Neutrophil serine proteases in cystic fibrosis: role in disease pathogenesis and rationale as a therapeutic target.

Chronic airway inflammation is a central feature in the pathogenesis of bronchiectasis (BE), which can be caused by cystic fibrosis (CFBE; hereafter referred to as CF lung disease) and non-CF-related conditions (NCFBE). Inflammation in both CF lung disease and NCFBE is predominantly driven by neutrophils, which release proinflammatory cytokines and granule proteins, including neutrophil serine proteases (NSPs). NSPs include neutrophil elastase, proteinase 3 and cathepsin G. An imbalance between NSPs and their antiproteases has been observed in people with CF lung disease and people with NCFBE. While the role of the protease/antiprotease imbalance is well established in both CF lung disease and NCFBE, effective therapies targeting NSPs are lacking. In recent years, the introduction of CF transmembrane conductance regulator (CFTR) modulator therapy has immensely improved outcomes in many people with CF (pwCF). Despite this, evidence suggests that airway inflammation persists, even in pwCF treated with CFTR modulator therapy. In this review, we summarise current data on neutrophilic inflammation in CF lung disease to assess whether neutrophilic inflammation and high, uncontrolled NSP levels play similar roles in CF lung disease and in NCFBE. We discuss similarities between the neutrophilic inflammatory profiles of people with CF lung disease and NCFBE, potentially supporting a similar therapeutic approach. Additionally, we present evidence suggesting that neutrophilic inflammation persists in pwCF treated with CFTR modulator therapy, at levels similar to those in people with NCFBE. Collectively, these findings highlight the ongoing need for new treatment strategies targeting neutrophilic inflammation in CF lung disease.

Kuramoto variables as eigenvalues of unitary matrices.

We generalize the Kuramoto model by interpreting the N variables on the unit circle as eigenvalues of a N-dimensional unitary matrix U in three versions: general unitary, symmetric unitary, and special orthogonal. The time evolution is generated by N^{2} coupled differential equations for the matrix elements of U, and synchronization happens when U evolves into a multiple of the identity. The Ott-Antonsen ansatz is related to the Poisson kernels that are so useful in quantum transport, and we prove it in the case of identical natural frequencies. When the coupling constant is a matrix, we find some surprising new dynamical behaviors.

A systematic literature review of the clinical and socioeconomic burden of bronchiectasis.

BACKGROUND: The overall burden of bronchiectasis on patients and healthcare systems has not been comprehensively described. Here, we present the findings of a systematic literature review that assessed the clinical and socioeconomic burden of bronchiectasis with subanalyses by aetiology (PROSPERO registration: CRD42023404162). METHODS: Embase, MEDLINE and the Cochrane Library were searched for publications relating to bronchiectasis disease burden (December 2017-December 2022). Journal articles and congress abstracts reporting on observational studies, randomised controlled trials and registry studies were included. Editorials, narrative reviews and systematic literature reviews were included to identify primary studies. PRISMA guidelines were followed. RESULTS: 1585 unique publications were identified, of which 587 full texts were screened and 149 were included. A further 189 citations were included from reference lists of editorials and reviews, resulting in 338 total publications. Commonly reported symptoms and complications included dyspnoea, cough, wheezing, sputum production, haemoptysis and exacerbations. Disease severity across several indices and increased mortality compared with the general population was reported. Bronchiectasis impacted quality of life across several patient-reported outcomes, with patients experiencing fatigue, anxiety and depression. Healthcare resource utilisation was considerable and substantial medical costs related to hospitalisations, treatments and emergency department and outpatient visits were accrued. Indirect costs included sick pay and lost income. CONCLUSIONS: Bronchiectasis causes significant clinical and socioeconomic burden. Disease-modifying therapies that reduce symptoms, improve quality of life and reduce both healthcare resource utilisation and overall costs are needed. Further systematic analyses of specific aetiologies and paediatric disease may provide more insight into unmet therapeutic needs.

Lentiviral Gene Therapy for Cystic Fibrosis: A Promising Approach and First-In-Human Trial.

Cystic fibrosis is a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. While cystic fibrosis is a multi-organ disease, the leading causes of morbidity and mortality are related to progressive lung disease. Current understanding of the effects of the broad spectrum of CFTR mutations on CFTR function has allowed for the development of CFTR modulator therapies. Despite the remarkable impact that these therapies have had, there remains a significant proportion of people with cystic fibrosis (estimated at 10-15% of the global cystic fibrosis population) who are genetically ineligible for, or intolerant to, current CFTR-targeting therapies and whose therapeutic needs remain unmet. Inhaled genetic therapies offer the prospect of addressing the unmet pulmonary treatment need in people with cystic fibrosis, with several approaches, including gene addition therapy (the focus of this review), RNA-based therapies, antisense oligonucleotides and gene editing, being explored. Various non-viral and viral vectors have been investigated for cystic fibrosis gene addition therapy for mutation-agnostic restoration of CFTR function in the lungs. Lentiviral vectors offer the prospect of highly efficient and long-lasting gene expression, and the potential to be safely and, in contrast to other commonly used viral vectors, effectively re-dosed. A third-generation lentiviral vector pseudotyped with Sendai virus F and HN envelope proteins (rSIV.F/HN) has been developed for the treatment of cystic fibrosis. Promising preclinical results support the progression of this vector carrying a full-length CFTR transgene (BI 3720931) into a first-in-human clinical trial expected to begin in 2024.

SLPI deficiency alters airway protease activity and induces cell recruitment in a model of muco-obstructive lung disease.

Secretory leukocyte protease inhibitor (SLPI) is an important cationic protein involved in innate airway immunity and highly expressed in mucosal secretions, shown to target and inhibit neutrophil elastase (NE), cathepsin G and trypsin activity to limit proteolytic activity. In addition to the potent anti-protease activity, SLPI has been demonstrated to exert a direct anti-inflammatory effect, which is mediated via increased inhibition and competitive binding of NF-κB, regulating immune responses through limiting transcription of pro-inflammatory gene targets. In muco-obstructive lung disorders, such as Chronic Obstructive Pulmonary Disease (COPD) and Cystic Fibrosis (CF), there is an observed elevation in airway SLPI protein concentrations as a result of increased lung inflammation and disease progression. However, studies have identified COPD patients presenting with diminished SLPI concentrations. Furthermore, there is a decrease in SLPI concentrations through cleavage and subsequent inactivation by NE degradation in Pseudomonas aeruginosa infected people with CF (pwCF). These observations suggest reduced SLPI protein levels may contribute to the compromising of airway immunity indicating a potential role of decreased SLPI levels in the pathogenesis of muco-obstructive lung disease. The Beta Epithelial Na+ Channel transgenic (ENaC-Tg) mouse model phenotype exhibits characteristics which replicate the pathological features observed in conditions such as COPD and CF, including mucus accumulation, alterations in airway morphology and increased pulmonary inflammation. To evaluate the effect of SLPI in muco-obstructive pulmonary disease, ENaC-Tg mice were crossed with SLPI knock-out (SLPI-/-) mice, generating a ENaC-Tg/SLPI-/- colony to further investigate the role of SLPI in chronic lung disease and determine the effect of its ablation on disease pathogenesis.

Outcomes of Surgical Treatment for Multiligament Knee Injuries in a Cohort Including Competitive Athletes With Long-Term Follow-Up.

Background: There is a paucity of outcomes data on surgical reconstruction for multiligament knee injury (MLKI) in the orthopaedic literature. Purpose: To examine functional and return-to-sports (RTS) outcomes and revision rates after single-stage reconstruction for MLKIs in a cohort containing a large proportion of competitive athletes over a 20-year period. Study Design: Case series; Level of evidence, 4. Methods: We identified all patients at our institution who underwent surgical reconstruction for an anterior cruciate ligament (ACL) or bicruciate (ACL-posterior cruciate ligament) MLKI between 2001 and 2020 and had ≥2 years of postoperative outcome data. Patient-reported outcomes were evaluated using the International Knee Documentation Committee (IKDC) form, a surgical satisfaction survey, and questions about subsequent knee surgery and RTS administered via telephone. Summary statistics for all outcomes data were calculated, and predictors of IKDC scores at follow-up were examined using univariable linear regression. Results: Out of 151 patients eligible for this study, outcomes data were collected in 119 patients (79%). The mean follow-up time was 8.3 ± 4.4 years, and the mean IKDC score at follow-up was 79 ± 17. A total of 83 competitive athletes were included; 62 of these athletes attempted to return to preinjury sport. Among the 62 who attempted RTS, 50 (81%) were successful, and 12 were unable to return due to limitations from their surgery. At follow-up, 112 of the overall cohort of 119 patients (94%) were either satisfied or very satisfied with their surgical outcome, and 91% stated the surgery met or exceeded their expectations. In addition, 24% had subsequent ipsilateral knee operations after their index multiligament knee reconstruction. Older age at surgery and female sex were associated with worse IKDC scores at follow-up. Conclusion: Despite the severity of the injuries in our cohort, we found high levels of patient-reported function and a high rate of successful RTS in the competitive athletes. Older age and female sex were associated with worse patient-reported knee function at follow-up.

Longitudinal Magnetic Resonance Imaging of Changes in Lung Morphology and Perfusion in Children with Cystic Fibrosis From Infancy through Adolescence.

RATIONALE: The progression of lung changes in cystic fibrosis (CF) from infancy through adolescence remains poorly understood due to limited longitudinal imaging data. OBJECTIVES: To assess changes in lung morphology and perfusion in children with CF through the pediatric age range by longitudinal chest magnetic resonance imaging (MRI). METHODS: 1112 annual chest MRI were performed in 226 patients with CF aged 0-18yr. MRI was assessed using a validated MRI scoring system. MEASUREMENTS AND MAIN RESULTS: The MRI global score continuously increased from 5.5±4.6 at infancy (0yr) to 17.9±8.4 at adolescence (range 12-18yr), and the MRI morphology score from 5.0±3.9 to 12.4±6.0 (P<0.001). Bronchiectasis/wall thickening prevalence increased from 89.1% at infancy to approx. 100% from preschool age (1-5yr), and the subscore increased from 3.1±1.9 at infancy to 6.6±2.1 at adolescence (P<0.001). Mucus plugging prevalence increased from 55.4% at infancy to 83.5% at adolescence, and the subscore increased from 1.2±1.6 to 3.7±2.5 in the same period (P<0.001). Perfusion abnormalities were found in 44.4% at infancy, and increased to approx. 90% from preschool age (P<0.001). The MRI perfusion score increased from 1.1±1.6 at infancy to 5.6±3.0 at adolescence (P<0.001). Chronic Pseudomonas aeruginosa infection was associated with higher MRI scores from school age (6-11yr, P<0.05-0.001). CONCLUSIONS: This is the first study assessing longitudinal changes in lung morphology and perfusion in CF throughout the pediatric age range, providing percentiles as age-specific reference for lung disease severity. Our data may facilitate the use of MRI as an endpoint in clinical trials in children with CF.

Cathepsin C (dipeptidyl peptidase 1) inhibition in adults with bronchiectasis: AIRLEAF®, a Phase II randomised, double-blind, placebo-controlled, dose-finding study.

Bronchiectasis is characterised by uncontrolled neutrophil serine protease (NSP) activity. Cathepsin C (CatC; dipeptidyl peptidase 1) activates NSPs during neutrophil maturation. CatC inhibitors can potentially reduce neutrophil-mediated lung damage. This Phase II, randomised, double-blind, placebo-controlled trial (AIRLEAF®; NCT05238675) evaluated efficacy, safety and optimal dosing of BI 1291583, a novel, reversible CatC inhibitor, in adults with bronchiectasis.In total, 322 participants were randomised (2:1:1:2) to receive one of three oral doses of BI 1291583 (1 mg/2.5 mg/5 mg) or placebo for 24 to 48 weeks. A multiple comparison procedure and modelling approach was used to demonstrate a non-flat dose-response curve based on the time to first pulmonary exacerbation up to Week 48. In addition, efficacy of individual BI 1291583 doses was evaluated based on the frequency of exacerbations, severe exacerbations (fatal or leading to hospitalisation and/or intravenous antibiotic administration), lung function and quality of life.A significant dose-dependent benefit of BI 1291583 over placebo was established based on time to first exacerbation (shape: Emax; adjusted p-value: 0.0448). Treatment with BI 1291583 5 mg and 2.5 mg numerically reduced the risk of an exacerbation compared with placebo (hazard ratios: 0.71 and 0.66, 95% CIs 0.48-1.05 and 0.40-1.08; both p>0.05). BI 1291583 2.5 mg showed numerically better efficacy compared with 5 mg across several endpoints; 1 mg was similar to placebo. The safety profile of BI 1291583 was similar to placebo.Treatment with BI 1291583 resulted in a reduction in the risk of experiencing an exacerbation in adults with bronchiectasis.

Kinetochore and ionomic adaptation to whole-genome duplication in Cochlearia shows evolutionary convergence in three autopolyploids.

Whole-genome duplication (WGD) occurs in all kingdoms and impacts speciation, domestication, and cancer outcome. However, doubled DNA management can be challenging for nascent polyploids. The study of within-species polyploidy (autopolyploidy) permits focus on this DNA management aspect, decoupling it from the confounding effects of hybridization (in allopolyploid hybrids). How is autopolyploidy tolerated, and how do young polyploids stabilize? Here, we introduce a powerful model to address this: the genus Cochlearia, which has experienced many polyploidization events. We assess meiosis and other polyploid-relevant phenotypes, generate a chromosome-scale genome, and sequence 113 individuals from 33 ploidy-contrasting populations. We detect an obvious autopolyploidy-associated selection signal at kinetochore components and ion transporters. Modeling the selected alleles, we detail evidence of the kinetochore complex mediating adaptation to polyploidy. We compare candidates in independent autopolyploids across three genera separated by 40 million years, highlighting a common function at the process and gene levels, indicating evolutionary flexibility in response to polyploidy.

Identification of common textile microplastics via autofluorescence spectroscopy coupled with k-means cluster analysis.

Microplastics are an emerging anthropogenic pollutant risk with a significant body of research dedicated to understanding the implications further. To generate the databases required to characterize the impact of microplastics on our environment, and improve recovery and recycling of current plastic materials, we need rapid, in-line characterization that can distinguish individual polymer types. Here, autofluorescence spectroscopy was investigated as an alternative characterization method to the current leading techniques based on vibrational spectroscopy. It was confirmed that the autofluorescence of seven common textile polymers (acrylic, polyester, nylon, polyethylene, polypropylene, cellulose/cotton, wool) arose due to the cluster-triggered emission phenomenon. Both simulated polymer aging via photooxidation and dyeing of the polymers were found to affect the resultant autofluorescence spectra. A total of 1485 spectra from 39 unique sample groups (polymer type, colour, and degree of photooxidation) were analysed via machine learning (k-means cluster analysis). Correct identification of the polymer type was achieved in 71% of the cases from only eight input values (normalized intensity values at three autofluorescence emission wavelengths, the total autofluorescence emission intensity, the sample RGB colour values, and the sample shape). This represents a significant step towards automated polymer identification at the sub-second time scales required for the in-line characterization of microplastics.

Long-Term Impact of Lumacaftor/Ivacaftor Treatment on Cystic Fibrosis Disease Progression in Children 2 Through 5 Years of Age Homozygous for F508del-CFTR: A Phase 2, Open-Label Clinical Trial.

RATIONALE: Clinical trials show that lumacaftor/ivacaftor (LUM/IVA) treatment has the potential to modify early cystic fibrosis (CF) disease progression in children as young as 2 years of age. OBJECTIVE: To assess the long-term impact of LUM/IVA treatment on CF disease progression in children aged 2 through 5 years. METHODS: This phase 2 trial had two parts: Part 1, a 48-week, randomized, double-blind, placebo-controlled study of LUM/IVA in children aged 2 through 5 years (previously reported) was followed by a 48-week open-label treatment period where all children received LUM/IVA (Part 2; reported here). Endpoints assessed in Part 2 included absolute changes from baseline in chest magnetic resonance imaging (MRI) global score at week 96; weight-for-age, stature-for-age, and body mass index (BMI)-for-age z-scores at week 96; lung clearance index (LCI2.5) through week 96; chest MRI morphological score, chest MRI perfusion score, weight, stature, BMI, and microbiology cultures (oropharyngeal swabs) at week 96; sweat chloride, serum levels of immunoreactive trypsinogen, fecal elastase-1 levels, and fecal calprotectin through week 96; and number of pulmonary exacerbations (PEx), time-to-first PEx, and number of CF-related hospitalizations. RESULTS: Forty-nine children received ≥1 dose of LUM/IVA in the open-label period (33 in the LUM/IVA to LUM/IVA group and 16 in the placebo to LUM/IVA group); mean exposure 47.1 (SD, 5.2) weeks. The mean absolute change in MRI global score (negative value = improvement) from baseline at Week 96 was -2.7 (SD 7.0; 95% CI, -5.2 to -0.1) in the LUM/IVA to LUM/IVA group and -5.6 (SD 6.9; 95% CI, -9.2 to -1.9) in the placebo to LUM/IVA group. Improvements in LCI2.5, sweat chloride concentration, and markers of pancreatic function and intestinal inflammation were also observed in both groups. Growth parameters remained stable in both groups. The majority of children had adverse events (AEs) considered mild (38.8%) or moderate (40.8%). Two (4.1%) children discontinued LUM/IVA treatment due to AEs (distal intestinal obstruction syndrome [n=1] and alanine aminotransferase increase [n=1]). CONCLUSION: These findings confirm the potential for early LUM/IVA treatment to alter the trajectory of CF disease progression, including CF lung disease, in children as young as 2 years of age. Clinical trial registration available at www. CLINICALTRIALS: gov, ID: NCT03625466.

Secondary Endpoint Utilization and Publication Rate among Phase III Oncology Trials.

Secondary endpoints (SEP) provide crucial information in the interpretation of clinical trials, but their features are not yet well understood. Thus, we sought to empirically characterize the scope and publication rate of SEPs among late-phase oncology trials. We assessed SEPs for each randomized, published phase III oncology trial across all publications and ClinicalTrials.gov, performing logistic regressions to evaluate associations between trial characteristics and SEP publication rates. After screening, a total of 280 trials enrolling 244,576 patients and containing 2,562 SEPs met the inclusion criteria. Only 22% of trials (62/280) listed all SEPs consistently between ClinicalTrials.gov and the trial protocol. The absolute number of SEPs per trial increased over time, and trials sponsored by industry had a greater number of SEPs (median 9 vs. 5 SEPs per trial; P < 0.0001). In total, 69% of SEPs (1,770/2,562) were published. The publication rate significantly varied by SEP category [X2 (5, N = 2,562) = 245.86; P < 0.001]. SEPs that place the most burden on patients, such as patient-reported outcomes and translational correlatives, were published at 63% (246/393) and 44% (39/88), respectively. Trials with more SEPs were associated with lower overall SEP publication rates. Overall, our findings are that SEP publication rates in late-phase oncology trials are highly variable based on the type of SEP. To avoid undue burden on patients and promote transparency of findings, trialists should weigh the biological and clinical relevance of each SEP together with its feasibility at the time of trial design. SIGNIFICANCE: In this investigation, we characterized the utilization and publication rates of SEPs among late-phase oncology trials. Our results draw attention to the proliferation of SEPs in recent years. Although overall publication rates were high, underpublication was detected among endpoints that may increase patient burden (such as translational correlatives and patient-reported outcomes).

Cystic fibrosis.

Cystic fibrosis is a rare genetic disease caused by mutations in CFTR, the gene encoding cystic fibrosis transmembrane conductance regulator (CFTR). The discovery of CFTR in 1989 has enabled the unravelling of disease mechanisms and, more recently, the development of CFTR-directed therapeutics that target the underlying molecular defect. The CFTR protein functions as an ion channel that is crucial for correct ion and fluid transport across epithelial cells lining the airways and other organs. Consequently, CFTR dysfunction causes a complex multi-organ disease but, to date, most of the morbidity and mortality in people with cystic fibrosis is due to muco-obstructive lung disease. Cystic fibrosis care has long been limited to treating symptoms using nutritional support, airway clearance techniques and antibiotics to suppress airway infection. The widespread implementation of newborn screening for cystic fibrosis and the introduction of a highly effective triple combination CFTR modulator therapy that has unprecedented clinical benefits in up to 90% of genetically eligible people with cystic fibrosis has fundamentally changed the therapeutic landscape and improved prognosis. However, people with cystic fibrosis who are not eligible based on their CFTR genotype or who live in countries where they do not have access to this breakthrough therapy remain with a high unmet medical need.

Rising to the Challenge: An ID Provider-Led Initiative to Address Penicillin Allergy Labels at a Large Veterans Affairs Medical Center.

Background: Given the negative consequences associated with a penicillin allergy label, broader penicillin allergy delabeling initiatives are highly desirable but hindered by the shortage of allergists in the United States. To address this problem at our facility, the infectious diseases section introduced a quality improvement initiative to evaluate and remove allergy labels among inpatient veterans. Methods: Between 15 November 2022 and 15 December 2023, we identified inpatients with a penicillin allergy label. We subsequently interviewed eligible candidates to stratify penicillin allergy risk and attempt to remove the allergy label directly via chart review, following inpatient oral amoxicillin challenge or outpatient community care allergy referral. Delabeling outcomes, subsequent penicillin-class prescriptions, and relabeling were tracked after successful allergy label removal. Results: We screened 272 veterans, of whom 154 were interviewed for this intervention. A total of 53 patients were delabeled: 26 directly, 23 following oral amoxicillin challenge, and 4 following outpatient allergy referrals. Of the patients who were delabeled, 25 received subsequent penicillin-class prescriptions. No adverse reactions occurred following inpatient oral amoxicillin challenges. Patients with a low-risk penicillin allergy history were more likely to undergo a challenge if admitted with an infectious diseases-related condition. Only 1 inappropriate relabeling event occurred during the study period, which was subsequently corrected. Conclusions: An infectious diseases provider-led initiative resulted in penicillin allergy label removal in more than one third of inpatients evaluated using direct removal or oral amoxicillin challenge. Efforts focused on patients who had been admitted for infections were particularly successful.

The Relationship Between All-Suture and Solid Medial-Row Anchors and Patient-Reported Outcomes for Double-Row Suture Bridge Rotator Cuff Repair.

Background: The use of all-suture anchors for rotator cuff repair is increasing. Potential benefits include decreased bone loss and decreased damage to the chondral surface. Minimal evidence exists comparing outcomes among medial-row anchor fixation methods in double-row suture bridge rotator cuff repair. Purpose: To compare the clinical outcomes between all-suture and solid medial-row anchors in double-row suture bridge rotator cuff repair. Study Design: Case series; Level of evidence, 4. Methods: A total of 352 patients (mean age at surgery, 60.3 years) underwent double-row suture bridge rotator cuff repair at our institution. Patients were separated into 2 groups based on whether they underwent all-suture (n = 280) or solid (n = 72) anchor fixation for the medial row. Outcomes data were collected via an ongoing longitudinal data repository or through telephone calls (minimum follow-up time, 2.0 years; mean follow-up time, 3.0 years). Outcomes were evaluated using the American Shoulder and Elbow Surgeons (ASES) standardized shoulder assessment form and the visual analog scale (VAS). The same rehabilitation protocol was administered to all patients. The proportions of patients meeting previously published Patient Acceptable Symptom State (PASS) thresholds were calculated for the outcome measures, and outcome scores and the proportions of patients meeting PASS thresholds between groups were compared using linear and logistic regression, respectively. Results: The groups did not differ in terms of age at surgery, sex distribution, rotator cuff tear size, or number of medial-row anchors used. The solid anchor group had a longer follow-up time compared with the all-suture anchor group (3.6 ± 0.7 vs 2.8 ± 0.8 years, respectively; P < .01). After controlling for follow-up time, the solid and all-suture anchor groups did not differ in ASES scores (89.6 ± 17.8 vs 88.8 ± 16.7, respectively; P = .44) or VAS scores (1.1 ± 2.1 vs 1.2 ± 2.1, respectively; P = .37). Similarly, after controlling for follow-up time, the solid and all-suture anchor groups did not differ in the proportions of patients meeting PASS cutoffs for the ASES (84.7% vs 80.7%, respectively; P = .44) or the VAS (80.6% vs 75.0%, respectively; P = .83). Conclusion: Double-row suture bridge rotator cuff repair using all-suture anchors for medial-row fixation demonstrated similar excellent clinical outcomes to rotator cuff repair using solid medial-row anchors.

Middle Rectal Artery Pseudoaneurysm: A Case of Massive Lower Gastrointestinal Bleeding Managed With Coil Embolization.

Pseudoaneurysms of the middle rectal artery are rare. When encountered, these have the potential for significant morbidity and mortality due to bleeding and potential rupture. Endovascular embolization is a feasible option in the management of these pseudoaneurysms. The present report describes a case of a 43-year-old male presenting with hemorrhagic shock secondary to lower gastrointestinal bleeding one day after undergoing excision of an external perineal condyloma, incision and drainage of a perirectal abscess, and biopsy of a perianal mass. Angiographic imaging revealed a right middle rectal artery pseudoaneurysm. Selective embolization of the right middle rectal artery and bilateral superior rectal arteries was successfully performed. At the two-week post-embolization follow-up, hemoglobin was stable, and the patient reported normal bowel movements with no episodes of bleeding per rectum.

Interpenetrated Structures for Enhancing Ion Diffusion Kinetics in Electrochemical Energy Storage Devices.

The architectural design of electrodes offers new opportunities for next-generation electrochemical energy storage devices (EESDs) by increasing surface area, thickness, and active materials mass loading while maintaining good ion diffusion through optimized electrode tortuosity. However, conventional thick electrodes increase ion diffusion length and cause larger ion concentration gradients, limiting reaction kinetics. We demonstrate a strategy for building interpenetrated structures that shortens ion diffusion length and reduces ion concentration inhomogeneity. This free-standing device structure also avoids short-circuiting without needing a separator. The feature size and number of interpenetrated units can be adjusted during printing to balance surface area and ion diffusion. Starting with a 3D-printed interpenetrated polymer substrate, we metallize it to make it conductive. This substrate has two individually addressable electrodes, allowing selective electrodeposition of energy storage materials. Using a Zn//MnO2 battery as a model system, the interpenetrated device outperforms conventional separate electrode configurations, improving volumetric energy density by 221% and exhibiting a higher capacity retention rate of 49% compared to 35% at temperatures from 20 to 0 °C. Our study introduces a new EESD architecture applicable to Li-ion, Na-ion batteries, supercapacitors, etc.

COVID-19 in Pediatric Populations.

The COVID-19 pandemic reshaped the landscape of respiratory viral illnesses, causing common viruses to fade as SARS-CoV-2 took precedence. By 2023, more than 96% of the children in the United States were estimated to have been infected with SARS-CoV-2, with certain genetic predispositions and underlying health conditions posing risk factors for severe disease in children. Children, in general though, exhibit immunity advantages, protecting against aspects of the SARS-CoV-2 infection known to drive increased severity in older adults. Post-COVID-19 complications such as multisystem inflammatory syndrome in children and long COVID have emerged, underscoring the importance of vaccination. Here, we highlight the risks of severe pediatric COVID-19, age-specific immunoprotection, comparisons of SARS-CoV-2 with other respiratory viruses, and factors contributing to post-COVID-19 complications in children.

Arp2/3-dependent endocytosis ensures Cdc42 oscillations by removing Pak1-mediated negative feedback.

The GTPase Cdc42 regulates polarized growth in most eukaryotes. In the bipolar yeast Schizosaccharomyces pombe, Cdc42 activation cycles periodically at sites of polarized growth. These periodic cycles are caused by alternating positive feedback and time-delayed negative feedback loops. At each polarized end, negative feedback is established when active Cdc42 recruits the Pak1 kinase to prevent further Cdc42 activation. It is unclear how Cdc42 activation returns to each end after Pak1-dependent negative feedback. We find that disrupting branched actin-mediated endocytosis disables Cdc42 reactivation at the cell ends. Using experimental and mathematical approaches, we show that endocytosis-dependent Pak1 removal from the cell ends allows the Cdc42 activator Scd1 to return to that end to enable reactivation of Cdc42. Moreover, we show that Pak1 elicits its own removal via activation of endocytosis. These findings provide a deeper insight into the self-organization of Cdc42 regulation and reveal previously unknown feedback with endocytosis in the establishment of cell polarity.

Characterization of a near isogenic barley line with high grain ß-amylase activity reveals a separation in the tight co-regulation of B-hordeins (Hor2) with endosperm-specific ß-amylase (Bmy1).

GSHO 2096 is a near isogenic barley line with extremely high grain ß-amylase activity, a desirable trait in the malting and brewing industry. High levels of grain ß-amylase activity are caused by a surge in endosperm-specific ß-amylase (Bmy1) gene expression during the early stages of grain development with high expression levels persisting throughout development. Origins of the high ß-amylase activity trait are perplexing considering GSHO 2096 is not supposed to have grain ß-amylase activity. GSHO 2096 is reported to be derived from a Bowman x Risø 1508 cross followed by recurrent backcrossing to Bowman (BC5). Risø 1508 carries a mutated form of the barley prolamin binding factor, which is responsible for Bmy1 expression during grain development. Thus, the pedigree of GSHO 2096 was explored to determine the potential origins of the high grain ß-amylase trait. Genotyping using the barley 50k iSelect SNP array revealed Bowman and GSHO 2096 were very similar (95.4 %) and provided evidence that both Risø 56 and 1508 are in the pedigree. Risø mutants 56 and 1508 both have perturbed hordein gene expression leading to a discernable pattern using SDS-PAGE. GSHO 2096 and Risø 56 have the same hordein pattern whereas Bowman and Risø 1508 have unique patterns. RNAseq revealed that Hor2 (B-hordein) gene expression was completely downregulated making it unique as the only known line with Bmy1 expression without Hor2 co-expression. Regardless of pedigree, GSHO 2096 remains an extremely valuable high ß-amylase activity line with potential utilization in breeding for malt quality.