Wirelessly Powered Visible Light-Emitting Implant for Surgical Guidance during Lumpectomy.

Achieving negative surgical margins, defined as no tumor found on the edges of the resected tissue, during lumpectomy for breast cancer is critical for mitigating the risk of local recurrence. To identify nonpalpable tumors that cannot be felt, pre-operative placements of wire and wire-free localization devices are typically employed. Wire-free localization approaches have significant practical advantages over wired techniques. In this study, we introduce an innovative localization system comprising a light-emitting diode (LED)-based implantable device and handheld system. The device, which is needle injectable and wire free, utilizes multiple wirelessly powered LEDs to provide direct visual guidance for lumpectomy. Two distinct colors, red and blue, provide a clear indication of tissue depth: blue light is absorbed strongly in tissue, visible within a close range of <1 cm, while red light remains visible through several centimeters of tissue. The LEDs, integrated with an impedance-matching circuit and receiver coil, are encapsulated in biocompatible epoxy for injection with a 12 G needle. Our findings demonstrate that the implant exhibits clearly perceivable depth-dependent color changes and remains visible through >2 cm of ex vivo chicken breast and bovine muscle tissue using less than 4 W of transmitted power from a handheld antenna. These miniaturized needle-injectable localization devices show promise for improving surgical guidance of nonpalpable breast tumors.

Direct observation of degassing during decompression of basaltic magma.

Transitions in eruptive style during volcanic eruptions strongly depend on how easily gas and magma decouple during ascent. Stronger gas-melt coupling favors highly explosive eruptions, whereas weaker coupling promotes lava fountaining and lava flows. The mechanisms producing these transitions are still poorly understood because of a lack of direct observations of bubble dynamics under natural magmatic conditions. Here, we combine x-ray radiography with a novel high-pressure/high-temperature apparatus to observe and quantify in real-time bubble growth and coalescence in basaltic magmas from 100 megapascals to surface. For low-viscosity magmas, bubbles coalesce and recover a spherical shape within 3 seconds, implying that, for lava fountaining activity, gas and melt remain coupled during the ascent up to the last hundred meters of the conduit. For higher-viscosity magmas, recovery times become longer, promoting connected bubble pathways. This apparatus opens frontiers in unraveling magmatic/volcanic processes, leading to improved hazard assessment and risk mitigation.

A qualitative exploration of barriers to efficient and effective structured medication reviews in primary care: Findings from the DynAIRx study.

INTRODUCTION: Structured medication reviews (SMRs), introduced in the United Kingdom (UK) in 2020, aim to enhance shared decision-making in medication optimisation, particularly for patients with multimorbidity and polypharmacy. Despite its potential, there is limited empirical evidence on the implementation of SMRs, and the challenges faced in the process. This study is part of a larger DynAIRx (Artificial Intelligence for dynamic prescribing optimisation and care integration in multimorbidity) project which aims to introduce Artificial Intelligence (AI) to SMRs and develop machine learning models and visualisation tools for patients with multimorbidity. Here, we explore how SMRs are currently undertaken and what barriers are experienced by those involved in them. METHODS: Qualitative focus groups and semi-structured interviews took place between 2022-2023. Six focus groups were conducted with doctors, pharmacists and clinical pharmacologists (n = 21), and three patient focus groups with patients with multimorbidity (n = 13). Five semi-structured interviews were held with 2 pharmacists, 1 trainee doctor, 1 policy-maker and 1 psychiatrist. Transcripts were analysed using thematic analysis. RESULTS: Two key themes limiting the effectiveness of SMRs in clinical practice were identified: 'Medication Reviews in Practice' and 'Medication-related Challenges'. Participants noted limitations to the efficient and effectiveness of SMRs in practice including the scarcity of digital tools for identifying and prioritising patients for SMRs; organisational and patient-related challenges in inviting patients for SMRs and ensuring they attend; the time-intensive nature of SMRs, the need for multiple appointments and shared decision-making; the impact of the healthcare context on SMR delivery; poor communication and data sharing issues between primary and secondary care; difficulties in managing mental health medications and specific challenges associated with anticholinergic medication. CONCLUSION: SMRs are complex, time consuming and medication optimisation may require multiple follow-up appointments to enable a comprehensive review. There is a need for a prescribing support system to identify, prioritise and reduce the time needed to understand the patient journey when dealing with large volumes of disparate clinical information in electronic health records. However, monitoring the effects of medication optimisation changes with a feedback loop can be challenging to establish and maintain using current electronic health record systems.

Neurocognitive demands reduce jump distance and coordination variability of the injured leg in athletes after anterior cruciate ligament reconstruction.

PURPOSE: The study aimed to evaluate the impact of neurocognitive reliance on jump distance and lower extremity kinematics in individuals who had undergone anterior cruciate ligament reconstruction (ACLR). This was achieved by comparing hop performance under standard and neurocognitive conditions. METHODS: Thirty-two patients after ACLR and 32 healthy controls (CTRL) participated. Both groups performed a single-leg hop for distance (SLHD) and two neurocognitive hop tests, each designed to evaluate distinct aspects of neurocognition. The neurocognitive tests included the reaction SLHD (R-SLHD), measuring reaction to a central stimulus and working memory SLHD (WM-SLHD) assessing response to a memorized stimulus amidst distractor stimuli. Distances were assessed for the three-hop tests. In addition, joint kinematics were collected to calculate lower extremity coordination of the lower extremity. SLHD performance was defined as the mean hop distance per condition per leg for each participant and was analyzed using a mixed ANOVA with condition and leg as the within-subjects factors and the group (ACLR or CTRL) as the between-subjects factor. Differences in joint coordination variability were analyzed using two-sample t-test statistical parametric mapping (SPM) with linear regression. RESULTS: The WM-SLHD resulted in a significantly decreased jump distance compared with the standard hop test both for ACLR and CTRL. Furthermore, the leg difference within the ACLR group increased under higher cognitive load as tested with the WM-SLHD, indicating leg-specific adaptations in lower extremity coordination. CONCLUSIONS: Neurocognitive single-leg hop tests resulted in reduced jump distance in CTRL and ACLR. The neurocognitive hop test revealed changes in coordination variability for the CTRL and the uninjured leg of ACLR individuals, whereas the injured leg's coordination variability remained unaltered, suggesting persistent cognitive control of movements post-ACLR. LEVEL OF EVIDENCE: Level III.

Incidence of Osteoarthritis Between ACL Reconstruction With Different Graft Types and Between ACL Reconstruction and Repair: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

Background: Variation in stiffness, fixation methods, and donor-site morbidity after anterior cruciate ligament reconstruction (ACLR) with different graft types and with anterior cruciate ligament suture repair (ACLSR) can lead to differences in dynamic knee laxity and consequent differences in posttraumatic osteoarthritis (PTOA) development. Purpose: To compare the incidence of PTOA between different graft types used for primary ACLR and between primary ACLR and ACLSR. It was hypothesized that the incidence of PTOA would vary between ACLR with different autografts and allografts and between ACLR and ACLSR. Study Design: Systematic review; Level of evidence, 1. Methods: A search of the literature was performed to identify all randomized controlled trials (RCTs) comparing radiographic evidence of PTOA after ACLR between different graft types-hamstring tendon (HT) autograft, bone-patellar tendon-bone (BPTB) autograft, quadriceps tendon autograft, and allograft-and between ACLR and ACLSR. The minimum follow-up was 2 years. Study quality was assessed using the modified Coleman Methodology Score. A meta-analysis was performed to determine whether there was a difference in the incidence of PTOA between the different graft types and between ACLR and ACLSR. Results: Eleven randomized controlled trials were included in the meta-analysis-HT: 440 patients (mean follow-up, 9.7 years); BPTB: 307 patients (mean follow-up, 11.8 years); allograft: 246 patients (mean follow-up, 5 years); ACLSR, 22 patients (5 years). No study reporting the incidence after ACLR with quadriceps tendon was included. The study quality ranged from 70 to 88. The meta-analysis indicated no significant difference in the incidence of PTOA between graft types used for ACLR and between ACLR and ACLSR (risk ratios: HT vs BPTB, 1.05; HT vs allograft, 0.81; BPTB vs allograft, 0.82; HT vs ACLSR, not estimable [P > .05 for all]). The combined number of patients with PTOA in all studies per graft type showed that patients who underwent ACLR with a BPTB autograft had the highest percentage of PTOA (HT, 23.4%; BPTB, 29.6%; allograft, 8.1%; ACLSR, 0%). However, excluding studies with a follow-up <5 years resulted in similar outcomes for patients with an HT autograft and a BPTB autograft. Conclusion: This meta-analysis reported no difference in the incidence of PTOA between graft types used for ACLR and between ACLR and ACLSR. More research is necessary to make a reliable conclusion about which technique is associated with the lowest incidence of PTOA after ACL surgery.

Coastal dunes as drivers of genetic differentiation in the honeypot ant Myrmecocystus baja (Formicidae: Formicinae).

Coastal dunes are unique habitats, threatened by human activities. In biogeographical terms, coastal dunes are habitat islands, being discrete and distinct patches of similar habitat among themselves, separated from each other by a different type of habitat. Furthermore, coastal dunes harbor endemic species, adapted to living solely in the habitats found on specific dune systems. For example, the honeypot ant Myrmecocystus baja is endemic and restricted to coastal dunes of Mexico's Baja California Pacific coast. This ecological and biogeographical scenario led to the questions whether their geographical isolation is reflected in their genetic diversity and structuring, and how their demographic history is related with the formation of the dune system habitats. To answer these questions, population genetic, isolation-with-migration, and phylogeographical analyses were carried out, based on mitochondrial and five nuclear intronic markers. Minimal gene flow was detected only between two of the dune systems sampled; otherwise, the M. baja populations were found to be isolated and genetically structured, and their divergence generally pre-dated the modern-day dune systems. It is therefore highly likely that these ants were already present in paleodunes and that each of the populations was established from founder populations as the dunes formed. These findings highlight the importance of coastal dunes for species such as the honeypot ant from Baja California, in promoting genetic differentiation.

Role of artificial intelligence, machine learning and deep learning models in corneal disorders - A narrative review.

In the last decade, artificial intelligence (AI) has significantly impacted ophthalmology, particularly in managing corneal diseases, a major reversible cause of blindness. This review explores AI's transformative role in the corneal subspecialty, which has adopted advanced technology for superior clinical judgment, early diagnosis, and personalized therapy. While AI's role in anterior segment diseases is less documented compared to glaucoma and retinal pathologies, this review highlights its integration into corneal diagnostics through imaging techniques like slit-lamp biomicroscopy, anterior segment optical coherence tomography (AS-OCT), and in vivo confocal biomicroscopy. AI has been pivotal in refining decision-making and prognosis for conditions such as keratoconus, infectious keratitis, and dystrophies. Multi-disease deep learning neural networks (MDDNs) have shown diagnostic ability in classifying corneal diseases using AS-OCT images, achieving notable metrics like an AUC of 0.910. AI's progress over two decades has significantly improved the accuracy of diagnosing conditions like keratoconus and microbial keratitis. For instance, AI has achieved a 90.7% accuracy rate in classifying bacterial and fungal keratitis and an AUC of 0.910 in differentiating various corneal diseases. Convolutional neural networks (CNNs) have enhanced the analysis of color-coded corneal maps, yielding up to 99.3% diagnostic accuracy for keratoconus. Deep learning algorithms have also shown robust performance in detecting fungal hyphae on in vivo confocal microscopy, with precise quantification of hyphal density. AI models combining tomography scans and visual acuity have demonstrated up to 97% accuracy in keratoconus staging according to the Amsler-Krumeich classification. However, the review acknowledges the limitations of current AI models, including their reliance on binary classification, which may not capture the complexity of real-world clinical presentations with multiple coexisting disorders. Challenges also include dependency on data quality, diverse imaging protocols, and integrating multimodal images for a generalized AI diagnosis. The need for interpretability in AI models is emphasized to foster trust and applicability in clinical settings. Looking ahead, AI has the potential to unravel the intricate mechanisms behind corneal pathologies, reduce healthcare's carbon footprint, and revolutionize diagnostic and management paradigms. Ethical and regulatory considerations will accompany AI's clinical adoption, marking an era where AI not only assists but augments ophthalmic care.

UPC2 mutations and development of azole resistance in Candida albicans hospital isolates from Lebanon.

OBJECTIVES: This study evaluated the role of Upc2 in the development of azole resistance in Candida albicans isolates from Lebanese hospitalized patients and determined a correlation between resistance and virulence. METHODS: The UPC2 gene which codes for an ergosterol biosynthesis regulator was sequenced and analysed in two azole-resistant and one azole-susceptible C. albicans isolates. An amino acid substitution screening was carried out on Upc2 with a focus on its ligand binding domain (LBD) known to interact with ergosterol. Then, Upc2 protein secondary structure prediction and homology modelling were conducted, followed by total plasma membrane ergosterol and cell wall chitin quantifications. For virulence, mouse models of systemic infection were generated and an agar adhesion and invasion test was performed. RESULTS: Azole-resistant isolates harboured novel amino acid substitutions in the LBD of Upc2 and changes in protein secondary structures were observed. In addition, these isolates exhibited a significant increase in plasma membrane ergosterol content. Resistance and virulence were inversely correlated while increased cell wall chitin concentration does not seem to be linked to resistance since even though we observed an increase in chitin concentration, it was not statistically significant. CONCLUSIONS: The azole-resistant C. albicans isolates harboured novel amino acid substitutions in the LBD of Upc2 which are speculated to induce an increase in plasma membrane ergosterol content, preventing the binding of azoles to their target, resulting in resistance.

Malware Detection for Internet of Things Using One-Class Classification.

The increasing usage of interconnected devices within the Internet of Things (IoT) and Industrial IoT (IIoT) has significantly enhanced efficiency and utility in both personal and industrial settings but also heightened cybersecurity vulnerabilities, particularly through IoT malware. This paper explores the use of one-class classification, a method of unsupervised learning, which is especially suitable for unlabeled data, dynamic environments, and malware detection, which is a form of anomaly detection. We introduce the TF-IDF method for transforming nominal features into numerical formats that avoid information loss and manage dimensionality effectively, which is crucial for enhancing pattern recognition when combined with n-grams. Furthermore, we compare the performance of multi-class vs. one-class classification models, including Isolation Forest and deep autoencoder, that are trained with both benign and malicious NetFlow samples vs. trained exclusively on benign NetFlow samples. We achieve 100% recall with precision rates above 80% and 90% across various test datasets using one-class classification. These models show the adaptability of unsupervised learning, especially one-class classification, to the evolving malware threats in the IoT domain, offering insights into enhancing IoT security frameworks and suggesting directions for future research in this critical area.

Immunonutrition with Omega-3 Fatty Acid Supplementation in Severe TBI: Retrospective Analysis of Patient Characteristics and Outcomes.

Early evidence-based medical interventions to improve patient outcomes after traumatic brain injury (TBI) are lacking. In patients admitted to the ICU after TBI, optimization of nutrition is an emerging field of interest. Specialized enteral nutrition (EN) formulas that include immunonutrition containing omega-3 polyunsaturated fatty acids (n-3 PUFAs) have been developed and are used for their proposed anti-inflammatory and proimmune properties; however, their use has not been rigorously studied in human TBI populations. A single-center, retrospective, descriptive observational study was conducted at the LAC + USC Medical Center. Patients with severe TBI (sTBI, Glasgow Coma Scale score ≤ 8) who remained in the ICU for ≥2 weeks and received EN were identified between 2017 and 2022 using the institutional trauma registry. Those who received immunonutrition formulas containing n-3 PUFAs were compared with those who received standard, polymeric EN with regard to baseline characteristics, clinical markers of inflammation and immune function, and short-term clinical outcomes. A total of 151 patients with sTBI were analyzed. Those who received immunonutrition with n-3 PUFA supplementation were more likely to be male, younger, Hispanic/Latinx, and have polytrauma needing non-central nervous system surgery. No differences in clinical markers of inflammation or infection rate were found. In multivariate regression analysis, immunonutrition was associated with reduced hospital length of stay (LOS). ICU LOS was also reduced in the subgroup of patients with polytrauma and TBI. This study identifies important differences in patient characteristics and outcomes associated with the EN formula prescribed. Study results can directly inform a prospective pragmatic study of immunonutrition with n-3 PUFA supplementation aimed to confirm the biomechanistic and clinical benefits of the intervention.

A novel frameshift variant in BCOR causes congenital nuclear cataract.

BACKGROUND: BCL6 co-repressor (BCOR) gene variants are involved in oculofaciocardiodental (OFCD) syndrome, acute myeloid leukaemia, renal tumours, and photoreceptor degenerative diseases. Here, we describe a British family with a pathogenic heterozygous variant in the BCOR gene causing congenital nuclear cataract. METHODS: Whole-exome sequencing was conducted on an individual affected by X-linked dominant congenital cataract in a three-generation family to establish the underlying genetic basis. Bioinformatics analysis confirmed the variants with damaging pathogenicity scores. RESULTS: A novel likely pathogenic frameshift variant BCOR NM_001123385.1: c.3621del; p.Lys1207AsnfsTer31, was identified and found to co-segregate with the disease in this family. CONCLUSIONS: This is apparently the first report of a variant in BCOR causing X-linked dominant congenital cataract which is potentially isolated or presenting with a remarkably mild systemic phenotype. Our findings extend the genetic basis for congenital cataract and add to the phenotypic spectrum of BCOR variants.

Molecular analysis of human tick-bitten skin yields signatures associated with distinct spatial and temporal trajectories - A proof-of-concept study.

Tick-associated diseases present challenges due to tridirectional interactions among host-specific responses, tick toxins and salivary proteins as well as microbes. We aimed to uncover molecular mechanisms in tick-bitten skin samples (cases) and contralateral skin samples (controls) collected simultaneously from the same participants, using spatial transcriptomics. Cases and controls analysed using NanoString GeoMx Digital Spatial Profiler identified 274 upregulated and 840 downregulated differentially expressed genes (DEGs), revealing perturbations in keratinization and immune system regulation. Samples of skin biopsies taken within 72 h post tick-bite DEGs had changes in protein metabolism and viral infection pathways as compared to samples taken 3 months post tick-bite, which instead displayed significant perturbations in several epigenetic regulatory pathways, highlighting the temporal nature of the host response following tick bites. Within-individual signatures distinguished tick-bitten samples from controls and identified between-individual signatures, offering promise for future biomarker discovery to guide prognosis and therapy.

Inflammatory responses in Atlantic lumpfish (Cyclopterus lumpus L.) after intraperitoneal injection of a vaccine against Aeromonas salmonicida and Vibrio salmonicida at different water temperatures.

Studying inflammatory responses induced by vaccination can contribute to a more detailed understanding of underlying immune mechanisms in lumpfish (Cyclopterus lumpus). Tissue samples from lumpfish intraperitoneally immunized with a divalent oil-adjuvanted vaccine (Aeromonas salmonicida and Vibrio salmonicida) at water temperatures of 5, 10, and 15°C were collected at 630 day degrees and 18 weeks post injection. The relative amount of secretory and membrane-bound immunoglobulin M (IgM) gene transcripts in the head kidney was determined by qPCR. Vaccine-induced inflammatory lesions were assessed on histological sections of abdominal pancreatic/intestinal tissue from vaccinated fish in all three temperature groups. Inflammatory cells forming dense aggregations in lesions showed proliferative activity, many of which were identified as eosinophilic-granulocyte-like cells. IgM+ cells were scattered in inflammatory tissue dominated by connective tissue, showing no difference in numbers between lesions from fish vaccinated at 5, 10, and 15°C. Relative gene expression analysis of secretory and membrane-bound IgM revealed low overall expression in the head kidney of vaccinated fish at both 630 day-degrees and 18 weeks post injection. The results of this study indicate that the vaccine stimulated prolonged local inflammatory responses at the injection site, which were not influenced by temperature.

A chimeric vaccine derived from Australian genotype IV Japanese encephalitis virus protects mice from lethal challenge.

In 2022, a genotype IV (GIV) strain of Japanese encephalitis virus (JEV) caused an unprecedented and widespread outbreak of disease in pigs and humans in Australia. As no veterinary vaccines against JEV are approved in Australia and all current approved human and veterinary vaccines are derived from genotype (G) III JEV strains, we used the recently described insect-specific Binjari virus (BinJV) chimeric flavivirus vaccine technology to produce a JEV GIV vaccine candidate. Herein we describe the production of a chimeric virus displaying the structural prM and E proteins of a JEV GIV isolate obtained from a stillborn piglet (JEVNSW/22) in the genomic backbone of BinJV (BinJ/JEVNSW/22-prME). BinJ/JEVNSW/22-prME was shown to be antigenically indistinguishable from the JEVNSW/22 parental virus by KD analysis and a panel of JEV-reactive monoclonal antibodies in ELISA. BinJ/JEVNSW/22-prME replicated efficiently in C6/36 cells, reaching titres of >107 infectious units/mL - an important attribute for vaccine manufacture. As expected, BinJ/JEVNSW/22-prME failed to replicate in a variety of vertebrate cells lines. When used to immunise mice, the vaccine induced a potent virus neutralising response against JEVNSW/22 and to GII and GIII JEV strains. The BinJ/JEVNSW/22-prME vaccine provided complete protection against lethal challenge with JEVNSW/22, whilst also providing partial protection against viraemia and disease for the related Murray Valley encephalitis virus. Our results demonstrate that BinJ/JEVNSW/22-prME is a promising vaccine candidate against JEV.

Inhibition of PDIs Downregulates Core LINC Complex Proteins, Promoting the Invasiveness of MDA-MB-231 Breast Cancer Cells in Confined Spaces In Vitro.

Eukaryotic cells tether the nucleoskeleton to the cytoskeleton via a conserved molecular bridge, called the LINC complex. The core of the LINC complex comprises SUN-domain and KASH-domain proteins that directly associate within the nuclear envelope lumen. Intra- and inter-chain disulphide bonds, along with KASH-domain protein interactions, both contribute to the tertiary and quaternary structure of vertebrate SUN-domain proteins. The significance of these bonds and the role of PDIs (protein disulphide isomerases) in LINC complex biology remains unclear. Reducing and non-reducing SDS-PAGE analyses revealed a prevalence of SUN2 homodimers in non-tumorigenic breast epithelia MCF10A cells, but not in the invasive triple-negative breast cancer MDA-MB-231 cell line. Furthermore, super-resolution microscopy revealed SUN2 staining alterations in MCF10A, but not in MDA-MB-231 nuclei, upon reducing agent exposure. While PDIA1 levels were similar in both cell lines, pharmacological inhibition of PDI activity in MDA-MB-231 cells led to SUN-domain protein down-regulation, as well as Nesprin-2 displacement from the nucleus. This inhibition also caused changes in perinuclear cytoskeletal architecture and lamin downregulation, and increased the invasiveness of PDI-inhibited MDA-MB-231 cells in space-restrictive in vitro environments, compared to untreated cells. These results emphasise the key roles of PDIs in regulating LINC complex biology, cellular architecture, biomechanics, and invasion.

Structural characterization and AlphaFold modeling of human T cell receptor recognition of NRAS cancer neoantigens.

T cell receptors (TCRs) that recognize cancer neoantigens are important for anti-cancer immune responses and immunotherapy. Understanding the structural basis of TCR recognition of neoantigens provides insights into their exquisite specificity and can enable design of optimized TCRs. We determined crystal structures of a human TCR in complex with NRAS Q61K and Q61R neoantigen peptides and HLA-A1 MHC, revealing the molecular underpinnings for dual recognition and specificity versus wild-type NRAS peptide. We then used multiple versions of AlphaFold to model the corresponding complex structures, given the challenge of immune recognition for such methods. Interestingly, one implementation of AlphaFold2 (TCRmodel2) was able to generate accurate models of the complexes, while AlphaFold3 also showed strong performance, although success was lower for other complexes. This study provides insights into TCR recognition of a shared cancer neoantigen, as well as the utility and practical considerations for using AlphaFold to model TCR-peptide-MHC complexes.

Combining phenotypic and genomic data to improve prediction of binary traits.

Plant breeders want to develop cultivars that outperform existing genotypes. Some characteristics (here 'main traits') of these cultivars are categorical and difficult to measure directly. It is important to predict the main trait of newly developed genotypes accurately. In addition to marker data, breeding programs often have information on secondary traits (or 'phenotypes') that are easy to measure. Our goal is to improve prediction of main traits with interpretable relations by combining the two data types using variable selection techniques. However, the genomic characteristics can overwhelm the set of secondary traits, so a standard technique may fail to select any phenotypic variables. We develop a new statistical technique that ensures appropriate representation from both the secondary traits and the genotypic variables for optimal prediction. When two data types (markers and secondary traits) are available, we achieve improved prediction of a binary trait by two steps that are designed to ensure that a significant intrinsic effect of a phenotype is incorporated in the relation before accounting for extra effects of genotypes. First, we sparsely regress the secondary traits on the markers and replace the secondary traits by their residuals to obtain the effects of phenotypic variables as adjusted by the genotypic variables. Then, we develop a sparse logistic classifier using the markers and residuals so that the adjusted phenotypes may be selected first to avoid being overwhelmed by the genotypic variables due to their numerical advantage. This classifier uses forward selection aided by a penalty term and can be computed effectively by a technique called the one-pass method. It compares favorably with other classifiers on simulated and real data.

Changes in Peak Inspiratory Flow After Acute Bronchodilation: An Observational Study of Patients with Stable Chronic Obstructive Pulmonary Disease.

Introduction: Identifying factors influencing peak inspiratory flow (PIF) is essential for aerosol drug delivery in stable patients with chronic obstructive pulmonary disease. While a minimum PIF for dry powder inhalers (DPIs) is established, acute bronchodilator (BD) effects on PIF remain unknown. Materials and Methods: An inspiratory flow meter (In-Check™ DIAL) was used to measure PIF in stable patients during a 24-week observational cross-sectional study. Additionally, bronchodilator responsiveness (BDR) was determined using the In-Check DIAL device and spirometry. Patients received four puffs of albuterol, and pre- and post-BD PIF, forced expiratory volume in one second (FEV1), and forced vital capacity were measured. Sixty-three patients completed acute BDR data collection from July 31, 2019, to November 9, 2021. Primary endpoints were pre- and post-BD spirometry and PIF. Statistical analyses included PIF correlations with FEV1. BD change was assessed according to inhaler resistance and sex (subgroup analysis). Results: Median patient age was 64.8 years, 85.7% were non-Hispanic White, and 57.1% were female. The median increase in absolute PIF (In-Check DIAL) was 5.0 L/min, and the % PIF change was 8.9%. With albuterol, 57.1% experienced a PIF BD change >5.0%, whereas 49.2% experienced a change >10.0%. Similarly, 55.6% experienced an FEV1 BD change >5.0% and 28.6% had a >10.0% FEV1 BD change with albuterol. PIF was weakly correlated with FEV1 BD change (absolute; % PIF; r = 0.28 [p = 0.02]; r = 0.21 [p = 0.11]). Pre- and post-BD median PIF were 75.5 and 83.5 L/min for low-to-medium-resistance DPI and 45.0 and 52.0 L/min for high-resistance, respectively. The median increases in pre- and post-BD PIF were 9.0 L/min in males and 4.5 L/min in females. In contrast to when using the In-Check DIAL device, we observed no consistent bronchodilatory effects on PIF measured by spirometry. Conclusions: Using the In-Check DIAL device, ∼50% of patients experienced >10% PIF increase after acute BD, potentially enhancing medication lung deposition. Further research is required to understand PIF's impact on medication delivery. ClinicalTrials.gov Identifier: NCT04168775.