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ABSTRACT Background Prompt detection and intervention are crucial for improving outcomes in acute invasive fungal rhinosinusitis (AIFS). Diagnostic prediction models assist in risk‐stratification, but their accuracy requires testing through external validation. This study aims to validate a previously published diagnostic prediction model for AIFS in an independent cohort. Methods A retrospective chart review was conducted at a tertiary care center (2008–2023) to identify patients with an otolaryngology consult for suspected AIFS. Of 65 patients identified, 11 (16.9%) were diagnosed with AIFS based on histopathology. Risk was calculated using Yin et al.’s predictive model. Predictive performance was assessed by calibration and discrimination. Results Patients had significantly higher rates of diabetes (46.2% vs. 26.1%, p = 0.002), long‐term steroid use (60% vs. 28.2%, p < 0.0001), and solid organ transplantation (38.5% vs. 8.5%, p < 0.001), compared with the development cohort, with conversely lower rates of hematologic malignancy (29.2% vs. 58.7, p < 0.001) and neutropenia (19.4% vs. 41%, p = 0.001). Despite these differences, both the three‐variable (C‐index: 0.844; 95% CI, 0.736–0.952) and four‐variable models (C‐index: 0.963; 95% CI, 0.919–1) showed adequate discrimination. Both models exhibited slight overprediction of risk, with a calibration‐in‐the‐large predicted risk of 24.1% (95% CI, 13.68–34.46) for the three‐variable model and 24.2% (95% CI, 13.76–34.57) for the four‐variable model. Calibration plots confirmed overprediction. Conclusion The AIFS diagnostic model demonstrates acceptable discrimination and calibration on external validation, with generalizability to patients with different comorbidities. Larger studies are recommended to further test the model's predictive performance and clinical applicability.

Abstract Background One in five adults aged 40 will develop heart failure (HF) during their lifetime. Risk factors (e.g., hypertension, diabetes mellitus, coronary artery disease, etc.) lead to structural and functional changes in cardiomyocytes, resulting in HF. At the cellular level, these changes consist of mis/over‐expression of genes that regulate cardiac identity (e.g., CamK2δ, PKC, Stat3, etc.). The current paradigm for treating HF is pharmacological or device‐based intervention; however, with few exceptions, the condition worsens with time. We are proposing to implement a change in HF treatment, shifting from a drug‐centric system to a cardiac target‐specific molecular approach that would reverse hypertrophy and adverse remodelling of affected cardiomyocytes. Methods A cardiomyocyte targeting peptide (CTP) was reversibly linked to miRNA106a for delivery to a mouse model of HF. Reversal of morphological, signalling, and physiological HF parameters was measured. Additionally, CTP‐miRNA106a was introduced into a human cardiomyocyte cell line to identify mechanism(s) at play for reversing HF characteristics (e.g., hypertrophy). Results Bio‐distribution studies showed that intravenously injected CTP‐miRNA106 delivered its cargo specifically to the heart within 30 min, followed by clearance of CTP from the heart to the kidneys, and to a lesser extent, the liver by 35 h with persistence of miRNA106a in cardiomyocytes until day 7 (the latest tested time‐point). CTP‐miRNA106a reversed angiotensin2/isoproterenol‐induced hypertrophy in 90% of the treated mice. We also identified two potential HF intracellular signalling pathways/mechanisms (PLCβ1/PKC/IP3 and NF‐κB) targeted by CTP‐miRNA106a that could benefit many pathophysiologies underlying HF, including inflammation. Conclusions CTP‐miRNA106a, a first‐of‐a‐kind cardiac‐specific drug, downregulates genes involved in cardiac hypertrophy and inflammation through the PLCβ1 and CamKIIδ kinase pathways. CTP delivery of miRNA106a cargo is specific to cardiomyocytes both in vitro and in vivo, and once delivered, many HF parameters, including hypertrophy, are reversed. Key points Cardiac Targeting Peptide (CTP) delivers, specifically to the heart, reversibly linked miRNA106a. MiRNA106a targets genes in various pathways known to cause heart failure when they are over/hyper activated returning their expression to normal levels. In vivo analyses using a mouse heart failure model resulted in reversal of heart failure parameters in 19/20 mice.

BACKGROUND: Hemorrhoidal disease and immunosuppression are prevalent. Management of hemorrhoidal disease in this patient population is challenging. Most societies recommend conservative management due to the presumed risks of morbid complications, including sepsis and impaired healing. Data on the risks of office-based and operative procedures in immunocompromised patients are scant. OBJECTIVE: To evaluate postoperative outcomes after both office-based procedures and operative intervention for hemorrhoidal disease in immunocompromised patients. DESIGN: Retrospective medical record review. SETTINGS: Single-center, tertiary referral center. PATIENTS: Adult patients were included who had hemorrhoidal disease and primarily medication-induced immunosuppression and were undergoing an office-based procedure or operative intervention for hemorrhoidal disease while on immunosuppression at Mayo Clinic in Rochester between 2010 and 2023. MAIN OUTCOME MEASURES: The primary outcome was the development of infectious complications or wound complications. RESULTS: Fifty-five immunocompromised patients, with a median age of 60 years, underwent a total of 68 hemorrhoidal procedures during the study time frame. All patients had immunosuppression induced by medication, except for 1 patient with bone marrow failure syndrome. The most common reason for immunosuppression was rheumatoid arthritis, followed by prior kidney transplant. The most common medications were chronic corticosteroids and methotrexate in more than one-third of patients each. Of 68 total interventions, hemorrhoidectomy (32%) and excision of a thrombosed hemorrhoid (26%) were the 2 most common operations performed. Sixteen adverse events were reported in 14 patients (25%). Three cases of postoperative cellulitis were documented after thrombosed external hemorrhoid excision, hemorrhoidopexy, and Whitehead hemorrhoidectomy. No postoperative intravenous antibiotics were administered. No cases of pelvic sepsis were documented. LIMITATIONS: The retrospective nature of the study and the heterogeneity of the study population. CONCLUSIONS: These data suggest that office-based and surgical procedures are safe and feasible in patients with immunosuppression. See Video Abstract . SEGURIDAD DE LOS PROCEDIMIENTOS PARA EL TRATAMIENTO DE HEMORROIDES EN PACIENTES INMUNODEPRIMIDOS: LA EXPERIENCIA DE LA CLÍNICA MAYO ANTECEDENTES: La enfermedad hemorroidal y la inmunosupresión son prevalentes. El tratamiento de la enfermedad hemorroidal en esta población de pacientes es difícil. La mayoría de las sociedades recomiendan un tratamiento conservador debido a los riesgos presuntos de complicaciones mórbidas, como sepsis y alteración de la cicatrización. Los datos sobre los riesgos de los procedimientos ambulatorios y quirúrgicos en pacientes inmunodeprimidos son escasos. OBJETIVO: Evaluar los resultados posoperatorios tras procedimientos ambulatorios y cirugía para la enfermedad hemorroidal en pacientes inmunodeprimidos. DISEÑO: Revisión retrospectiva de historias clínicas. ENTORNO: Centro terciario de referencia único. PACIENTES: Pacientes adultos con enfermedad hemorroidal e inmunosupresión inducida principalmente por medicamentos que se sometieron a un procedimiento ambulatorio o a una intervención quirúrgica para la enfermedad hemorroidal mientras estaban en tratamiento inmunosupresor en la Clínica Mayo de Rochester entre 2010 y 2023. PPRINCIPALES MEDIDAS DE RESULTADO: El resultado principal fue la aparición de complicaciones infecciosas o complicaciones de la herida. RESULTADOS: Cincuenta y cinco pacientes inmunodeprimidos, con una mediana de edad de 60 años, se sometieron a un total de 68 procedimientos hemorroidales durante el periodo de estudio. Todos los pacientes presentaban inmunosupresión inducida por medicación, excepto uno con síndrome de insuficiencia medular. La causa más frecuente de inmunosupresión fue la artritis reumatoide, seguida de un trasplante renal previo. Los medicamentos más frecuentes fueron los corticosteroides crónicos y el metotrexato, en más de un tercio de los pacientes. De las 68 intervenciones totales, la hemorroidectomía (32 %) y la extirpación de una hemorroide trombosada (26 %) fueron las dos operaciones más comunes realizadas. Se notificaron 16 eventos adversos en 14 (25 %) pacientes. Se documentaron tres casos de celulitis posoperatoria tras la extirpación de una hemorroide externa trombosada, una hemorroidopexia y una hemorroidectomía de Whitehead. No se administraron antibióticos intravenosos postoperatorios. No se documentaron casos de sepsis pélvica. LIMITACIONES: El carácter retrospectivo del estudio y la heterogeneidad de la población estudiada. CONCLUSIONES: Estos datos sugieren que los procedimientos ambulatorios y quirúrgicos son seguros y viables en pacientes con inmunosupresión. (AI-generated translation )

Background: Transfusion has a persistent low risk of transfusion-transmitted infection and transfusion-associated graft- versus -host disease that may be addressed using pathogen reduction. The Red Cell Pathogen Inactivation (ReCePI) trial tested whether amustaline/glutathione pathogen-reduced red cells are noninferior to conventional transfusions for support of acute surgical blood loss. Methods: A phase 3, double-blinded, noninferiority trial randomized cardiac or thoracic–aorta surgery patients with increased risk of red cell transfusion to receive pathogen-reduced or conventional red cells during and for 7 days postsurgery. The primary endpoint was the proportion of patients with acute kidney injury (AKI), which is defined as an increase from baseline of greater than or equal to 0.3 mg/dl serum creatinine within 48 h of surgery. Noninferiority was claimed if the upper bound 95% CI of the treatment difference was less than half (50%) of the observed conventional arm incidence. Adverse events and treatment-emergent red cell antibodies were assessed for 28 and 75 days, respectively. Results: A total of 581 subjects were randomized, and 321 (55%) were transfused with study red cells. Transfused subjects in both arms had similar baseline demographics, medical histories, hemoglobin levels, and surgical procedures. Hemoglobin day 3 nadir levels (8.6 g/dl [7.8 to 9.2] in the pathogen-reduced arm; 8.4 g/dl [7.8 to 9.3] in the conventional arm; P = 0.52) were comparable. Incidence of AKI by 48 h was 46 of 157 (29.3%) in the pathogen-reduced arm and 45 of 161 (28.0%) in the conventional arm (treatment difference, 0.7%; 95% CI, −8.9 to 10.4%; noninferiority margin, 14.0%; P = 0.001 for noninferiority). AKI within 7 days by Kidney Disease Improving Global Outcomes staging criteria was not different (59 of 159 [37.1%] in the pathogen-reduced arm; 55 of 162 [34.0%] in the conventional arm; P = 0.53), but stage III was more common in the pathogen-reduced arm (pathogen-reduced arm, 15 of 159 [9.4%]; conventional arm, 7 of 162 [4.3%]; P = 0.075). Of 159 pathogen-reduced red cell recipients, 5 (3.1%) developed specific, low-titer antibodies without evidence of hemolysis. Conclusions: The incidence of AKI in recipients of pathogen-reduced red cells was noninferior to conventional red cell transfusion. Treatment-emergent antibodies were uncommon and not clinically significant.

Background & Aims: Liver transplantation (LT) remains the only cure for severe polycystic liver disease (PLD). However, LT indications and strategies vary across Europe, resulting in (unwanted) practice variation and unequal access to care for patients with PLD. This study aimed to (1) identify existing PLD-specific LT criteria across European countries, (2) assess which criteria are considered relevant by specialist, and (3) map the variation in liver-kidney transplant strategies among patients with autosomal dominant polycystic kidney disease (ADPKD). Methods: National PLD-specific LT criteria were collected, and if unavailable ERN RARE-Liver representatives from that country were asked to provide information. An online survey was conducted amongst hepatologists, LT surgeons, and nephrologists managing patients with PLD. The survey assessed relevant LT indications/listing requirements, clinical case evaluations, and explored preferences for liver-kidney transplantation in patients with ADPKD. Results: Defined LT criteria for patients with PLD were available in only 8 of the 17 assessed countries and showed substantial variation. Sixty-nine clinicians (43 hepatologists, 15 surgeons, 11 nephrologists), predominantly from LT centers (75.4%), completed the survey. Key LT indications were recurrent liver cyst infections (78.3%), significant impaired quality of life (75.4%), and severe malnutrition (75.4%). In ADPKD simultaneous liver-kidney transplantation (SLK) was preferred by 40.4% of respondents, primarily due the favorable immunological profile (47.6%) and prevention of renal failure (33.3%). In contrast, those favoring a liver-first approach (30.8%), followed by sequential kidney transplant, highlighted the potential harm to the kidney graft during SLK (62.5%). Conclusions: Uniform PLD-specific LT criteria in Europe are lacking. While recurrent liver cyst infections, decreased quality of life, and malnutrition are widely recognized as crucial LT indications, they are insufficiently reflected in existing criteria, contributing to unequal access to LT. Moreover, considerable variation exists in liver-kidney transplantation for ADPKD patients, with a current lack of evidence to support one approach over another.

Fundamental to medical education, gross anatomy first introduces medical students to human mortality, often provoking stress. Sense of purpose, a key aspect of well-being, may serve as a protective factor. We studied students’ sense of purpose during an anatomy course, examining its links to performance, spirituality, and belief in an afterlife. Fifty medical students who took a 7-week gross anatomy course in 2022 or 2023 completed the Life Engagement Test at the beginning, middle, and end of the course. We collected other data including demographics, religious/spiritual beliefs, and previous exposure to body donors. Practical and final examinations assessed course performance. Strong sense of purpose at the three measurement points was positively correlated with practical exam performance (r = 0.40, P = .004; r = 0.44, P = .003; r = 0.30, P = .047, respectively) but not National Board of Medical Examiners’ anatomy subject exam performance. Staunch believers and non-believers in an afterlife maintained a stable sense of purpose, while students uncertain about the afterlife experienced a decline from the beginning to the middle of the course and even more to the end ( P = .046; P = .008, respectively). These students also had significantly lower practical examination performance as compared to other students (95% CI [−10.84, −0.52]). In conclusion, a strong sense of purpose predicts better performance in a 7-week anatomy course. Both believers and non-believers in an afterlife do well, but students wavering in their beliefs experience a declining sense of purpose and lower grades. Supporting these students when they confront human mortality, including in other contexts such as palliative care/hospice settings, may be beneficial.

Increases in aortic wave reflection and aortic pulsatile load are known contributors to hypertension, cardiovascular risk, and pulsatile stress to end organs. To our knowledge, this is the first study to demonstrate that evening binge alcohol consumption increases heart rate, aortic pulsatile load, and aortic augmentation index the following morning when compared with fluid control. These findings highlight the deleterious overnight cardiovascular effects of binge alcohol consumption in young adults.

Abstract Gastrointestinal (GI) endoscopy has evolved from a diagnostic tool into a therapeutic modality, leading to a higher incidence of bleeding complications during and after procedures. To address this issue, various hemostatic agents have been developed, including injectable, mechanical, thermal, and topical products. Topical hemostatic agents, available in powder or gel forms, can be used as standalone treatments or as adjuncts to traditional hemostatic therapies to control or prevent bleeding. This Technical and Technology Review examines the commercially available topical hemostatic agents used in endoscopy, specifically Purastat, TC-325 Hemospray, EndoClot PHS, Nexpowder, Ankaferd Blood Stopper, and CG GEL. A systematic literature review was conducted up to January 2025, focusing on randomized controlled trials (RCTs), meta-analyses, and observational studies. Each product was assessed for its composition, mechanism of action, regulatory status, mode of use, efficacy, safety, and financial considerations. Purastat showed 94% efficacy in acute GI bleeding, reducing delayed bleeding to 4.3% in endoscopic submucosal dissection (ESD) and endoscopic mucosal resection cases, with significantly lower thermal device usage. TC-325 Hemospray achieved 85%–98.5% primary hemostasis in upper and lower GI bleeding, with pooled hemostasis rates of 93.1% and rebleeding rates of 8.9%. It was also effective in malignancy-related bleeding, with hemostasis success up to 100%. EndoClot PHS demonstrated 76%–100% hemostasis efficacy, comparable with TC-325, with rebleeding rates of 24%–25%. It showed prophylactic potential post-ESD, with rebleeding rates of 7.3%–9.1%. Nexpowder achieved 94% hemostasis in refractory upper GI bleeds and reduced rebleeding in lower GI bleeds to 5.5% at 28 days. Ankaferd Blood Stopper demonstrated 73%–100% hemostasis across various GI bleeding sources, including peptic ulcers and malignancies, though further data on rebleeding are needed. Topical hemostatic agents offer effective options for managing GI bleeding. Products like Purastat, TC-325 Hemospray, EndoClot PHS, Nexpowder, Ankaferd Blood Stopper, and CG GEL have shown promising results in achieving hemostasis; however, further RCTs and cost-effectiveness analyses are needed to better establish their roles in endoscopic practice.