Giant 20 × 35 cm brachial artery pseudoaneurysm after fistulogram treated with surgical resection of pseudoaneurysm and patch angioplasty of brachial artery.

Brachial artery pseudoaneurysms are a rare entity, which can occur secondary to infectious, traumatic, or iatrogenic causes. We present a 78-year-old female with end-stage renal disease on hemodialysis via a right brachio-basilic arteriovenous fistula. She had previously undergone numerous fistulograms and endovascular interventions for right upper extremity swelling due to prolonged bleeding following dialysis. After a recent fistulogram she developed recurrent arm swelling. Duplex showed a large hematoma without any evidence of vascular flow. However, intraoperatively, she was noted to have a giant 20 × 35 cm pseudoaneurysm of the brachial artery. Therapeutic options include endovascular stenting, embolization, thrombin injection, ultrasound-guided compression, and surgery. We elected to perform resection of the large pseudoaneurysm and arteriovenous fistula ligation due to the large size. Given her end-stage renal disease status and lacking quality autogenous vein, we were able to perform a patch angioplasty repair of her brachial artery without requiring a bypass.

Patterns of CRS with Teclistamab in Relapsed/Refractory Multiple Myeloma patients with Prior T-Cell Redirection Therapy.

Teclistamab (Tec) is a first-in-class BCMA X CD3 bispecific T-cell engager antibody approved for treating multiple myeloma progressing after at least 4 lines of therapy. The objective of this study was to evaluate the rate of cytokine release syndrome (CRS) in patients who were treated with commercial Tec and had prior exposure to other T-cell redirection therapies. A retrospective chart review was performed to identify patients who completed the Tec step-up dosing phase between November 2022 and November 2023. Patients were divided into 2 cohorts based on prior exposure to T-cell redirection therapy (cohort 1: T-cell redirection therapy experienced; cohort 2: T-cell redirection therapy naïve). The primary objective was to compare the differences in the rates of CRS between the two cohorts. Univariate and multivariate logistic regression analyses were performed to assess the association between CRS rates with Tec and prior treatment with T-cell redirection therapy. A total of 72 patients were included in the analysis (27 in cohort 1 and 45 in cohort 2). The CRS rates were significantly lower in cohort 1 (37%, n=10) compared to cohort 2 (80%, n=36; p=0.0004). Based on multivariate logistic regression analysis, patients without prior exposure to T-cell redirection therapy (cohort 2) had about a 4-fold increase in the incidence of CRS (95% CI: 1.40-14.90, p=0.0002) with Tec. In our study, prior exposure to T-cell redirection therapy reduced the risk of CRS with Tec during the step-up dosing phase. This observation will allow for the optimization of CRS prophylactic strategies for Tec.

Intestinal microbiome profiles in broiler chickens raised without antibiotics exhibit altered microbiome dynamics relative to conventionally raised chickens.

The present study was undertaken to profile and compare the cecal microbial communities in conventionally (CONV) grown and raised without antibiotics (RWA) broiler chickens. Three hundred chickens were collected from five CONV and five RWA chicken farms on days 10, 24, and 35 of age. Microbial genomic DNA was extracted from cecal contents, and the V4-V5 hypervariable regions of the 16S rRNA gene were amplified and sequenced. Analysis of 16S rRNA sequence data indicated significant differences in the cecal microbial diversity and composition between CONV and RWA chickens on days 10, 24, and 35 days of age. On days 10 and 24, CONV chickens had higher richness and diversity of the cecal microbiome relative to RWA chickens. However, on day 35, this pattern reversed such that RWA chickens had higher richness and diversity of the cecal microbiome than the CONV groups. On days 10 and 24, the microbiomes of both CONV and RWA chickens were dominated by members of the phylum Firmicutes. On day 35, while Firmicutes remained dominant in the RWA chickens, the microbiome of CONV chickens exhibited am abundance of Bacteroidetes. The cecal microbiome of CONV chickens was enriched with the genus Faecalibacterium, Pseudoflavonifractor, unclassified Clostridium_IV, Bacteroides, Alistipes, and Butyricimonas, whereas the cecal microbiome of RWA chickens was enriched with genus Anaerofilum, Butyricicoccu, Clostridium_XlVb and unclassified Lachnospiraceae. Overall, the cecal microbiome richness, diversity, and composition were greatly influenced by the management program applied in these farms. These findings provide a foundation for further research on tailoring feed formulation or developing a consortium to modify the gut microbiome composition of RWA chickens.

FOXO1 is a master regulator of memory programming in CAR T cells.

A major limitation of chimeric antigen receptor (CAR) T cell therapies is the poor persistence of these cells in vivo1. The expression of memory-associated genes in CAR T cells is linked to their long-term persistence in patients and clinical efficacy2-6, suggesting that memory programs may underpin durable CAR T cell function. Here we show that the transcription factor FOXO1 is responsible for promoting memory and restraining exhaustion in human CAR T cells. Pharmacological inhibition or gene editing of endogenous FOXO1 diminished the expression of memory-associated genes, promoted an exhaustion-like phenotype and impaired the antitumour activity of CAR T cells. Overexpression of FOXO1 induced a gene-expression program consistent with T cell memory and increased chromatin accessibility at FOXO1-binding motifs. CAR T cells that overexpressed FOXO1 retained their function, memory potential and metabolic fitness in settings of chronic stimulation, and exhibited enhanced persistence and tumour control in vivo. By contrast, overexpression of TCF1 (encoded by TCF7) did not enforce canonical memory programs or enhance the potency of CAR T cells. Notably, FOXO1 activity correlated with positive clinical outcomes of patients treated with CAR T cells or tumour-infiltrating lymphocytes, underscoring the clinical relevance of FOXO1 in cancer immunotherapy. Our results show that overexpressing FOXO1 can increase the antitumour activity of human CAR T cells, and highlight memory reprogramming as a broadly applicable approach for optimizing therapeutic T cell states.

Unscheduled healthcare interactions in multiple myeloma patients receiving T cell redirection therapies.

Outcomes for relapsed/refractory multiple myeloma (RRMM) patients have dramatically improved following the development and now growing utilization of B cell maturation antigen targeted chimeric antigen receptor (CAR) T cell therapy and bispecific antibody (BsAb) therapy. However, healthcare utilization as a quality-of-life metric in these growing populations has not been thoroughly evaluated. We performed a retrospective cohort study evaluating the frequency and cause of unscheduled healthcare interactions (UHIs) among RRMM patients responding to B-cell maturation antigen targeted BsAbs and CAR T cell therapies (N = 46). This included analysis of remote UHIs including calls to physicians' offices and messages sent through an online patient portal. Our results showed that nearly all (89%) RRMM patients receiving these therapies required a UHI during the first 125 days of treatment, with a mean of 3.7 UHIs per patient. RRMM patients responding to BsAbs were significantly more likely to remotely contact their physicians' offices (1.8-fold increase, p = 0.038) or visit an urgent care center (>3-fold increase, p = 0.012) than RRMM patients responding to CAR T cell therapies. This was largely due to increased reports of mild upper respiratory tract infections in BsAb patients. Our results underscore the need to develop preemptive management strategies for commonly reported symptoms that RRMM patients experience while receiving CAR T cell or BsAb therapies. This preemptive management may significantly reduce unnecessary healthcare utilization in this vulnerable patient population.

Early Effects of Scaling Up Dolutegravir-Based ARV Regimens Among Children Living with HIV in Malawi.

Viral suppression (VS) in children has remained suboptimal compared to that in adults. We evaluated the impact of transitioning children weighing < 20 kg to a pediatric formulation of dolutegravir (pDTG) on VS in Malawi. We analyzed routine retrospective program data from electronic medical record systems pooled across 169 healthcare facilities in Malawi supported by the Elizabeth Glaser Pediatric AIDS Foundation (EGPAF). We included children who weighed < 20 kg and received antiretroviral therapy (ART) between July 2021-June 2022. Using descriptive statistics, we summarized demographic and clinical characteristics, ART regimens, ART adherence, and VS. We used logistic regression to identify factors associated with post-transition VS. A total of 2468 Children Living with HIV (CLHIV) were included, 55.3% of whom were < 60 months old. Most (83.8%) had initiated on non-DTG-based ART; 71.0% of these had a viral load (VL) test result before transitioning to pDTG, and 62.5% had VS. Nearly all (99.9%) CLHIV transitioned to pDTG-based regimens. Six months after the transition, 52.7% had good ART adherence, and 38.6% had routine VL testing results; 81.7% achieved VS. Post-transition VS was associated with good adherence and pre-transition VS: adjusted odds ratios of 2.79 (95% CI 1.65-4.71), p < 0.001 and 5.32 (95% CI 3.23-9.48), p < 0.001, respectively. After transitioning to pDTG, VS was achieved in most children tested within the first 6 months. However, adherence remained suboptimal post-transition and VL testing at 6 months was limited. Interventions to improve VL testing and enhance ART adherence are still needed in CLHIV on pDTG-based regimens.

Durvalumab After Chemoradiotherapy in Patients With Unresectable Stage III Non-Small Cell Lung Cancer.

Importance: The PACIFIC trial established consolidation durvalumab as the standard of care following chemoradiotherapy (CRT) for patients with unresectable stage III non-small cell lung cancer (NSCLC). Understanding its benefit in routine US clinical practice is critical. Objective: To report characteristics, treatment patterns, and outcomes of patients who did or did not receive durvalumab. Design, Setting, and Participants: Two prespecified cohorts were curated in this retrospective cohort study (SPOTLIGHT). Deidentified patient-level data from a US database (Flatiron Health) were analyzed. Patients had unresectable stage III NSCLC, were diagnosed on or after January 1, 2011, had 2 or more visits on or afterward, and received CRT. Data were analyzed from May 2021 to October 2023. Exposures: Patients started durvalumab after CRT (durvalumab cohort) or ended CRT without durvalumab (nondurvalumab cohort) by June 30, 2019, to allow 15 or more months of follow-up from CRT end. Main Outcomes and Measures: End points included progression-free survival (PFS), overall survival (OS), time to first subsequent therapy or death (TFST), and time to distant metastasis or death (TTDM). Results: The durvalumab cohort included 332 patients (median [IQR] age, 67.5 [60.8-74.0] years; 187 were male [56.3%], 27 were Black [8.7%], 33 were other races [10.7%], and 249 were White [80.6%]) and the nondurvalumab cohort included 137 patients (median (IQR) age, 70.0 [64.0-75.0] years; 89 [65.0%] were male, 11 [8.9%] were Black, 19 [15.4%] were other races, and 93 [75.6%] were White). Most patients had a smoking history (durvalumab, 316 patients [95.2%] and nondurvalumab, 132 patients [96.4%]) and Eastern Cooperative Oncology Group performance status 0 through 1 (durvalumab, 251 patients [90.9%] and nondurvalumab, 88 patients [81.5%]). Median (IQR) CRT duration was 1.6 (1.4-1.8) months for the durvalumab cohort and 1.5 (1.4-1.8) months for the nondurvalumab cohort. Median time to durvalumab discontinuation was 9.5 months (95% CI, 7.8-10.6 months). Median TFST and TTDM were not reached (NR) in the durvalumab cohort and 8.3 months (95% CI, 4.8-11.8 months) and 11.3 months (95% CI, 6.4-14.5 months), respectively, in the nondurvalumab cohort. Median PFS and OS were 17.5 months (95% CI, 13.6-24.8 months) and NR in the durvalumab cohort and 7.6 months (95% CI, 5.2-9.8 months) and 19.4 months (95% CI, 11.7-24.0 months) in the nondurvalumab cohort. In Cox regression analyses of patients who completed concurrent CRT without progression, durvalumab was associated with a lower risk of progression or death (hazard ratio [HR], 0.36; 95% CI, 0.26-0.51) and lower risk of death (HR, 0.27; 95% CI, 0.16-0.43), adjusted for prior platinum agent and patient characteristics. Conclusions and Relevance: In this cohort study, findings were consistent with PACIFIC, and durvalumab was associated with a lower risk of progression and/or death. Further investigation is warranted to explain why patients did not receive durvalumab after its approval.

Pre-operative Embolization of a Cerebellar Hemangioblastoma Using Polyvinyl Alcohol (PVA) and Target Tetra 360 Detachable Coil.

Due to its hypervascularity, hemangioblastoma, a rare primary central nervous system intracranial tumor, has been treated with pre-operative embolization prior to surgical resection. Here, we describe a case treated as such. A 37-year-old male presented with worsening chronic headache and right ear tinnitus was found to have a hypervascular, heterogeneous right cerebellar lesion suspicious for arteriovenous malformation or hemangioblastoma. He underwent polyvinyl alcohol (PVA) and Target Tetra 360 (Fremont, CA: Stryker Neurovascular) detachable coil embolization followed by complete tumor resection. Pathology was consistent with hemangioblastoma. He presented with complete resolution of his symptoms immediately post-operatively and at a two-week follow-up. Our case highlighted the importance of pre-operative embolization to help achieve complete tumor resection which is considered curative in the treatment of hypervascular hemangioblastoma. The Target Tetra 360 detachable coil embolization is another material that can be considered.

An Algorithm for Treatment of Symptomatic Chronic Subdural Hematomas.

INTRODUCTION: Although chronic subdural hematoma (CSDH) is a common neurosurgical disease, there is a lack of algorithms for the treatment of asymptomatic and symptomatic CSDH. The purpose of this article is to describe an algorithm developed using our institutional experience for the treatment of symptomatic CSDH that aims to decrease symptoms and/or hematoma size or to completely resolve both. Our algorithm for treatment of symptomatic CSDH includes subdural drain (SDD) placement via twist-drill craniostomy (TDC) as the first-line treatment, followed by supplemental tissue plasminogen activator (tPA) as second-line treatment, with possible middle meningeal artery embolization (MMAE), followed by craniotomy as the last therapeutic option. This study investigated the efficacy of our institution's algorithm in treating symptomatic CSDH. METHODS: A retrospective study was conducted from 2019 to 2023 identifying patients with CSDH treated with TDC. Electronic medical records were used to gather patient demographics, clinical presentation, radiographic findings, treatment modalities, and clinical outcomes. RESULTS: There were a total of 109 patients with 128 SDD placements. All 109 patients underwent TDC; among them, 37 patients received tPA instillation with three patients requiring craniotomy. Factors including age, gender, race, mechanism of injury, blood thinner usage, Glasgow Coma Scale (GCS), neurologic exam, thickness of CSDH, and midline shift were comparable for all patients regardless of treatment received. The mean number of neomembranes was higher in patients who eventually required craniotomy (4.5) compared to those treated with TDC only (1.8) and TDC+tPA (2.1) (p=0.0035). There was a greater mean hematoma drainage in patients who received tPA instillation without craniotomy (586.7 mL) than those treated with TDC only (293.0 mL) (p<0.0001). Clinical improvement was found in 52/72 patients (72.2%) treated with TDC only, 23/34 patients (67.6%) treated with TDC+tPA only, and 0/3 patients (0.0%) treated with TDC+tPA+craniotomy. Radiographic improvement in mean thickness of CSDH and midline shift, respectively, was found in patients treated with TDC only (p<0.0001; p<0.0001) and TDC+tPA (p<0.0001; p<0.0001) but not in TDC+tPA+craniotomy (p=0.1494; p=0.0762). There were also fewer neomembranes after TDC+tPA treatment only (2.1 vs. 0.5, p<0.0001). Seven patients were readmitted that did not follow the algorithm and only patients treated following the algorithm showed clinical and radiographic improvement. CONCLUSIONS: Using our institutional algorithm, our study demonstrates successful clinical outcomes in treating symptomatic CSDH and recurrent CSDH with minimally invasive therapeutic interventions including SDD via TDC and tPA, thereby minimizing the utilization of more invasive interventions including craniotomy.

Radiographic Union Assessment in Surgically Treated Distal Femur Fractures: A Systematic Review.

BACKGROUND: Distal femur fractures are known to have challenging nonunion rates. Despite various available treatment methods aimed to improve union, optimal interventions are yet to be determined. Importantly, there remains no standard agreement on what defines radiographic union. Although various proposed criteria of defining radiographic union exist in the literature, there is no clear consensus on which criteria provide the most precise measurement. The use of inconsistent measures of fracture healing between studies can be problematic and limits their generalizability. Therefore, this systematic review aims to identify how fracture union is defined based on radiographic parameters for surgically treated distal femur fractures in current literature. METHODS: In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, Medline, EMBASE, Cochrane Central Register of Controlled Trials, and Web of Science Core Collection databases were searched from inception to October 2022. Studies that addressed surgically treated distal femur fractures with reported radiographic union assessment were included. Outcomes extracted included radiographic definition of union; any testing of validity, reliability, or responsiveness; reported union rate; reported time to fracture union; and any functional outcomes correlated with radiographic union. RESULTS: Sixty articles with 3,050 operatively treated distal femur fractures were included. Operative interventions included lateral locked plate (42 studies), intramedullary nail (15 studies), dynamic condylar screw or blade plate (7 studies), dual plate or plate and nail construct (5 studies), distal anterior-posterior/posterior-anterior screws (1 study), and external fixation with a circular frame (1 study). The range of mean follow-up time reported was 4.3 to 44 months. The most common definitions of fracture union included "bridging or callus formation across 3 of 4 cortices" in 26 (43%) studies, "bony bridging of cortices" in 21 (35%) studies, and "complete bridging of cortices" in 9 (15%) studies. Two studies included additional assessment of radiographic union using the Radiographic Union Scale in Tibial fracture (RUST) or modified Radiographic Union Scale in Tibial fracture (mRUST) scores. One study included description of validity, and the other study included reliability testing. The reported mean union rate of distal femur fractures was 89% (range 58%-100%). The mean time to fracture union was documented in 49 studies and found to be 18 weeks (range 12-36 weeks) in 2,441 cases. No studies reported correlations between functional outcomes and radiographic parameters. CONCLUSION: The current literature evaluating surgically treated distal femur fractures lacks consistent definition of radiographic fracture union, and the appropriate time point to make this judgement is unclear. To advance surgical optimization, it is necessary that future research uses validated, reliable, and continuous measures of radiographic bone healing and correlation with functional outcomes. LEVEL OF EVIDENCE: Level IV. See Instructions for Authors for a complete description of levels of evidence.

Treatment of chickens with lactobacilli prior to challenge with Clostridium perfringens modifies innate responses and gut morphology.

Necrotic enteritis caused by Clostridium perfringens (CP), is a common enteric disease of poultry that has been previously controlled by in-feed antibiotics. However, due to the rapid emergence of antimicrobial resistance, alternatives to antibiotics such as probiotics have received considerable attention because of their immunomodulatory and intestinal health benefits. The present study investigated the effects of probiotic lactobacilli on gut histomorphology and intestinal innate responses in chickens. Day-old male broiler chickens were treated with 1 × 107 or 1 × 108 colony-forming units (CFU) of a lactobacilli cocktail on days 1, 7, 14, and 20 post-hatch, while control groups were not treated with lactobacilli. On day 21, birds in all groups (except the negative control) were challenged with 3 × 108 CFU of CP for 3 days. Intestinal tissue samples were collected before and after the CP challenge to assess gene expression and for histomorphological analysis. Lactobacilli treatment at a dose of 1 × 108 CFU conferred partial protection against NE by lowering lesion scores, increasing villus height in the ileum and reducing crypt depth in the jejunum. In addition, 1 × 108 CFU of lactobacilli enhanced the expression of Toll-like receptor (TLR) 2, interferon-gamma (IFN-γ), interleukin (IL)-10, IL-12, and IL-13 in both the jejunum and ileum at different timepoints and subsequently decreased the expression of transforming growth factor beta (TGF-ß) and IL-1ß post-CP challenge. In conclusion, the results indicate that treatment with lactobacilli mitigated NE in a dose-dependent manner via improvement of intestinal morphology and modulation of innate immune response in chickens.

Patient Satisfaction in Neurosurgery Clinic.

BACKGROUND: National commercial surveys are used to assess patient satisfaction. However, the information obtained does not always correspond to the clinical situation and therefore may be inadequate to help improve a specific patient experience when through no fault of its design, results in low response rates and inadequate specifics. OBJECTIVE: The objective is to investigate patient satisfaction using real-time in-person patient experience survey responses at the end of a neurosurgical clinic visit and review the results from these survey responses and those from national commercial survey responses provided by the hospital for the ability to affect change. METHODS: This is a prospective study from October 2023 to December 2023 during which a paper copy of 10 questionnaires derived from a national commercial outpatient clinical survey was given to every unique patient who was neurologically capable of filling it out at the end of his or her neurosurgery clinic visit. The electronic medical record was used to collect patient demographics and details of the clinic visit. National commercial survey responses from July 2022 to November 2023 provided by the hospital were reviewed. RESULTS: A total of 149 patients were seen in the neurosurgery clinic from October 2023 to December 2023, 121 patients were given the in-person patient satisfaction survey, and the response rate was 100%. The mean age was 46.5 years with females constituted 45.5% of the patient sample. The visit type included 46 (38.0%) new patients, 53 (43.8%) returning patients, and 22 (18.2%) post-op patients, of which 45.5% presented with cranial pathologies. Comparing the patient satisfaction level between those seen by one provider and those seen by two providers, such as resident, or mid-level with attending, patients seen by two providers were less satisfied with "feeling respected by the providers" (4.92 vs. 4.64, p=0.0088), "feeling listened to by the providers" (4.84 vs. 4.50, p=0.0180), and "feeling appreciated that the providers discussed illness prevention" (4.72 vs. 4.29, p=0.0232). Due to a lack of necessary information from our national commercial outpatient clinic survey responses provided by the hospital, a direct comparison between the in-person survey and our national commercial outpatient clinic survey was not made. CONCLUSIONS: Patient satisfaction surveys when not given in real-time in-person run the risk of low response rate and lack of specifics to help guide providers in quality improvement. Our data supports the use of real-time in-person patient satisfaction surveys that not only increase response rate but also provide useful information to help improve patient experience.

Impact of Lactate Dehydrogenase and Hemoglobin Levels on Clinical Outcomes in Patients With Paroxysmal Nocturnal Hemoglobinuria: Results From the National Korean PNH Registry.

BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic disorder caused by uncontrolled terminal complement activation, which leads to intravascular hemolysis (IVH), thromboembolism (TE), renal failure, and premature mortality. METHODS: We performed a secondary analysis of data collected from patients enrolled in the Korean National PNH Registry to assess the relative importance of risk factors, specifically lactate dehydrogenase (LDH) and hemoglobin (Hb), in predicting the incidence of TE, impaired renal function, and death in complement inhibitor-naïve patients with PNH. RESULTS: Multivariate regression modeling indicated that LDH ≥ 1.5 × upper limit of normal (ULN), male sex, and pain were associated with increased risk of TE (P = 0.016, 0.045, and 0.033, respectively), hemoglobinuria and pain were associated with an increased risk of impaired renal function (P = 0.034 and 0.022, respectively), and TE was associated with an increased incidence of death (P < 0.001). Hb < 8 g/dL was not a predictor of TE, impaired renal function, or death in multivariate regression analyses. Standardized mortality ratio analysis indicated that LDH ≥ 1.5 × ULN (P < 0.001), Hb < 8 g/dL (P < 0.001), and Hb ≥ 8 g/dL (P = 0.004) were all risk factors for death; in contrast, patients with LDH < 1.5 × ULN had similar mortality to the general population. CONCLUSION: In complement inhibitor-naïve patients with PNH, LDH ≥ 1.5 × ULN was a significant predictor of TE, and TE was a significant predictor of death. Hb was not a significant predictor of TE, impaired renal function, or death. Therefore, controlling IVH will improve clinical outcomes for patients with PNH.

Handheld Osteotome Laminectomy in Cadavers and a Case Study.

Laminectomy is a commonly performed surgery to decompress the spinal canal to relieve spinal canal stenosis secondary to a variety of etiologies such as degenerative spinal changes, fractures, tumors, vascular lesions, and infections. Advances in technologies have allowed for more precise osteotomies and offer more protection to nearby structures; however, these technologies may not always be available at some facilities. To the best of the authors' knowledge, we describe an innovative technique to perform laminectomy using a handheld osteotome, which is widely available and at low cost. Our experience with cadavers and a case study shows that the technique appears to be safe and effective and may have the potential to reduce the procedure length of a laminectomy.

Extraventricular Drain Care Bundle Decreases Cerebrospinal Fluid Infection Rates Associated With Extraventricular Drain-Related Procedures and Systemic Infection.

BACKGROUND: Infection associated with extraventricular drain (EVD)-related procedures is well known. OBJECTIVE: To investigate the impact of our institution's EVD care bundle on the infection rates associated with EVD-related procedures. METHODS: A retrospective study was conducted from June 2022 to June 2023 to compare the infection rate six months before and six months after the implantation of the EVD care bundle. RESULTS: A total of 58 patients were included in the study (n=33 patients in 2022 and n=25 patients in 2023). The infection rate was 21.2% (7/33) prior to the implementation of the EVD care bundle and 0.0% (0/25) afterward. The seven patients with cerebrospinal fluid (CSF) infection did not have a higher total number of EVD-related procedures compared to the other 26 patients without CSF infection (8.0 vs. 9.4, p=0.7364); however, the mean number of EVD replacements was higher in patients with CSF infection (1.4 vs. 3.4, p=0.0028). The total number of EVD-related procedures was not different between 2022 and 2023 (8.3 vs. 5.2, respectively, p=0.1892); however, the mean number of EVD replacements was lower in 2023 (1.8 vs. 1.0, p=0.0257). In 2022, 22/33 patients had systemic infection, among which 7/22 also had CSF infection. In 2023, 13/25 patients had a systemic infection, among which 0/13 had CSF infection. CONCLUSIONS: The EVD care bundle consisting of standardizations, checklists, and monitoring reduces the CSF infection rates associated with EVD-related procedures and systemic infection.

Predictors for improvement in patient-reported outcomes: post hoc analysis of a phase 3 randomized, open-label study of eculizumab and ravulizumab in complement inhibitor-naive patients with paroxysmal nocturnal hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by uncontrolled terminal complement activation leading to intravascular hemolysis (IVH), thrombosis, and impairments in quality of life (QoL). The aim of this study was to identify the clinical drivers of improvement in patient-reported outcomes (PROs) in patients with PNH receiving the complement component 5 (C5) inhibitors eculizumab and ravulizumab.This post hoc analysis assessed clinical outcomes and PROs from 246 complement inhibitor-naive patients with PNH enrolled in a phase 3 randomized non-inferiority study that compared the C5 inhibitors ravulizumab and eculizumab (study 301; NCT02946463). The variables of interest were lactate dehydrogenase (LDH) levels, a surrogate measure of IVH, and hemoglobin (Hb) levels. PROs were collected using Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) and European Organisation for Research and Treatment of Cancer, Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) to assess fatigue and QoL, respectively.Improvements in absolute mean LDH levels were significantly associated with improvements in mean FACIT-F score (p = 0.0024) and EORTC QLQ-C30 global health (GH) score (p < 0.0001) from baseline to day 183. Improvements in scores were achieved despite a non-significant increase in Hb levels. To understand the interaction between LDH and Hb, a regression analysis was performed: LDH response with Hb improvements was a significant predictor of improvement in fatigue. The independent effect of improved Hb did not significantly affect FACIT-F or EORTC QLQ-C30 GH scores.These findings suggest that LDH levels are an important determinant of fatigue and QoL outcomes in patients with PNH. CTR: NCT02946463, October 27, 2016.

Identification and targeting of treatment resistant progenitor populations in T-cell Acute Lymphoblastic Leukemia.

Refractoriness to initial chemotherapy and relapse after remission are the main obstacles to cure in T-cell Acute Lymphoblastic Leukemia (T-ALL). Biomarker guided risk stratification and targeted therapy have the potential to improve outcomes in high-risk T-ALL; however, cellular and genetic factors contributing to treatment resistance remain unknown. Previous bulk genomic studies in T-ALL have implicated tumor heterogeneity as an unexplored mechanism for treatment failure. To link tumor subpopulations with clinical outcome, we created an atlas of healthy pediatric hematopoiesis and applied single-cell multiomic (CITE-seq/snATAC-seq) analysis to a cohort of 40 cases of T-ALL treated on the Children's Oncology Group AALL0434 clinical trial. The cohort was carefully selected to capture the immunophenotypic diversity of T-ALL, with early T-cell precursor (ETP) and Near/Non-ETP subtypes represented, as well as enriched with both relapsed and treatment refractory cases. Integrated analyses of T-ALL blasts and normal T-cell precursors identified a bone-marrow progenitor-like (BMP-like) leukemia sub-population associated with treatment failure and poor overall survival. The single-cell-derived molecular signature of BMP-like blasts predicted poor outcome across multiple subtypes of T-ALL within two independent patient cohorts using bulk RNA-sequencing data from over 1300 patients. We defined the mutational landscape of BMP-like T-ALL, finding that NOTCH1 mutations additively drive T-ALL blasts away from the BMP-like state. We transcriptionally matched BMP-like blasts to early thymic seeding progenitors that have low NR3C1 expression and high stem cell gene expression, corresponding to a corticosteroid and conventional cytotoxic resistant phenotype we observed in ex vivo drug screening. To identify novel targets for BMP-like blasts, we performed in silico and in vitro drug screening against the BMP-like signature and prioritized BMP-like overexpressed cell-surface (CD44, ITGA4, LGALS1) and intracellular proteins (BCL-2, MCL-1, BTK, NF-κB) as candidates for precision targeted therapy. We established patient derived xenograft models of BMP-high and BMP-low leukemias, which revealed vulnerability of BMP-like blasts to apoptosis-inducing agents, TEC-kinase inhibitors, and proteasome inhibitors. Our study establishes the first multi-omic signatures for rapid risk-stratification and targeted treatment of high-risk T-ALL.

Normothermic Ex Situ Machine Perfusion of Vascularized Composite Allografts with Oxygen Microcarriers for 12 Hours Using Real-Time Mitochondrial Redox Quantification.

BACKGROUND: Normothermic ex situ perfusion of vascularized composite allografts (VCAs) necessitates high oxygen demand and, thus, increased metabolic activity, which, in turn, requires the use of blood-based perfusion solutions. However, blood-derived perfusates, in turn, constitute an antigenic load. To circumvent this immunogenic problem, we used a perfusate enriched with acellular dextrane oxygen microcarriers to perfuse rat hindlimbs. METHODS: Rat hindlimbs (n = 11) were perfused with either (non-), oxygenated dextrane-enriched Phoxilium, or Phoxilium enriched with dextrane oxygen microcarriers (MO2) for 12 h at 37 °C or stored on ice. Oxygenation of the skeletal muscle was assessed with Raman spectroscopy, tissue pO2-probes, and analysis of the perfusate. Transmission electronic microscopy was utilized to assess the ultrastructure of mitochondria of the skeletal muscle. RESULTS: For all evaluated conditions, ischemia time until perfusion was comparable (22.91 ± 1.64 min; p = 0.1559). After 12 h, limb weight increased significantly by at least 81%, up to 124% in the perfusion groups, and by 27% in the static cold storage (SCS) group. Raman spectroscopy signals of skeletal muscle did not differ substantially among the groups during either perfusion or static cold storage across the duration of the experiment. While the total number of skeletal muscle mitochondria decreased significantly compared to baseline, mitochondrial diameter increased in the perfusion groups and the static cold storage group. CONCLUSION: The use of oxygen microcarriers in ex situ perfusion of VCA with acellular perfusates under normothermic conditions for 12 h facilitates the maintenance of mitochondrial structure, as well as a subsequent recovery of mitochondrial redox status over time, while markers of muscle injury were lower compared to conventional oxygenated acellular perfusates.