Cross-sectional study to investigate the seroprevalence and risk factors of Toxoplasma gondii among women attending the antenatal clinic in Namwala, Zambia.

BACKGROUND: Toxoplasmosis is a zoonotic parasitic disease caused by Toxoplasma gondii (T. gondii). It has a wide host range and is capable of vertical transmission in pregnant women, which may lead to undesirable pregnancy outcomes such as congenital malformations, miscarriage, premature birth and stillbirth. This study investigated the seroprevalence of T. gondii infection among pregnant women attending the antenatal clinic at Namwala District Hospital in Southern Zambia. METHODS: This was a cross-sectional study where blood was collected, and the serum was tested for Toxoplasma IgG and IgM. A questionnaire was administered to participants on demographic characteristics and risk factors. Data were entered in Microsoft Excel and exported to STATA version 14 for analysis. RESULTS: A total of 401 women were enrolled in the study from 3 March to 5 August 2021. The seroprevalence of Toxoplasma IgG was 4.2% (n=17), while the seroprevalence of Toxoplasma IgM was 0.7% (n=3). The median age was 27 (IQR: 24-30) years, and a larger proportion had primary-level education (n=223, 55.6%). The majority (81.6%) of the women were married. None of the risk factors investigated in this study were significant for T. gondii infection. CONCLUSION: There was a low seroprevalence of T. gondii infection among pregnant women in the Namwala district of Southern Province, Zambia, and regular screening may not be warranted in this population. Continued research on toxoplasmosis is recommended to understand its epidemiology across Zambia.

MICAL2 Is a Super Enhancer Associated Gene that Promotes Pancreatic Cancer Growth and Metastasis.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest solid cancers and thus identifying more effective therapies is a major unmet need. In this study we characterized the super enhancer (SE) landscape of human PDAC to identify novel, potentially targetable, drivers of the disease. Our analysis revealed that MICAL2 is a super enhancer-associated gene in human PDAC. MICAL2 is a flavin monooxygenase that induces actin depolymerization and indirectly promotes SRF transcription by modulating the availability of serum response factor coactivators myocardin related transcription factors (MRTF-A and MRTF-B). We found that MICAL2 is overexpressed in PDAC and correlates with poor patient prognosis. Transcriptional analysis revealed that MICAL2 upregulates KRAS and EMT signaling pathways, contributing to tumor growth and metastasis. In loss and gain of function experiments in human and mouse PDAC cells, we observed that MICAL2 promotes both ERK1/2 and AKT activation. Consistent with its role in actin depolymerization and KRAS signaling, loss of MICAL2 expression also inhibited macropinocytosis. Through in vitro phenotypic analyses, we show that MICAL2, MRTF-A and MRTF-B influence PDAC cell proliferation, migration and promote cell cycle progression. Importantly, we demonstrate that MICAL2 is essential for in vivo tumor growth and metastasis. Interestingly, we find that MRTF-B, but not MRTF-A, phenocopies MICAL2-driven phenotypes in vivo . This study highlights the multiple ways in which MICAL2 impacts PDAC biology and suggests that its inhibition may impede PDAC progression. Our results provide a foundation for future investigations into the role of MICAL2 in PDAC and its potential as a target for therapeutic intervention.

Evaluating the feasibility and acceptability of a co-designed physical activity intervention for rural middle schoolers: a pilot study.

BACKGROUND: Lack of physical activity is a concern for children across diverse backgrounds, particularly affecting those in rural areas who face distinct challenges compared to their urban counterparts. Community-derived interventions are needed that consider the unique context and additional physical activity barriers in under-resourced rural settings. Therefore, a prospective pre-post pilot/feasibility study of Hoosier Sport was conducted over 8-weeks with 6th and 7th grade children in a low-socioeconomic rural middle school setting. The primary objective of the present study was to assess trial- and intervention-related feasibility indicators; and the secondary objective was to collect preliminary assessment data for physical activity levels, fitness, psychological needs satisfaction, and knowledge of physical activity and nutrition among participating youth. METHODS: This prospective 8-week pilot/feasibility study took place in the rural Midwestern United States where twenty-four middle school students participated in a mixed-methods pre-post intervention during physical education classes. The intervention included elements like sport-based youth development, individualized goal setting, physical activity monitoring, pedometer usage, and health education. Data were collected at baseline (T1) and post-intervention (T3), with intermediate measures during the intervention (T2). Qualitative data were integrated through semi-structured interviews. Analytical methods encompassed descriptive statistics, correlations, repeated measures ANOVA, and thematic analysis. RESULTS: Key findings indicate robust feasibility, with intervention-related scores (FIM, AIM, and IAM) consistently surpassing the "good" threshold and 100% retention and recruitment success. Additionally, participants showed significant physical performance improvement, shifting from the 25th to the 50th percentile in the 6-minute walk test (p < 0.05). Autonomy and competence remained high, reflecting positive perceptions of program practicality. Nutrition knowledge, initially low, significantly improved at post-intervention (p < 0.01), highlighting the efficacy of targeted nutritional education in Hoosier Sport. CONCLUSIONS: This study pioneers a community-engaged model for physical activity intervention in under-resourced rural settings. Positive participant feedback, coupled with improvements in physical fitness and psychosocial factors, highlights the potential of the co-design approach. The findings offer valuable insights and a practical template for future community-based research, signaling the promising impact of such interventions on holistic well-being. This research lays the foundation for subsequent phases of the ORBIT model, emphasizing collaborative, community-driven approaches to address the complex issue of declining physical activity levels among adolescents.

Efficacy of Fecal Microbiota, Live-jslm (REBYOTA®), Among Patients Exposed to Non-Clostridioides difficile Infection Antibiotics: Post Hoc Subgroup Analysis of a Phase 2 Open-Label Study.

Background: Antibiotic use is a major risk factor for recurrent Clostridioides difficile infection (CDI) due to the associated disruption in gut microbiota. Fecal microbiota, live-jslm (REBYOTA®; RBL, previously RBX2660), is the first microbiota-based live biotherapeutic approved by the US Food and Drug Administration to prevent recurrent CDI in adults following standard-of-care antibiotic treatment. To investigate the impact of non-CDI antibiotics on the durability of RBL, a subgroup analysis was conducted on PUNCH™ Open-Label study participants who received non-CDI antibiotics during the period between RBL administration and up to 2 years after. Methods: Participants in PUNCH™ Open-Label who received non-CDI antibiotics after RBL administration were included in this subgroup analysis. Treatment response was defined as the absence of CDI diarrhea needing retreatment at the last evaluable time point (8 weeks, 6 months, 1 year, or 2 years) after RBL administration. Results: Among participants from PUNCH™ Open-Label, 43 received non-CDI antibiotics after RBL administration but before CDI recurrence as evaluated over a 2-year period. Across all evaluable time points, 86% (37/43) of participants had a treatment response regardless of when non-CDI antibiotic exposure occurred. Treatment response was sustained for a median 470 days (IQR, 212-648) from the first day of non-CDI antibiotic use. Most participants (5/6) with CDI recurrences received a high-risk antibiotic. Conclusions: RBL remained efficacious in participants with a history of recurrent CDI after subsequent non-CDI antibiotic exposure. Clinical Trials Registration: NCT02589847 (https://clinicaltrials.gov/study/NCT02589847).

Prevalence and correlates of common mental disorders among participants of the Uganda Genome Resource: Opportunities for psychiatric genetics research.

Genetics research has potential to alleviate the burden of mental disorders in low- and middle-income-countries through identification of new mechanistic pathways which can lead to efficacious drugs or new drug targets. However, there is currently limited genetics data from Africa. The Uganda Genome Resource provides opportunity for psychiatric genetics research among underrepresented people from Africa. We aimed at determining the prevalence and correlates of major depressive disorder (MDD), suicidality, post-traumatic stress disorder (PTSD), alcohol abuse, generalised anxiety disorder (GAD) and probable attention-deficit hyperactivity disorder (ADHD) among participants of the Uganda Genome Resource. Standardised tools assessed for each mental disorder. Prevalence of each disorder was calculated with 95% confidence intervals. Multivariate logistic regression models evaluated the association between each mental disorder and associated demographic and clinical factors. Among 985 participants, prevalence of the disorders were: current MDD 19.3%, life-time MDD 23.3%, suicidality 10.6%, PTSD 3.1%, alcohol abuse 5.7%, GAD 12.9% and probable ADHD 9.2%. This is the first study to determine the prevalence of probable ADHD among adult Ugandans from a general population. We found significant association between sex and alcohol abuse (adjusted odds ratio [AOR] = 0.26 [0.14,0.45], p < 0.001) and GAD (AOR = 1.78 [1.09,2.49], p = 0.019) respectively. We also found significant association between body mass index and suicidality (AOR = 0.85 [0.73,0.99], p = 0.041), alcohol abuse (AOR = 0.86 [0.78,0.94], p = 0.003) and GAD (AOR = 0.93 [0.87,0.98], p = 0.008) respectively. We also found a significant association between high blood pressure and life-time MDD (AOR = 2.87 [1.08,7.66], p = 0.035) and probable ADHD (AOR = 1.99 [1.00,3.97], p = 0.050) respectively. We also found a statistically significant association between tobacco smoking and alcohol abuse (AOR = 3.2 [1.56,6.67], p = 0.002). We also found ever been married to be a risk factor for probable ADHD (AOR = 2.12 [0.88,5.14], p = 0.049). The Uganda Genome Resource presents opportunity for psychiatric genetics research among underrepresented people from Africa.

Light-activated azobenzene peptide inhibitor of the PD-1/PD-L1 interaction.

Inhibiting the PD-1/PD-L1 protein-protein interaction is a key immunotherapy for cancer. Antibodies dominate the clinical space but are costly, with limited applicability and immune side effects. We developed a photo-controlled azobenzene peptide that selectively inhibits the PD-1/PD-L1 interaction when in the cis isomer only. Activity is demonstrated in in vitro and cellular assays.

Mitochondrial bioenergetics are not associated with myofibrillar protein synthesis rates.

BACKGROUND: Mitochondria represent key organelles influencing cellular homeostasis and have been implicated in the signalling events regulating protein synthesis. METHODS: We examined whether mitochondrial bioenergetics (oxidative phosphorylation and reactive oxygen species (H2O2) emission, ROS) measured in vitro in permeabilized muscle fibres represent regulatory factors for integrated daily muscle protein synthesis rates and skeletal muscle mass changes across the spectrum of physical activity, including free-living and bed-rest conditions: n = 19 healthy, young men (26 ± 4 years, 23.4 ± 3.3 kg/m2) and following 12 weeks of resistance-type exercise training: n = 10 healthy older men (70 ± 3 years, 25.2 ± 2.1 kg/m2). Additionally, we evaluated the direct relationship between attenuated mitochondrial ROS emission and integrated daily myofibrillar and sarcoplasmic protein synthesis rates in genetically modified mice (mitochondrial-targeted catalase, MCAT). RESULTS: Neither oxidative phosphorylation nor H2O2 emission were associated with muscle protein synthesis rates in healthy young men under free-living conditions or following 1 week of bed rest (both P > 0.05). Greater increases in GSSG concentration were associated with greater skeletal muscle mass loss following bed rest (r = -0.49, P < 0.05). In older men, only submaximal mitochondrial oxidative phosphorylation (corrected for mitochondrial content) was positively associated with myofibrillar protein synthesis rates during exercise training (r = 0.72, P < 0.05). However, changes in oxidative phosphorylation and H2O2 emission were not associated with changes in skeletal muscle mass following training (both P > 0.05). Additionally, MCAT mice displayed no differences in myofibrillar (2.62 ± 0.22 vs. 2.75 ± 0.15%/day) and sarcoplasmic (3.68 ± 0.35 vs. 3.54 ± 0.35%/day) protein synthesis rates when compared with wild-type mice (both P > 0.05). CONCLUSIONS: Mitochondrial oxidative phosphorylation and reactive oxygen emission do not seem to represent key factors regulating muscle protein synthesis or muscle mass regulation across the spectrum of physical activity.

Bimanual Coordination in Children with Bilateral Cerebral Palsy: A Cross-Sectional Study.

AIM: To compare bimanual coordination in children with bilateral cerebral palsy (BCP) with that of children with typical development (TD) and correlate bimanual coordination with clinical measures of hand function. METHODS: 3-D kinematic data were collected from 14 children with BCP (mean age 13 years 1 month; range 7.3-17.2 years, 5 females) and 14 age-matched children with TD (mean age 13 years 1 month, range 7.0-16.0 years, 7 females) as they opened a drawer with one hand and activated a switch inside it with the other hand at self-paced and as-fast-as-possible speeds. Hand roles varied in each condition. Participants' hand function levels were classified using the Manual Ability Classification System. Unimanual dexterity and bimanual performance were evaluated using the Box and Blocks Test and Both Hands Assessment respectively. RESULTS: Participants with BCP performed the bimanual task more slowly (p < 0.001) and sequentially, as evidenced by greater time differences between the two hands achieving the end goal (p = 0.01). Faster speeds, particularly when the less affected hand opened the drawer, facilitated time-related measures of bimanual coordination (p < 0.05). Bimanual coordination correlated with all clinical measures of hand function (p < 0.05). CONCLUSION: For children with BCP, speed and hand used for each subcomponent of the task influence bimanual coordination. Better bimanual coordination is associated with less impairment of both hands.

Integrating rapid habitat mapping with community metrics and functional traits to assess estuarine ecological conditions: A New Zealand case study.

Estuarine ecosystems are under pressure from anthropogenic stressors in many parts of the world. In a New Zealand estuary, we integrated rapid habitat mapping, univariate and multivariate benthic community metrics and functional traits-based metrics to provide a holistic assessment of its ecological condition. Our integrative approach identified 11 different habitat classes across the study estuary and revealed how univariate, multivariate, and functional traits-based metrics varied spatially. Variation was driven mainly by sedimentary conditions, particularly, the sediment's organic matter and silt-clay content. Degraded conditions were apparent in several parts of the estuary, which overlapped with areas showing high concentrations of decaying algae, anoxic conditions, and low values of univariate and functional metrics. Our holistic approach, integrating mapping and quantitative community assessments, provided a more complete picture of estuarine conditions and enabled us to identify locations across the estuary with the greatest potential for restoration success.

Absolute-judgment models better predict eyewitness decision-making than do relative-judgment models.

When presented with a lineup, the witness is tasked with identifying the culprit or indicating that the culprit is not present. The witness then qualifies the decision with a confidence judgment. But how do witnesses go about making these decisions and judgments? According to absolute-judgment models, witnesses determine which lineup member provides the strongest match to memory and base their identification decision and confidence judgment on the absolute strength of this MAX lineup member. Conversely, relative-judgment models propose that witnesses determine which lineup member provides the strongest match to memory and then base their identification decision and confidence judgment on the relative strength of the MAX lineup member compared to the remaining lineup members. We took a critical test approach to test the predictions of both models. As predicted by the absolute-judgment model, but contrary to the predictions of the relative-judgment model, witnesses were more likely to correctly reject low-similarity lineups than high-similarity lineups (Experiment 1), and more likely to reject biased lineups than fair lineups (Experiment 2). Likewise, witnesses rejected low-similarity lineups with greater confidence than high-similarity lineups (Experiment 1) and rejected biased lineups with greater confidence than fair lineups (Experiment 2). Only a single pattern was consistent with the relative model and inconsistent with the absolute model: suspect identifications from biased lineups were made with greater confidence than suspect identifications from fair lineups (Experiment 2). The results suggest that absolute-judgment models better predict witness decision-making than do relative-judgment models and that pure relative-judgment models are unviable.

NMDA and GABA Receptor-Mediated Plasticity Induced by 10-Hz Repetitive Transcranial Magnetic Stimulation.

Although 10-Hz repetitive transcranial magnetic stimulation (rTMS) is an FDA-approved treatment for depression, we have yet to fully understand the mechanism through which rTMS induces therapeutic and durable changes in the brain. Two competing theories have emerged suggesting that 10-Hz rTMS induces N-methyl-D-aspartate receptor (NMDAR)-dependent long-term potentiation (LTP), or alternatively, removal of inhibitory gamma-aminobutyric acid receptors (GABARs). We examined these two proposed mechanisms of action in the human motor cortex in a double-blind, randomized, four-arm crossover study in healthy subjects. We tested motor-evoked potentials (MEPs) before and after 10-Hz rTMS in the presence of four drugs separated by 1-week each: placebo, NMDAR partial agonist d-cycloserine (DCS 100mg), DCS 100mg + NMDAR partial antagonist dextromethorphan (DMO 150mg; designed to "knock down" DCS-mediated facilitation), and GABAR agonist lorazepam (LZP 2.5mg). NMDAR agonism by DCS enhanced rTMS-induced cortical excitability more than placebo. This enhancement was blocked by combining DCS with NMDAR antagonist, DMO. If GABARs are removed by rTMS, GABAR agonism via LZP should lack its inhibitory effect yielding higher post/pre MEPs. However, MEPs were reduced after rTMS indicating stability of GABAR numbers. These data suggest that 10-Hz rTMS facilitation in the healthy motor cortex may enact change in the brain through NMDAR-mediated LTP-like mechanisms rather than through GABAergic reduction.

Skeletal effects of sleeve gastrectomy, by sex and menopausal status and in comparison to Roux-en-Y gastric bypass surgery.

Context: Roux-en-Y gastric bypass (RYGB) has deleterious effects on bone mass, microarchitecture, and strength. Data are lacking on the skeletal effects of sleeve gastrectomy (SG), now the most commonly performed bariatric surgical procedure. Objective: We examined changes in bone turnover, areal and volumetric bone mineral density (aBMD, vBMD), and appendicular bone microarchitecture and estimated strength after SG. We compared the results to those previously reported after RYGB, hypothesizing lesser effects after SG than RYGB. Design Setting Participants: Prospective observational cohort study of 54 adults with obesity undergoing SG at an academic center. Main Outcome Measures: Skeletal characterization with biochemical markers of bone turnover, dual-energy X-ray absorptiometry (DXA), quantitative computed tomography (QCT), and high-resolution peripheral QCT (HR-pQCT) was performed preoperatively and 6- and 12-months postoperatively. Results: Over 12 months, mean percentage weight loss was 28.8%. Bone turnover marker levels increased, and total hip aBMD decreased -8.0% (95% CI -9.1%, -6.7%, p<0.01). Spinal aBMD and vBMD declines were larger in postmenopausal women than men. Tibial and radial trabecular and cortical microstructure worsened, as did tibial estimated strength, particularly in postmenopausal women. When compared to data from a RYGB cohort with identical design and measurements, some SG biochemical, vBMD, and radial microstructural parameters were smaller, while other changes were not. Conclusions: Bone mass, microstructure, and strength decrease after SG. Some skeletal parameters change less after SG than after RYGB, while for others, we find no evidence for smaller effects after SG. Postmenopausal women may be at highest risk of skeletal consequences after SG.

Fabrication and assessment of a bio-inspired synthetic tracheal tissue model for tracheal tube cuff leakage testing.

Introduction: Leakage of orogastric secretions past the cuff of a tracheal tube is a contributory factor in ventilator-associated pneumonia. Current bench test methods specified in the International Standard for Anaesthetic and Respiratory Equipment (EN ISO 5361:2023) to test cuff leakage involve using a glass or plastic rigid cylinder model of the trachea. There is a need for more realistic models to inform cuff leakage. Methods: We used human computerised tomography data and additive manufacturing (3D printing), combined with casting techniques to fabricate a bio-inspired synthetic tracheal model with analogous tissue characteristics. We conducted cuff leakage tests according to EN ISO 5361:2023 and compared results for high-volume low-pressure polyvinyl chloride and polyurethane cuffs between the rigid cylinder trachea with our bio-inspired model. Results: The tracheal model demonstrated close agreement with published tracheal tissue hardness for cartilaginous and membranous soft tissues. For high-volume low-pressure polyvinyl chloride cuffs the leakage rate was >50% lower in the bio-inspired tracheal model compared with the rigid cylinder model (151 [8] vs 261 [11] ml h-1). For high-volume low-pressure polyurethane cuffs, much lower leakage rates were observed than polyvinyl chloride cuffs in both models with leakage rates higher for the bio-inspired trachea model (0.1 [0.2] vs 0 [0] ml h-1). Conclusion: A reproducible tracheal model that incorporates the mechanical properties of the human trachea can be manufactured from segmented CT images and additive manufactured moulds, providing a useful tool to inform future cuff development, leakage testing for industrial applications, and clinical decision-making. There are differences between cuff leakage rates between the bio-inspired model and the rigid cylinder recommended in EN ISO 5361:2023. The bio-inspired model could lead to more accurate and realistic cuff leakage rate testing which would support manufacturers in refining their designs. Clinicians would then be able to choose better tracheal tubes based on the outcomes of this testing.

Total Synthesis of a Peptide Diatom Sex Pheromone Bearing a Sulfated Aspartic Acid.

The peptide sex-inducing pheromone SIP+ (1) bearing an unusual sulfated aspartic acid residue induces sexual reproduction in diatom populations. Herein, we report the first total synthesis of SIP+ using both a sulfated building block approach and a solid-phase peptide synthesis (SPPS)-compatible late-stage sulfation strategy to assemble the natural product. The modular approaches provide concise routes to useful quantities of the natural product for future structure activity relationship studies examining the role of SIP+ in diatom biology.

Comparison of accuracy, revision, and perioperative outcomes in robot-assisted spine surgeries: systematic review and meta-analysis.

OBJECTIVE: Pedicle screw placement guidance is critical in spinal fusions, and spinal surgery robots aim to improve accuracy and reduce complications. Current literature has yet to compare the relative merits of available robotic systems. In this review, the authors aimed to 1) assess the current state of spinal robotics literature; 2) conduct a meta-analysis of robotic performance based on accuracy, speed, and safety; and 3) offer recommendations for robotic system selection. METHODS: Following PRISMA guidelines, the authors conducted a systematic literature review across PubMed, Embase, Cochrane Library, Web of Science, and Scopus as of April 28, 2022, for studies on approved robots for placing lumbar pedicle screws. Three reviewers screened and extracted data relating to the study characteristics, accuracy rate, intraoperative revisions, and reoperations. Secondary performance metrics included operative time, blood loss, and radiation exposure. The authors statistically compared the performance of the robots using a random-effects model to account for variation within and between the studies. Each robot was also compared with performance benchmarks of traditional techniques including freehand, fluoroscopic, and CT-navigated insertion. Finally, we performed a Duval and Tweedie trim-and-fill test to assess for the presence of publication bias. RESULTS: The authors identified 46 studies, describing 4670 patients and 25,054 screws, that evaluated 4 different robotic systems: Mazor X, ROSA, ExcelsiusGPS, and Cirq. The weighted accuracy rates of Gertzbein-Robbins classification grade A or B screws were as follows: ExcelsiusGPS, 98.0%; ROSA, 98.0%; Mazor, 98.2%; and Cirq, 94.2%. No robot was significantly more accurate than the others. However, the accuracy of the ExcelsiusGPS was significantly higher than that of traditional methods, and the accuracies of the Mazor and ROSA were significantly higher than that of fluoroscopy. The intraoperative revision rates were Cirq, 0.55%; ROSA, 0.91%; Mazor, 0.98%; and ExcelsiusGPS, 1.08%. The reoperation rates were Cirq, 0.28%; ExcelsiusGPS, 0.32%; and Mazor, 0.76% (no reoperations were reported for ROSA). Operative times were similar for all robots. Both the ExcelsiusGPS and Mazor were associated with significantly less blood loss than the ROSA. The Cirq had the lowest radiation exposure. Robots tended to be more accurate and generally their use was associated with fewer reoperations and less blood loss than freehand, fluoroscopic, or CT-navigated techniques. CONCLUSIONS: Robotic platforms perform comparably based on key metrics, with high accuracy rates and low intraoperative revision and reoperation rates. The spinal robotics publication rate will continue to accelerate, and choosing a robot will depend on the context of the practice.

A rare case of aortitis presenting as chest pain: a case report and literature review.

Introduction and importance: Chest pain is a frequent reason patients seek medical attention. The broad spectrum of potential etiologies makes determining the underlying cause of chest pain complex. Among cardiovascular etiologies, aortitis is a rare but life-threatening possibility that should be considered in the differential diagnosis. Case presentation: A 53-year-old female with a history of smoking presented with progressively worsening chest and epigastric pain over several weeks. She had seen multiple physicians previously for the same symptoms with unremarkable work-ups. Physical examination was notable for severe tenderness upon palpation of her lower abdomen. The electrocardiogram and troponins were unremarkable. Computed tomography of the abdomen revealed aneurysmal dilatation of the abdominal aorta, soft tissue thickening, and surrounding inflammatory stranding, consistent with aortitis. Infectious and autoimmune work-ups were unremarkable. Intravenous steroids were initiated, and her symptoms improved significantly. Her aortitis was attributed to inflammation secondary to chronic smoking. Clinical discussion: Aortitis is a rare condition with varied clinical presentations. Etiologies of aortitis include infection and non-infectious inflammation. Diagnosis of aortitis requires a thorough clinical assessment and prompt imaging of the aorta, with computed tomography being the preferred imaging modality. Conclusion: Evaluation for cardiovascular chest pain must extend beyond an electrocardiogram and troponin level. Imaging should be considered in patients with atypical symptoms. Aortitis is a rare but important diagnosis requiring immediate treatment.

Hepatic artery infusion pump (HAIP) therapy in combination with targeted delivery of IL-12 for patients with metastatic colorectal cancer or intrahepatic cholangiocarcinoma: a phase II trial protocol.

Background: Treatment of advanced liver tumors remains challenging. Although immune checkpoint inhibition has revolutionized treatment for many cancers, responses in colorectal liver metastases and biliary tract cancers remain suboptimal. Investigation into additional immunomodulatory therapies for these cancers is needed. Interleukin-12 (IL-12) is a pro-inflammatory cytokine with robust anti-tumor activity, but systemic adverse effects largely terminated therapeutic development of recombinant human IL-12 (rhIL-12). PDS01ADC is a novel human monoclonal antibody (NHS76) conjugated to two IL-12 heterodimers with established safety in phase I trials. The NHS76 antibody specifically targets histone/DNA complexes which are accessible only in regions of cell death and this antibody has been shown to accumulate locally in tumors. Methods: Patients with unresectable metastatic colorectal cancer (mCRC) or unresectable intrahepatic cholangiocarcinoma (ICC) will receive synchronization of subcutaneous PDS01ADC with floxuridine delivered via a hepatic artery infusion pump (HAIP). The primary outcome measured in this study will be overall response rate as measured by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Secondary outcomes measured in this study will include hepatic and non-hepatic progression-free survival (PFS), overall survival, and safety of PDS01ADC combination therapy with HAIP. Discussion: Poor clinical response of these liver tumors to immunotherapy is likely due to various factors, including poor immune infiltrate into the tumor and immunosuppression by the tumor microenvironment. By exploiting the tumor cell death induced by HAIP locoregional therapy in combination with systemic chemotherapy, PDS01ADC is poised to modulate the tumor immune microenvironment to improve outcomes for patients undergoing HAIP therapy. Trial Registration: ClinicalTrials.gov (ID NCT05286814 version 2023-10-18); https://clinicaltrials.gov/study/NCT05286814?term=NCT05286814&rank=1.

Effect of Supplemental Oxygen on Physiological Responses to Exercise in Fibrotic Interstitial Lung Disease.

PURPOSE: We studied the effect of O2 supplementation on physiological response to exercise in patients with moderate to severe interstitial lung disease (ILD). METHODS: 13 patients (age 66 ± 10 yrs., 7 males) with ILD (TLC 71 ± 22% predicted, carbon monoxide diffusion capacity (DLCO) 44 ± 16% predicted) and 13 healthy individuals (age 50 ± 17 yrs., 7 males) were tested. ILD patients performed symptom-limited cardiopulmonary exercise tests and constant work-rate tests (CWRTs) at 80% of the work-rate (WR) at the gas exchange threshold (GET). Tests breathing room air (RA, 21% O2) were compared to tests performed breathing 30% O2. Oxygen-uptake (V̇O2) kinetics were calculated from the CWRT results. RESULTS: In the ILD group, peak WR, peak V̇O2 and V̇O2 at the GET improved significantly when breathing 30% O2 compared to RA (mean ± SD 66 ± 23 vs 75 ± 26 watts, 15 ± 2 vs 17 ± 4 ml/kg/min and 854 ± 232 vs 932 ± 245 ml/min; p = 0.004, p = 0.001 and p = 0.01, respectively). O2 saturation (SPO2%) at peak exercise was higher with 30% O2 (97 ± 4% vs 88 ± 9%, p = 0.002). The time constant (tau) of V̇O2 kinetics was faster in ILD patients while breathing 30% O2 (41 ± 10 sec) compared to RA (52 ± 14 sec, p = 0.003). There was a negative linear relation between tau and SPO2% with RA (r = -0.76, p = 0.006) and while breathing 30% O2 (r = -0.68, p = 0.02). CONCLUSIONS: Using a clinically applicable level of O2 supplementation (30%) improved maximal, aerobic exercise capacity and V̇O2 kinetics in ILD patients, likely due to increased blood O2 content subsequently increasing the O2 delivery to the working muscles.

Collaterals at angiography guide clinical outcomes after endovascular stroke therapy in HERMES.

BACKGROUND: Robust collateral circulation has been linked with better reperfusion and clinical outcomes. It remains unclear how individual assessments of collateral circulation may be translated into clinical practice. METHODS: The pooled Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke Trials (HERMES) angiography dataset was analyzed by a centralized, independent imaging core blinded to other clinical data. Conventional angiography was acquired immediately prior to endovascular therapy. Collaterals were graded with the American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology (ASITN) system and associated with baseline patient characteristics, reperfusion, and day 90 modified Rankin Score (mRS). Both 90-day all-cause mortality and day 90 mRS were modeled via multivariable logistic regression. RESULTS: Angiography was available in 376/605 (62%) patients. Baseline ASPECTS (Alberta Stroke Program Early CT Score) (p=0.043), history of diabetes mellitus (p=0.048), site of occlusion (p<0.001), and degree of subsequent Thrombolysis in Cerebral Infarction (TICI) reperfusion (p<0.001) were associated with collateral grades. ASITN collateral grade was strongly associated with ordinal mRS from baseline to 90 days in an unadjusted analysis (p<0.001). Multivariable regression demonstrated that collateral status is a strong determinant of mRS outcome in the presence of other predictors (OR=1.37 per grade, 95% CI [1.05 to 1.74], p=0.018). By comparing ORs, 1 unit of ASITN was determined to be approximately equivalent to 4.5 points of NIHSS, 11 years of age, 1.5 points of ASPECTS, or 100 min less delay from onset to puncture, in terms of impact on mRS. CONCLUSIONS: Individual collateral physiology may contribute significantly to reperfusion success and clinical outcomes after acute ischemic stroke. Building a consensus for the role of angiographic collateral assessment in the allocation of adjuvant reperfusion therapies may help galvanize a precision medicine approach in stroke.