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Background: Hypoplastic left heart syndrome (HLHS) is defined as “a spectrum of congenital cardiovascular malformations with normally aligned great arteries without a common atrioventricular junction, characterized by underdevelopment of the left heart with significant hypoplasia of the left ventricle including atresia, stenosis, or hypoplasia of the aortic or mitral valve, or both valves, and hypoplasia of the ascending aorta and aortic arch”. Without treatment, HLHS is usually lethal in the neonate. Many hypotheses have been advanced to explain the etiology of HLHS; however, no single theory appears to fully explain the phenotypic variability seen in HLHS. Furthermore, many of these theories offer no explanations regarding the precipitating events which lead to the development of HLHS. Objective: This review considers and critically evaluates the strengths and weaknesses of the leading theories proposed to explain the pathogenesis of HLHS—including hemodynamic disturbances, primary myocardial structural defects, valvar malformations, and genetic or epigenetic alterations that may provoke developmental and anatomic abnormalities. After presenting each model, we propose a novel, comprehensive, and data-driven framework which may assist researchers in developing models for the pathogenesis of the various subtypes of HLHS. Methods: Key findings from human fetal imaging, histopathology, genetic studies, and animal models were considered, as well as the hypothetical contribution of each in observed HLHS phenotypes. The rationales for these findings as causal factors initiating individual HLHS patterns, as well as how they might contribute to HLHS in general, were critically analyzed. Results: The flow theory is strongly supported by animal models and in utero interventions that demonstrate the impact of altered hemodynamics on cardiac morphogenesis. However, the flow theory fails to identify initial causes of disturbed flow or related histological features of HLHS like endocardial fibroelastosis. The myocardial and valve-first models suggest an important role in developmental defects, but do not necessarily have a strong experimental basis that provides explanations for how they mediate HLHS. Genetic studies in patients with HLHS have identified several candidate causal mutations. However, such genetic causes of HLHS exhibit incomplete phenotypic penetrance and clinical impact. A multifactorial framework attempts to integrate these diverse mechanisms and may provide the most coherent explanation that can accommodate the heterogeneity and variable presentation of HLHS. Such a framework may identify multiple forces that drive disease but does not provide useful pathways for future research about HLHS. Conclusions: No single hypothesis has fully explained how HLHS is initiated, progresses, and presents with the clinical conditions that are encountered by cardiac surgeons and cardiologists. The most current models suggest that the spectrum of HLHS reflects acomplex interaction between genetic susceptibility, flow-dependent cardiac remodeling, and environmental factors in utero. A multifactorial model integrates these diverse mechanisms and may provide the most coherent explanation for the various phenotypic variations in HLHS. Based on our analysis of the most current data and the strengths and weaknesses of the current theoretical frameworks, we propose a novel research strategy aimed at identifying specific cardiac progenitor cell populations whose dysregulation may represent a unifying explanation for the etiology of the various phenotypes of HLHS. Based on the arguments made throughout this manuscript that evaluate the various genetic, structural, and hemodynamic models of initiation of disease, we believe that the significant phenotypic variability across the spectrum of HLHS (i.e., the different anatomic subtypes for “classic” HLHS) most likely reflects different underlying etiologies and mechanisms. At the very least, it is very likely that the timing of the insult is critical in determining anatomic subtype. Based on the published data and the arguments within this manuscript, it seems naive to think that there is a single unifying mechanism explain all forms of HLHLS.

Over the past three decades, the emergence of recombinant antibodies has positioned them as the fastest-growing class of therapeutic proteins and as well as crucial reagents for both diagnostics and specific research applications. The industrial production of most therapeutic antibodies currently relies on mammalian cell lines, primarily Chinese Hamster Ovary (CHO) cells, which remain the gold standard in biopharmaceutical manufacturing due to their exceptionally high production yields, robustness, regulatory acceptance, and consistent product quality. Nevertheless, new approaches using specifically adapted expression systems are emerging. These new host organisms enable the production of antibodies with posttranslational modifications that closely resemble those found in the human system, without the need for animal-derived source materials. For diagnostic and research purposes, a broad range of production systems has been developed. These include Gram-negative and Gram-positive bacteria, yeasts, filamentous fungi, insect cell lines, and transgenic plants. Additionally, smaller single domain antibodies and bispecific fragments that do not require glycosylation can be successfully produced in bacteria for therapeutic applications. Some of these molecules have already been approved by regulatory authorities in the European Union and the United States, and several more are currently in clinical trials. This review therefore focuses on the broad and evolving landscape of recombinant antibody production systems and their applicability across various fields.

Expert consensus recommendations from 21 academic centers were established for appropriate radiography utilization at 12 potentially low-yield anatomic sites through a multidisciplinary process endorsed by six major American medical societies.

Objective(s): To (1) report on the long-term recurrence rate of surgically managed pleomorphic adenoma (PA) and (2) assess long-term surgical outcomes after parotidectomy Methods: Cross-sectional survey of all patients with a pathologic diagnosis of PA who underwent surgical management in a tertiary care center from 01/1997 to 12/2023 and had access to an electronic patient portal. Surveys were delivered via electronic patient portal or phone call with 6 questions to assess recurrence and long-term surgical outcomes. Time to first recurrence and recurrence free survival were analyzed using a Kaplan-Meier curve. Results: Seven hundred-forty-five patients met inclusion criteria and received the survey, with a 56% response rate (n = 420). The clinical median follow-up length was 51 days, which extended to a median length of 6.2 years following the survey. The median change in follow-up length was 5.37 years ( P < .001). The recurrence rate was 1% at 5 years, with a median time to first recurrence of 7.54 years. 13% and 9% of responders reported facial asymmetry and incisional cosmetic concerns, respectively. 33% of patients reported experiencing Frey syndrome, which increased from 5.2% of survey responders with documented Frey syndrome at their original post-operative assessment. Conclusion: Long-term assessment of PA outcomes confirms low recurrence rates, suggesting regular surveillance of recurrence is likely unnecessary. Complaints of Frey syndrome increased in frequency with longer term follow-up, which should be considered during patient counseling. Level of Evidence: 3

IgG4-related disease (IgG4-RD) is a relatively recently described condition whose etiology and pathophysiology remain unclear. Histopathological features include dense lymphoplasmacytic tissue infiltration with numerous IgG4-positive plasma cells, storiform fibrosis, and obliterative phlebitis. Most individuals with IgG4-RD are asymptomatic; however, the disease can affect nearly any organ, leading to a wide range of clinical presentations. The four most common patterns are hepatopancreatobiliary disease, systemic disease, head and neck disease, and retroperitoneal disease. Diagnosis is challenging due to diverse organ involvement and is most often confirmed by biopsy. Elevated serum IgG4 concentration can support the diagnosis, though high IgG4 levels are neither highly sensitive nor specific for IgG4-RD. Immunohistochemical IgG4 staining is crucial, especially in patients without elevated serum IgG4. Differential diagnosis is necessary, as IgG4+ plasma cell infiltration is also seen in inflammatory and malignant conditions. First-line treatment consists of glucocorticoids (prednisone), although favorable outcomes have also been achieved with rituximab. Prognosis varies: the disease may resolve spontaneously or follow a relapsing–remitting course. If left untreated or undertreated, IgG4-RD can cause irreversible organ damage and even death. Finally, correlations have been made between IgG4 and different allergic reactions.

Introduction Lynch syndrome (LS) is a hereditary cancer syndrome that increases risk for colorectal and other cancers. We hypothesize that vaccines against tumor-associated antigens CEA, MUC1, and brachyury, simultaneously delivered in an adenovirus serotype-5 vector (Tri-Ad5) combined with the immune-enhancing IL-15 receptor superagonist nogapendekin-alfa-inbakicept (NAI) will reduce the incidence of colorectal neoplasms in LS carriers. Methods In this ongoing phase IIB double-blind placebo-controlled trial, two open-label safety phases (SPs) assessed safety of Tri-Ad5 alone (SP1, n=10) and with added NAI (SP2, n=10). A randomized controlled trial (RCT) follows the SPs. After baseline colonoscopy, vaccine dosing occurs at weeks 0, 4 and 8; Tri-Ad5 alone in SP1 and Tri-Ad5 plus NAI in SP2, with identical boosters at Week 52. The RCT phase participants (n=138) were randomized to receive Tri-Ad5 plus NAI or placebo. All participants complete colonoscopy at Weeks 52 and 104 for assessment of the primary endpoint: cumulative colorectal neoplasm incidence. Secondary endpoints include safety, tolerability, and immunogenicity. Results All 20 SP participants (median age 57.5 (range 42–75), 70% female, 15% minority) received all prime and booster series. SP1 participants reported 139 adverse events (AEs) and SP2 participants reported 178. AEs were predominantly grade 1; no treatment-related serious adverse events (SAEs) occurred. The most common treatment-related AEs were reactogenic events including grade 3 rash (without skin necrosis or breakdown) at NAI injection site (100% of SP2 participants). The RCT phase (n=138) recently completed accrual. Discussion In LS carriers without active cancer, the combination of Tri-Ad5 + NAI was well-tolerated; the RCT phase is ongoing. Clinical Trial Registration https://clinicaltrials.gov/study/ , identifier NCT05419011.

ABSTRACT Aims We aimed to examine the association between GLP‐1 RA use and suicidal ideation or behaviours through a systematic review of observational studies. Materials and Methods A comprehensive search of MEDLINE, PubMed, EMBASE, CINAHL and PsycINFO was conducted from database inception through December 11, 2025. Observational studies investigating suicidal ideation, suicide attempts or complete suicide among adults using GLP‐1 RAs were included. Eligibility screening, data extraction and risk of bias assessments were performed independently and in duplicate, with disagreements resolved by a third reviewer. Results Forty‐three studies were included. Findings varied by study design. Some case reports suggested a temporal relationship between GLP‐1 RA use and suicidal ideation. Cross‐sectional studies and case–control studies identified a negative association between GLP‐1 RAs and suicide attempts. Pharmacovigilance and cohort studies showed more mixed results, with some studies identifying a positive association between semaglutide or liraglutide and suicidal ideation, while others paradoxically reported a negative association with suicidal behaviours (i.e., attempts and intentional self‐harm) or completed suicide. Conclusions While evidence does not support GLP ‐1 RAs as a causative agent for suicidality, due to multiple risk factors in this population, clinicians should routinely assess mental health status before and during GLP ‐1 RA treatment regardless of indication. Importantly, a history of concurrent mental health conditions should not preclude use of a GLP ‐1 RA ; rather, individual patient factors should be accounted for when making prescribing decisions.

Abstract Purpose This analysis aims to provide a comprehensive overview of lung transplantation trends in the United States from January 1, 1988, through January 31, 2025. By examining key variables such as recipient ABO blood group, donor type (deceased or living), demographic factors, and geographic distribution, the goal is to highlight the evolution and current state of lung transplantation practices. Methods Data were obtained from the Organ Procurement and Transplantation Network (OPTN), encompassing all reported lung transplants during the specified time period. Relevant metrics included the number of transplants per year, recipient characteristics (blood type, race/ethnicity, gender, and age), donor type (deceased versus living), and state-level transplant volumes. Simple descriptive statistics (e.g., frequencies and percentages) were used to identify trends and capture the distribution of transplants among different demographic groups and geographic regions. Results A total of 55,435 lung transplants were performed in the United States between 1988 and early 2025. The vast majority (over 99%) utilized deceased donors, underscoring the limited role of living-donor lobar transplantation, with only 253 procedures reported nationally. Among recipients, ABO blood group O was the most common (∼45%), followed by group A (∼40%), group B (∼11%), and group AB (∼4%). Male recipients represented approximately 57% of transplants, while females accounted for 43%. Regarding race/ethnicity, White non-Hispanic patients constituted roughly 80% of all recipients, with Black non-Hispanic (8%) and Hispanic/Latino (8%) recipients forming smaller but significant proportions. Age distribution data revealed that individuals aged 50 to 64 years received nearly half of all lung transplants, and those over 65 years composed about a quarter of total recipients, reflecting a gradual shift in acceptance criteria favoring older adults. Geographically, California reported the highest volume of lung transplants, attributable to its large population and multiple high-volume transplant centers, while other states such as Florida, Ohio, North Carolina, and Missouri also demonstrated notable activity. Conclusion Lung transplantation in the United States has witnessed substantial expansion in both volume and scope since 1988, with the majority of procedures involving deceased donor lungs. A small number of living-donor lung transplants, while demonstrating innovative clinical possibilities, remains limited. The demographic profile of recipients continues to shift, evidenced by a growing proportion of older adults and a predominance of ABO type O and White, non-Hispanic recipients. Despite these advancements, persistent gaps in access, particularly among underrepresented racial and ethnic groups, highlight the need for further refinement in organ allocation policies and broader support services. This abstract is funded by: None

Abstract Background Lung transplantation remains the accepted treatment modality of choice for life-threatening advanced lung disease due to established benefits of improving survival and functional status of the patients. However, the annual mortality of lung waitlist candidates remains high, reflecting ongoing donor-recipient mismatches and prolonged wait times. Modalities such as extracorporeal membrane oxygenation (ECMO) have been effectively used as a “bridge to transplant” (BTT) in high-risk patients on waitlist. Objective To evaluate trends in ECMO utilization, waitlist dynamics, and outcomes among lung transplant candidates between 2018 and 2024, with emphasis on the use of ECMO as a bridge to transplantation. Methods We conducted a retrospective chart review of all ECMO runs performed between 2018 to 2024 at the Mayo Clinic Florida Hospital. Among these, patients who underwent evaluation for lung transplantation were identified, and their waitlisting patterns, transplant outcomes, and peri-transplant ECMO status were described. Results Between 2018 and 2024, a total of 348 ECMO runs were recorded among 293 patients. Annual ECMO runs increased steadily from 17 in 2018 to 83 in 2024 (2019: 33, 2020: 30, 2021: 61, 2022: 56, 2023: 68, 2024: 83). Out of these patients, 142 underwent evaluation for lung transplantation and 133 (93.67%) were placed on the waitlist. Among waitlisted patients, 105 (78.9%) were listed before ECMO initiation, 23 (17.3%) during ECMO, and 5 (3.8%) after decannulation. Waitlist outcomes included 116 (87.2%) transplanted, 16 (12.0%) deaths before transplant, and 1 (0.8%) clinical improvement precluding transplant. Among 116 transplanted patients, 36 patients (31.03%) received ECMO as a bridge to lung transplantation. The annual patients bridged with ECMO demonstrated a progressive rise: 1 (2019), 3 (2020), 9 (2021), 6 (2022), 9 (2023), and 8 (2024). Among these 36 patients, 29 (80.56%) remained on ECMO support in the immediate post-transplant period. At the latest follow-up, mortality among BTT recipients was 9 (25%). Conclusion ECMO utilization has expanded substantially over the past several years reflecting its expanding role in supporting critically ill patients. There has been increased utilization of ECMO as a bridge to lung transplantation in order to support high risk candidates awaiting donor organs. The post-transplant mortality among BTT recipients was 25%, which highlights the importance of peri-transplant management to optimize long-term outcomes in this high-risk cohort. This abstract is funded by: None

Abstract Rationale Secondhand exposure to electronic nicotine products is driven by exhaled emissions. Eliminating heat and combustion may reduce exhaled toxic carbonyls. Methods In a 4-day within-subject crossover, six adults each used four devices after 24-hour abstinence: an NHNC nebulization device (Bluesky), a coil-heated ENDS (RELX), a heated-tobacco device (IQOS), and a heated aerosol device (Marlboro). For each condition, paired pre-use exhaled blank and post-use exhaled samples were collected; 50 L of exhaled breath was captured post-use. Nicotine and 12 carbonyls were quantified (DNPH/activated-carbon with HPLC). Primary endpoint: within-subject change (Δ, post-pre) in total carbonyls (μg/50 L). Secondary: Δ acetaldehyde and Δ acrolein. Results The exhaled carbonyls(within-subject change, post-pre) in total differed markedly across devices: Bluesky (non-heated, non-combustion; NHNC) 0.85 ± 6.99, RELX 4.41 ± 2.58, IQOS 62.38 ± 21.77, Marlboro 80.73 ± 20.24 (p = 0.0015). Bluesky had significantly lower total exhaled carbonyls than IQOS (p = 0.0077) and Marlboro (p = 0.0021, μg/50 L; mean±SD), with a nonsignificant trend versus RELX (p = 0.945). For acetaldehyde, Bluesky was lower than all three (Bluesky 0.20 ± 0.16 vs. RELX 1.93 ± 0.86, p = 0.016; vs IQOS 43.08 ± 16.70, p = 0.0044; vs Marlboro 65.40 ± 13.69, p = 0.00025, μg/50 L). For acrolein, average exhaled volume was 0.54 ± 6.94 (Bluesky), 1.35 ± 2.05 (RELX), 7.94 ± 6.07 (IQOS), and −1.86 ± 5.09 (Marlboro); pairwise differences vs Bluesky were not significant after correction (p ≥ 0.37, μg/50 L). Conclusions In a controlled, within-subject comparison using exhaled breath as a proxy for secondhand aerosol, the NHNC nebulization device (Bluesky) produced near-zero average increment in total exhaled carbonyls, whereas heated devices—particularly heated-tobacco—showed order-of-magnitude higher increases. These descriptive data support the hypothesis that removing heat and combustion from nicotine aerosolization can materially reduce exhaled carbonyl burden relevant to secondhand exposure. Larger, randomized studies with standardized capture and enhanced nicotine quantification are warranted. This abstract is funded by: Pneuma Respiratory.Inc