Persistent Impairment in Immune Reconstitution and Worse Survival Outcomes in Allogeneic Stem Cell Transplantation Patients with Early Coronavirus Disease 2019 Infection.

Patients undergoing allogenic hematopoietic stem cell transplantation (HSCT) are at an increased risk of mortality due to transplantation-related complications in the first year post-transplantation, owing in part to the profound immune dysregulation with T cell and B cell lymphopenia and functional impairment. Although several large studies have reported higher mortality rates from Coronavirus disease 2019 (COVID-19) in HSCT recipients, to date no study has focused on the impact of early COVID-19 infection on immune reconstitution post-transplantation and the correlation with transplantation outcomes. We retrospectively analyzed 61 consecutive adult patients who underwent their first allogeneic HSCT at our institution. Thirteen patients (21.3%) experienced early COVID-19 infection, with a median time to diagnosis of 100 days post-transplantation. In multivariable analysis, patients with early COVID-19 infection had significantly worse overall survival (adjusted hazard ratio [aHR], 4.06; 95% confidence interval [CI], 1.26 to 13.05; P = .019) and progression-free survival (aHR, 6.68; 95% CI, 2.11 to 21.11; P = .001). This was attributed mainly to higher nonrelapse mortality (NRM) among early COVID-19 patients (P = .042). Allogeneic HSCT recipients with early COVID-19 infection had significant delays in absolute lymphocyte count (95% CI, -703.69 to -56.79; P = .021), CD3+CD4+ cell (95% CI, -105.35 to -11.59; P = .042), CD3+CD8+ cell (95% CI, -324.55 to -57.13; P = .038), and CD3-CD56+ cell (95% CI, -193.51 to -47.31; P = .014) recovery compared to those without early COVID-19 infection. Our findings suggest that patients with early COVID-19 infection after allogeneic HSCT have higher NRM and worse survival, at least in part due to impaired immune reconstitution post-transplantation.

ChatGPT Provides Unsatisfactory Responses to Frequently Asked Questions Regarding Anterior Cruciate Ligament Reconstruction.

PURPOSE: To determine whether the free online artificial intelligence platform ChatGPT could accurately, adequately, and appropriately answer questions regarding anterior cruciate ligament (ACL) reconstruction surgery. METHODS: A list of 10 questions about ACL surgery was created based on a review of frequently asked questions that appeared on websites of various orthopaedic institutions. Each question was separately entered into ChatGPT (version 3.5), and responses were recorded, scored, and graded independently by 3 authors. The reading level of the ChatGPT response was calculated using the WordCalc software package, and readability was assessed using the Flesch-Kincaid grade level, Simple Measure of Gobbledygook index, Coleman-Liau index, Gunning fog index, and automated readability index. RESULTS: Of the 10 frequently asked questions entered into ChatGPT, 6 were deemed as unsatisfactory and requiring substantial clarification; 1, as adequate and requiring moderate clarification; 1, as adequate and requiring minor clarification; and 2, as satisfactory and requiring minimal clarification. The mean DISCERN score was 41 (inter-rater reliability, 0.721), indicating the responses to the questions were average. According to the readability assessments, a full understanding of the ChatGPT responses required 13.4 years of education, which corresponds to the reading level of a college sophomore. CONCLUSIONS: Most of the ChatGPT-generated responses were outdated and failed to provide an adequate foundation for patients' understanding regarding their injury and treatment options. The reading level required to understand the responses was too advanced for some patients, leading to potential misunderstanding and misinterpretation of information. ChatGPT lacks the ability to differentiate and prioritize information that is presented to patients. CLINICAL RELEVANCE: Recognizing the shortcomings in artificial intelligence platforms may equip surgeons to better set expectations and provide support for patients considering and preparing for ACL reconstruction.

Strategies to Mitigate the Drug-Drug Interaction between Nirmatrelvir/Ritonavir and Tacrolimus in Allogeneic Hematopoietic Stem Cell Transplant Recipients on Azole Antifungals: Results of a Case Series.

INTRODUCTION: Nirmatrelvir/ritonavir (NIM/r) inhibits tacrolimus metabolism resulting in a profound drug-drug interaction that is further complicated by the use of azole antifungals. CASE PRESENTATIONS: We describe three strategies, in 4 patient cases, for the initiation of NIM/r in allogeneic hematopoietic stem cell transplant (alloHSCT) recipients on tacrolimus at the time of diagnosis. Patients 1 and 2 (strategy 1) experienced prolonged, elevated tacrolimus concentrations after an empiric 33% reduction in tacrolimus dose and adjustment of azole antifungal at NIM/r initiation (strategy 1) and with complete discontinuation of tacrolimus and azole antifungal at NIM/r initiation (strategy 2). Patients 3 and 4 (strategy 3) did not experience elevated tacrolimus concentrations on NIM/r treatment with complete discontinuation of tacrolimus and azole antifungal and a 12-24-h delay in NIM/r initiation. Reinitiation of tacrolimus after NIM/r completion resulted in variable tacrolimus concentrations. CONCLUSION: NIM/r-tacrolimus is a serious drug-drug interaction which can be mitigated by early discontinuation of tacrolimus and azole antifungals, close monitoring, and reinitiation of tacrolimus and antifungal 48-72 h after completion of therapy.

Association of Systemic Hormonal Contraceptives With Reconstruction Procedures for Patellar Instability.

Background: Previous research suggests that estrogen plays a role in increased ligamentous laxity observed within the female population. Whereas many studies have sought to evaluate the impact of exogenous estrogen on anterior cruciate ligament injuries, research has not yet explored its impact on the medial patellofemoral ligament. Furthermore, less is known about the role of exogenous progesterone on ligamentous structures. Purpose: To determine whether women prescribed systemic estrogen (ethinyl estradiol) or progesterone (norgestimate or etonogestrel) hormonal contraceptives had an increased risk of undergoing reconstruction surgery for patellar instability compared with women without a prescription for systemic hormonal contraceptives. Study Design: Cross-sectional study; Level of evidence, 3. Methods: The TriNetX Research Network database was queried using International Classification of Disease and Common Procedural Terminology codes for women aged 15 to 26 years who underwent reconstruction procedures for patellar instability between 2012 and 2022. Women were grouped according to whether they had a coded prescription for a systemic hormonal contraceptive containing either ethinyl estradiol or etonogestrel; controls were matched by age, sex, race, and ethnicity. The relative risk (RR) of undergoing reconstruction for patellar instability was determined for each contraceptive. Results: After 1-to-1 propensity score matching, 0.054% (525/980,878) of women prescribed a systemic contraceptive containing ethinyl estradiol underwent reconstruction procedures for patellar instability compared with 0.043% (417/980,878) of controls (RR, 1.3; 95% CI, 1.1-1.4; P = .0004). Likewise, 0.058% (67/116,260) of women prescribed a form of systemic contraceptive containing only etonogestrel underwent reconstruction procedures for patellar instability compared with 0.026% (30/116,260) of controls (RR, 2.2; 95% CI, 1.5-3.4; P = .0002). Conclusion: Female patients prescribed systemic contraceptives containing estrogen or progesterone had an increased rate of reconstruction procedures for patellar instability.

Improving Randomized-Controlled Trials in Foot and Ankle Orthopaedics: The Need to Include Sociodemographic Patient Data.

BACKGROUND: The representation of sociodemographic data within randomized-controlled trials (RCT) regarding foot and ankle surgery is undefined. The purpose of this study was to determine the incidence of sociodemographic data being reported in contemporary foot and ankle RCTs. METHODS: Randomized-controlled trials within the PubMed database from 2016 to 2021 were searched and the full text of 40 articles was reviewed to identify sociodemographic variables reported in the manuscript. Data regarding race, ethnicity, insurance status, income, work status, and education were collected. RESULTS: Race was reported in the results in 4 studies (10.0%), ethnicity in 1 (2.5%), insurance status in 0 (0%), income in 1 (2.5%), work status in 3 (7.5%) and education in 2 (5.0%). In any section other than the results, race was reported in 6 studies (15.0%), ethnicity in 1 (2.5%), insurance status in 3 (7.5%), income in 6 (15.0%), work status in 6 (15.0%), and education in 3 (7.5%). There was no difference in sociodemographic data by journal (P = .212), year of publication (P = .216), or outcome study (P = .604). CONCLUSION: The overall rate of sociodemographic data reported in foot and ankle RCTs is low. There was no difference in the reporting of sociodemographic data between journal, year of publication, or outcome study. LEVEL OF EVIDENCE: Level II.

Once-Daily Foscarnet Is Effective for Human Herpesvirus 6 Reactivation after Hematopoietic Stem Cell Transplantation.

Human herpesvirus 6 (HHV-6) reactivation is common after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and is associated with higher mortality and increased transplantation-related complications. We hypothesized that preemptive treatment with a short course of foscarnet at a lower cutpoint of plasma HHV-6 viral load would be effective in treating early HHV-6 reactivation, preventing complications and precluding hospitalization of these patients. We reviewed outcomes of adult patients (age ≥18 years) who received preemptive treatment with once-daily foscarnet 60 to 90 mg/kg for 7 days for HHV-6 reactivation after allo-HSCT at our institution between May 2020 and November 2022. Plasma HHV-6 viral load was monitored by quantitative PCR twice monthly in the first 100 days post-transplantation and twice weekly after reactivation until resolution. Eleven patients with a median age of 46 years (range, 23 to 73 years) were included in the analysis. HSCT was performed with a haploidentical donor in 10 patients and with an HLA-matched related donor in 1 patient. The most common diagnosis was acute leukemia (9 patients). Myeloablative and reduced-intensity conditioning regimens were used in 4 and 7 patients, respectively. Ten of the 11 patients received post-transplantation cyclophosphamide-based graft-versus-host disease prophylaxis. The median follow-up was 440 days (range, 174 to 831 days), and the median time to HHV-6 reactivation was 22 days post-transplantation (range, 15 to 89 days). The median viral load at first reactivation was 3,100 copies/mL (range, 210 to 118,000 copies/mL), and the median peak viral load was 11,300 copies/mL (range, 600 to 983,000 copies/mL). All patients received a short course of foscarnet at either 90 mg/kg/day (n = 7) or 60 mg/kg/day (n = 4). In all patients, plasma HHV-6 DNA was undetectable at completion of 1 week of treatment. No HHV-6 encephalitis or pneumonitis occurred. All patients achieved neutrophil and platelet engraftment after a median of 16 days (range, 8 to 22 days) and 26 days (range, 14 to 168 days), respectively, with no secondary graft failure. No complications related to foscarnet administration were noted. One patient with very high HHV-6 viremia had recurrent reactivation and received a second course of foscarnet as an outpatient. A short course of once-daily foscarnet is effective in treating early HHV-6 reactivation post-transplantation and may reduce the incidence of HHV-6-related and treatment-related complications and preclude hospitalization in these patients.

Diagnosis, Prognosticators, and Management of Acute Invasive Fungal Rhinosinusitis: Multidisciplinary Consensus Statement and Evidence-Based Review with Recommendations.

BACKGROUND: Acute invasive fungal sinusitis (AIFS) is an aggressive disease that requires prompt diagnosis and multidisciplinary treatment given its rapid progression. However, there is currently no consensus on diagnosis, prognosis, and management strategies for AIFS, with multiple modalities routinely employed. The purpose of this multi-institutional and multidisciplinary evidence-based review with recommendations (EBRR) is to thoroughly review the literature on AIFS, summarize the existing evidence, and provide recommendations on the management of AIFS. METHODS: The PubMed, EMBASE, and Cochrane databases were systematically reviewed from inception through January 2022. Studies evaluating management for orbital, non-sinonasal head and neck, and intracranial manifestations of AIFS were included. An iterative review process was utilized in accordance with EBRR guidelines. Levels of evidence and recommendations on management principles for AIFS were generated. RESULTS: A review and evaluation of published literature was performed on 12 topics surrounding AIFS (signs and symptoms, laboratory and microbiology diagnostics, endoscopy, imaging, pathology, surgery, medical therapy, management of extrasinus extension, reversing immunosuppression, and outcomes and survival). The aggregate quality of evidence was varied across reviewed domains. CONCLUSION: Based on the currently available evidence, judicious utilization of a combination of history and physical examination, laboratory and histopathologic techniques, and endoscopy provide the cornerstone for accurate diagnosis of AIFS. In addition, AIFS is optimally managed by a multidisciplinary team via a combination of surgery (including resection whenever possible), antifungal therapy, and correcting sources of immunosuppression. Higher quality (i.e., prospective) studies are needed to better define the roles of each modality and determine diagnosis and treatment algorithms.

SlicerHeart: An open-source computing platform for cardiac image analysis and modeling.

Cardiovascular disease is a significant cause of morbidity and mortality in the developed world. 3D imaging of the heart's structure is critical to the understanding and treatment of cardiovascular disease. However, open-source tools for image analysis of cardiac images, particularly 3D echocardiographic (3DE) data, are limited. We describe the rationale, development, implementation, and application of SlicerHeart, a cardiac-focused toolkit for image analysis built upon 3D Slicer, an open-source image computing platform. We designed and implemented multiple Python scripted modules within 3D Slicer to import, register, and view 3DE data, including new code to volume render and crop 3DE. In addition, we developed dedicated workflows for the modeling and quantitative analysis of multi-modality image-derived heart models, including heart valves. Finally, we created and integrated new functionality to facilitate the planning of cardiac interventions and surgery. We demonstrate application of SlicerHeart to a diverse range of cardiovascular modeling and simulation including volume rendering of 3DE images, mitral valve modeling, transcatheter device modeling, and planning of complex surgical intervention such as cardiac baffle creation. SlicerHeart is an evolving open-source image processing platform based on 3D Slicer initiated to support the investigation and treatment of congenital heart disease. The technology in SlicerHeart provides a robust foundation for 3D image-based investigation in cardiovascular medicine.

Dynamic Annular Modeling of the Unrepaired Complete Atrioventricular Canal Annulus.

BACKGROUND: Repair of complete atrioventricular canal (CAVC) is often complicated by atrioventricular valve regurgitation, particularly of the left-sided valve. Understanding the 3-dimensional (3D) structure of the atrioventricular canal annulus before repair may help to inform optimized repair. However, the 3D shape and movement of the CAVC annulus has been neither quantified nor rigorously compared with a normal mitral valve annulus. METHODS: The complete annuli of 43 patients with CAVC were modeled in 4 cardiac phases using transthoracic 3D echocardiograms and custom code. The annular structure was compared with the annuli of 20 normal pediatric mitral valves using 3D metrics and statistical shape analysis (Procrustes analysis). RESULTS: The unrepaired CAVC annulus varied in shape significantly throughout the cardiac cycle. Procrustes analysis visually demonstrated that the average normalized CAVC annular shape is more planar than the normal mitral annulus. Quantitatively, the annular height-to-valve width ratio of the native left CAVC atrioventricular valve was significantly lower than that of a normal mitral valve in all systolic phases (P < .001). CONCLUSIONS: The left half of the CAVC annulus is more planar than that of a normal mitral valve with an annular height-to-valve width ratio similar to dysfunctional mitral valves. Given the known importance of annular shape to mitral valve function, further exploration of the association of 3D structure to valve function in CAVC is warranted.

Modeling Tool for Rapid Virtual Planning of the Intracardiac Baffle in Double-Outlet Right Ventricle.

PURPOSE: Biventricular repair of double-outlet right ventricle (DORV) necessitates the creation of a complex intracardiac baffle. Creation of the optimal baffle design and placement thereof can be challenging to conceptualize, even with 2-dimensional and 3-dimensional images. This report describes a recently developed methodology for creating virtual baffles to inform intraoperative repair. DESCRIPTION: A total of 3 heart models of DORV were created from cardiac magnetic resonance images. Baffles were created and visualized using custom software. EVALUATION: This report demonstrates application of the tool to virtual planning of the baffle for repair of DORV in 3 cases. Models were examined by a multidisciplinary team, on screen and in virtual reality. Baffles could be rapidly created and revised to facilitate planning of the surgical procedure. CONCLUSIONS: Virtual modeling of the baffle pathway by using cardiac magnetic resonance, creation of physical templates for the baffle, and visualization in virtual reality are feasible and may be beneficial for preoperative planning of complex biventricular repairs in DORV. Further work is needed to demonstrate clinical benefit or improvement in outcomes.

A clade of SARS-CoV-2 viruses associated with lower viral loads in patient upper airways.

BACKGROUND: The rapid spread of SARS-CoV-2, the causative agent of Coronavirus disease 2019 (COVID-19), has been accompanied by the emergence of distinct viral clades, though their clinical significance remains unclear. Here, we aimed to investigate the phylogenetic characteristics of SARS-CoV-2 infections in Chicago, Illinois, and assess their relationship to clinical parameters. METHODS: We performed whole-genome sequencing of SARS-CoV-2 isolates collected from COVID-19 patients in Chicago in mid-March, 2020. Using these and other publicly available sequences, we performed phylogenetic, phylogeographic, and phylodynamic analyses. Patient data was assessed for correlations between demographic or clinical characteristics and virologic features. FINDINGS: The 88 SARS-CoV-2 genome sequences in our study separated into three distinct phylogenetic clades. Clades 1 and 3 were most closely related to viral sequences from New York and Washington state, respectively, with relatively broad distributions across the US. Clade 2 was primarily found in the Chicago area with limited distribution elsewhere. At the time of diagnosis, patients infected with Clade 1 viruses had significantly higher average viral loads in their upper airways relative to patients infected with Clade 2 viruses, independent of disease severity. INTERPRETATION: These results show that multiple variants of SARS-CoV-2 were circulating in the Chicago area in mid-March 2020 that differed in their relative viral loads in patient upper airways. These data suggest that differences in virus genotype can impact viral load and may influence viral spread. FUNDING: Dixon Family Translational Research Award, Northwestern University Clinical and Translational Sciences Institute (NUCATS), National Institute of Allergy and Infectious Diseases (NIAID), Lurie Comprehensive Cancer Center, Northwestern University Emerging and Re-emerging Pathogens Program.

Three-Dimensional Modeling of Surgically Implanted Stent-Based Valves in the Mitral Position in Children.

PURPOSE: In children with a mitral annulus too small to accommodate traditional prostheses, surgical implantation of stent-based valves is a promising option. However no reliable preoperative methods exist to guide patient selection, device sizing, and positioning. We describe a novel methodology to visualize and quantify device fit in 3-dimensional echocardiogram (3DE)-derived heart models. DESCRIPTION: Heart models were created from existing preoperative 3DEs using custom software. Valve models were virtually implanted into the models, and both device fit and left ventricular outflow tract (LVOT) area were quantified. EVALUATION: The 3DEs of 3 patients who underwent Melody valve placement in the mitral position were retrospectively modeled: 1 with LVOT obstruction, 1 with perivalvar leak, and 1 without complications. In all cases 2-dimensional measurements underestimated 3D annular dimensions, and the patient with clinical LVOT obstruction had the lowest predicted LVOT area-to-aortic area ratio (0.5). CONCLUSIONS: 3DE-based preoperative modeling of surgical implantation of stent-based valves in the mitral position may improve quantification of mitral valve dimensions and inform risk stratification for potential LVOT obstruction.

Epidemiology and outcomes of hospitalized adults with respiratory syncytial virus: A 6-year retrospective study.

OBJECTIVES: Respiratory syncytial virus (RSV) is an important cause of morbidity and mortality in adults. Existing studies are limited by the number of seasons studied and most have focused on the immunocompromised. METHODS: A retrospective cohort study was conducted on all adults (≥18 years) with a positive RSV molecular test admitted from 2009 to 2015 to one hospital in Chicago, IL. Epidemiologic and outcomes data were collected after IRB approval. RESULTS: Of the 489 eligible patients, 227 had RSV A and 262 had RSV B. Patients had a median age of 61 years and comorbidity (eg, chronic lung disease [40.6%], obesity [37.8%], and cardiac disease [34.3%]). On presentation, most had cough (86.5%), fever (42.4%), and shortness of breath (38.2%). Severe disease was present in 27.6% of patients. Antibiotic was used in 76.3% inpatients and 45.8% at discharged despite few patients (4.7%) having documented bacterial infections. Supplemental oxygen and mechanical ventilation were utilized in 44.6% and 12.3%, respectively, while ICU level care was required in 26.9%. Most patients were discharged home (82.7%). Most deaths (68.4%, 13/19) were attributed to pneumonia or hypoxemia likely from RSV. Most fatal cases were seen in those with recent cancer treatment and older adults. CONCLUSIONS: Respiratory syncytial virus in hospitalized adults is associated with significant morbidity and mortality with 26.9% requiring ICU level care. Antibiotics are commonly prescribed to patients with documented RSV, and antibiotics are frequently continued after diagnosis. Novel antiviral therapies are needed for RSV to improve outcomes and potentially improve antibiotic stewardship in patients without a bacterial infection.

Advances in respiratory virus therapeutics - A meeting report from the 6th isirv Antiviral Group conference.

The International Society for Influenza and other Respiratory Virus Diseases held its 6th Antiviral Group (isirv-AVG) conference in Rockville, Maryland, November 13-15, 2018. The three-day program was focused on therapeutics towards seasonal and pandemic influenza, respiratory syncytial virus, coronaviruses including MERS-CoV and SARS-CoV, human rhinovirus, and other respiratory viruses. Updates were presented on several influenza antivirals including baloxavir, CC-42344, VIS410, immunoglobulin, immune plasma, MHAA4549A, pimodivir (JNJ-63623872), umifenovir, and HA minibinders; RSV antivirals including presatovir (GS-5806), ziresovir (AK0529), lumicitabine (ALS-008176), JNJ-53718678, JNJ-64417184, and EDP-938; broad spectrum antivirals such as favipiravir, VH244, remdesivir, and EIDD-1931/EIDD-2801; and host directed strategies including nitazoxanide, eritoran, and diltiazem. Other topics included considerations of novel endpoints such as ordinal scales and patient reported outcomes (PRO), and study design issues, and other regulatory considerations for antiviral drug development. The aim of this report is to provide a summary of the presentations given at this meeting.

The Application of Virtual Reality for Preoperative Planning of Lymphovenous Anastomosis in a Patient with a Complex Lymphatic Malformation.

The management of lymphatic malformations (LMs) is challenging, particularly for large and complex lesions involving anatomical structures in the adjacent tissue. While lymphovenous anastomosis (LVA) has been reported as an effective treatment for lymphedema, it has hardly been described as a treatment for LM. Virtual reality has the ability to visualize human structures in three dimensions and can be used for the preoperative planning of complex cases. Here, we describe the first case of the management of an LM by LVA preoperatively planned with virtual reality. A young woman presented with an LM previously treated by gross excision. Following persistent complaints of swelling, a minimally invasive microsurgical intervention was planned. The results of the single photon emission tomography with computed tomography (SPECT-CT) and lymphoscintigraphy were analyzed using a virtual reality program, and a 3D patient-specific model was constructed. Based on the combined findings of this 3D model and lymphography with a fluorescent marker, a precise skin incision could be determined and one lymph vessel was anastomosed to a nearby vein. The swelling of the thigh reduced and the discomfort disappeared. Although more reports are needed to confirm its efficacy, LVA planned with virtual reality constructed images appears to be a valuable treatment option for complex lesions, including LMs.