions ENT during MT for MeVO stroke occurs infrequently and does not significantly affect the clinical outcomes. These findings suggest ENT risk should not deter clinicians from performing MT in patients with MeVO. Further prospective studies are needed to validate these results.

Objectives While extracorporeal shockwave therapy (ESWT) may be an efficacious adjunctive treatment option for musculoskeletal injuries, current research is limited by significant heterogeneity within treatment protocols. This study aims to establish international expert consensus recommendations on ESWT terminology, parameters, procedural considerations, contraindications and side effects in the application of ESWT to sports injuries. Methods A systematic literature search was performed on the use of ESWT for musculoskeletal and sports medicine injuries to identify potential panellists, followed by the development of a steering committee-led questionnaire. A three-stage, modified Delphi questionnaire was provided to a panel of 41 international clinical and research experts across 13 countries. Panellists had the opportunity to suggest edits to existing statements or recommend additional statements in Round 1. Consensus was defined as≥75% agreement. Results All 41 panellists completed Rounds 1, 2 and 3. Consensus was reached on 69/118 statements (58.5%), including recommendations on terminology and fundamental concepts, indications for use, procedural aspects for tendinopathy and bone pathologies, treatment correlations with imaging, periprocedural and postprocedural considerations, absolute and relative contraindications and potential side effects. Of the 49 statements that did not reach consensus, 17/49 (34.7%) were related to procedural aspects of bone pathology. Conclusion This international panel presents recommendations on ESWT terminology, indications and treatment considerations to guide ESWT use and decision-making by sports medicine clinicians. While our panel supported the use of ESWT in the treatment of bone pathologies, certain procedural aspects of ESWT specific to these injuries did not reach consensus and require further investigation.

Background Intra-articular corticosteroid (IACS) injection and peri-articular corticosteroid injection are commonly used to treat musculoskeletal conditions. Results vary by musculoskeletal region, but most studies report short-term benefit with mixed results on long-term relief. Publications showed adverse events from single corticosteroid injections. Recommended effective doses were lower than those currently used by clinicians. Methods Development of the practice guideline for joint injections was approved by the Board of Directors of the American Society of Regional Anesthesia and Pain Medicine and the participating societies. A Corticosteroid Safety Work Group coordinated the development of three guidelines: peripheral nerve blocks and trigger points; joints; and neuraxial, facet, and sacroiliac joint injections. The topics included safety of the technique in relation to landmark-guided, ultrasound-guided, or radiology-aided injections; effect of the addition of the corticosteroid on the efficacy of the injectate; and adverse events related to the injection. Experts on the topics were assigned to extensively review the literature and initially develop consensus statements and recommendations. A modified version of the US Preventive Services Task Force grading of evidence and strength of recommendation was followed. A modified Delphi process was adhered to in arriving at a consensus. Results This guideline focuses on the safety and efficacy of corticosteroid joint injections for managing joint chronic pain in adults. The joints that were addressed included the shoulder, elbow, hand, wrist, hip, knee, and small joints of the hands and feet. All the statements and recommendations were approved by all participants and the Board of Directors of the participating societies after four rounds of discussion. There is little evidence to guide the selection of one corticosteroid over another. Ultrasound guidance increases the accuracy of injections and reduces procedural pain. A dose of 20 mg triamcinolone is as effective as 40 mg for both shoulder IACS and subacromial subdeltoid bursa corticosteroid injections. The commonly used dose for hip IACS is 40 mg triamcinolone or methylprednisolone. Triamcinolone 40 mg is as effective as 80 mg for knee IACS. Overall, IACS injections result in short-term pain relief from a few weeks to a few months. The adverse events include an increase in blood glucose, adrenal suppression, detrimental effect on cartilage lining the joint, reduction of bone mineral density, and postoperative joint infection. Conclusions In this practice guideline, we provided specific recommendations on the role of corticosteroids in joint, bursa, and peritendon injections for musculoskeletal pain.