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Summary: Background: Chest X-rays (CXR) are essential for diagnosing a variety of conditions, but when used on new populations, model generalizability issues limit their efficacy. Generative AI, particularly denoising diffusion probabilistic models (DDPMs), offers a promising approach to generating synthetic images, enhancing dataset diversity. This study investigates the impact of synthetic data supplementation on the performance and generalizability of medical imaging research. Methods: The study employed DDPMs to create synthetic CXRs conditioned on demographic and pathological characteristics from the CheXpert dataset. These synthetic images were used to supplement training datasets for pathology classifiers, with the aim of improving their performance. The evaluation involved three datasets (CheXpert, MIMIC-CXR, and Emory Chest X-ray) and various experiments, including supplementing real data with synthetic data, training with purely synthetic data, and mixing synthetic data with external datasets. Performance was assessed using the area under the receiver operating curve (AUROC). Findings: Adding synthetic data to real datasets resulted in a notable increase in AUROC values (up to 0.02 in internal and external test sets with 1000% supplementation, p-value

Patients who recovered from the novel coronavirus disease 2019 (COVID-19) may experience a range of long-term symptoms. Since the lung is the most common site of the infection, pulmonary sequelae may present persistently in COVID-19 survivors. To better understand the symptoms associated with impaired lung function in patients with post-COVID-19, we aimed to build a deep learning model which conducts two tasks: to differentiate post-COVID-19 from healthy subjects and to identify post-COVID-19 subtypes, based on the latent representations of lung computed tomography (CT) scans. CT scans of 140 post-COVID-19 subjects and 105 healthy controls were analyzed. A novel contrastive learning model was developed by introducing a lung volume transform to learn latent features of disease phenotypes from CT scans at inspiration and expiration of the same subjects. The model achieved 90% accuracy for the differentiation of the post-COVID-19 subjects from the healthy controls. Two clusters (C1 and C2) with distinct characteristics were identified among the post-COVID-19 subjects. C1 exhibited increased air-trapping caused by small airways disease (4.10%, p = 0.008) and diffusing capacity for carbon monoxide %predicted (DLCO %predicted, 101.95%, p < 0.001), while C2 had decreased lung volume (4.40L, p < 0.001) and increased ground glass opacity (GGO%, 15.85%, p < 0.001). The contrastive learning model is able to capture the latent features of two post-COVID-19 subtypes characterized by air-trapping due to small airways disease and airway-associated interstitial fibrotic-like patterns, respectively. The discovery of post-COVID-19 subtypes suggests the need for different managements and treatments of long-term sequelae of patients with post-COVID-19.

Abstract Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease and the traditional variables extracted from computed tomography (CT) images may not be sufficient to describe all the topological features of lung tissues in COPD patients. We employed an unsupervised three-dimensional (3D) convolutional autoencoder (CAE)-feature constructor (FC) deep learning network to learn from CT data and derive tissue pattern-clusters jointly. We then applied exploratory factor analysis (EFA) to discover the unobserved latent traits (factors) among pattern-clusters. CT images at total lung capacity (TLC) and residual volume (RV) of 541 former smokers and 59 healthy non-smokers from the cohort of the SubPopulations and Intermediate Outcome Measures in the COPD Study (SPIROMICS) were analyzed. TLC and RV images were registered to calculate the Jacobian (determinant) values for all the voxels in TLC images. 3D Regions of interest (ROIs) with two data channels of CT intensity and Jacobian value were randomly extracted from training images and were fed to the 3D CAE-FC model. 80 pattern-clusters and 7 factors were identified. Factor scores computed for individual subjects were able to predict spirometry-measured pulmonary functions. Two factors which correlated with various emphysema subtypes, parametric response mapping (PRM) metrics, airway variants, and airway tree to lung volume ratio were discriminants of patients across all severity stages. Our findings suggest the potential of developing factor-based surrogate markers for new COPD phenotypes.

Nebulin-based nemaline myopathy is a heterogenous disease with unclear pathological mechanisms. Here, the authors generate a mouse model that mimics the most common genetic cause of the disease and demonstrate that muscle weakness in this model is associated with twisted actin filaments and altered tropomyosin and troponin behaviour.

Abstract Background Nebulin is a critical thin filament-binding protein that spans from the Z-disk of the skeletal muscle sarcomere to near the pointed end of the thin filament. Its massive size and actin-binding property allows it to provide the thin filaments with structural and regulatory support. When this protein is lost, nemaline myopathy occurs. Nemaline myopathy causes severe muscle weakness as well as structural defects on a sarcomeric level. There is no known cure for this disease. Methods We studied whether sarcomeric structure and function can be improved by introducing nebulin’s Z-disk region into a nebulin-deficient mouse model (Neb cKO) through adeno-associated viral (AAV) vector therapy. Following this treatment, the structural and functional characteristics of both vehicle-treated and AAV-treated Neb cKO and control muscles were studied. Results Intramuscular injection of this AAV construct resulted in a successful expression of the Z-disk fragment within the target muscles. This expression was significantly higher in Neb cKO mice than control mice. Analysis of protein expression revealed that the nebulin fragment was localized exclusively to the Z-disks and that Neb cKO expressed the nebulin fragment at levels comparable to the level of full-length nebulin in control mice. Additionally, the Z-disk fragment displaced full-length nebulin in control mice, resulting in nemaline rod body formation and a worsening of muscle function. Neb cKO mice experienced a slight functional benefit from the AAV treatment, with a small increase in force and fatigue resistance. Disease progression was also slowed as indicated by improved muscle structure and myosin isoform expression. Conclusions This study reveals that nebulin fragments are well-received by nebulin-deficient mouse muscles and that limited functional benefits are achievable.

Additive manufacturing of ceramics is transforming electromagnetics by providing density-varying lattices and stochastic foams within arbitrary envelopes. Periodic structures can now be fabricated with zirconia which offers the highest permittivity of any 3D printable material possible to be printed with nearly-full-density. By arranging a lattice with variation in the strut and node sizings as well as unit cell dimensions, the effective density of a structure can be spatially-modulated gracefully and with unprecedented freedom. These variations in density directly translate into variations in the effective permittivity of the bulk lattice (estimated locally and globally with a combination of mixing formulas, curve fits, and capacitance models). A lattice had previously been fabricated with a rectangular envelope for evaluation of effective global permittivity of the overall structure using a network analyzer. For this work, the structure was scanned with X-ray computed tomography (CT) to capture the three dimensional density of the structure including both the solid ceramic elements as well as the interstitial space. Software was developed that reads CT scan data and provides a 3D data structure with a pointwise unit cell estimation of the effective permittivity throughout the volume - a model well suited for electromagnetic simulations to optimize advanced microwave devices. The proposed technique serves as a foundation for the non-destructive estimation of space-varying permittivity within 3D printed lattices and foams.

**Background:** Few studies have estimated the real-world economic burden such as all-cause and follicular lymphoma-related costs and health care resource utilization (HCRU) in patients with follicular lymphoma (FL). **Objectives:** This study evaluated outcomes in patients who were newly initiated with FL indicated regimens by line of therapy with real-world data. **Methods:** A retrospective study was conducted among patients with FL from MarketScan® databases between January 1, 2010 and December 31, 2013. Patients were selected if they were ≥18 years old when initiated on a FL indicated therapy, had at least 1 FL-related diagnosis, ≥1 FL commonly prescribed systemic anti-cancer therapy after diagnosis, and did not use any FL indicated regimen in the 24 months prior to the first agent. These patients were followed up at least 48 months and the outcomes, including the distribution of regimens by line of therapy, the treatment duration by line of therapy, all-cause and FL-related costs, and HCRU by line of therapy were evaluated. **Results:** This study identified 598 patients who initiated FL indicated treatment. The average follow-up time was approximately 5.7 years. Of these patients, 50.2% (n=300) were female, with a mean age of 60.7 years (SD=13.1 years) when initiating their treatment with FL indicated regimens. Overall, 598 (100%) patients received first-line therapy, 180 (43.6%) received second-line therapy, 51 received third-line therapy, 21 received fourth-line therapy, and 10 received fifth-line therapy. Duration of treatment by each line of therapy was 370 days, 392 days, 162 days, 148 days, and 88 days, respectively. The most common first-line regimens received by patients were rituximab (n=201, 33.6%), R-CHOP (combination of rituximab, cyclophosphamide, doxorubicin hydrochloride [hydroxydaunomycin]; n=143, 24.0%), BR (combination of bendamustine and rituximab; n=143, 24.0%), and R-CVP (combination of rituximab, cyclophosphamide, vincristine, and prednisone; n=71, 11.9%). The most common second-line treatment regimens were (N=180): rituximab (n=78, 43.3%) and BR (n=41, 22.8%). Annualized all-cause health care costs per patient ranged from US$97 141 (SD: US$144 730) for first-line to US$424 758 (SD: US$715 028) for fifth-line therapy. **Conclusions:** The primary regimens used across treatment lines conform to those recommended by the National Comprehensive Cancer Network clinical practice guidelines. The economic burden for patients with FL is high and grows with subsequent lines of therapy.

The Proline, Glutamate, Valine and Lysine-rich (PEVK) region of titin constitutes an entropic spring that provides passive tension to striated muscle. To study the functional and structural repercussions of a small reduction in the size of the PEVK region, we investigated skeletal muscles of a mouse with the constitutively expressed C-terminal PEVK exons 219–225 deleted, the TtnΔ219–225 model (MGI: TtnTM 2.1Mgot). Based on this deletion, passive tension in skeletal muscle was predicted to be increased by ∼17% (sarcomere length 3.0 μm). In contrast, measured passive tension (sarcomere length 3.0 μm) in both soleus and EDL muscles was increased 53 ± 11% and 62 ± 4%, respectively. This unexpected increase was due to changes in titin, not to alterations in the extracellular matrix, and is likely caused by co-expression of two titin isoforms in TtnΔ219–225 muscles: a larger isoform that represents the TtnΔ219–225 N2A titin and a smaller isoform, referred to as N2A2. N2A2 represents a splicing adaption with reduced expression of spring element exons, as determined by titin exon microarray analysis. Maximal tetanic tension was increased in TtnΔ219–225 soleus muscle (WT 240 ± 9; TtnΔ219–225 276 ± 17 mN/mm2), but was reduced in EDL muscle (WT 315 ± 9; TtnΔ219–225 280 ± 14 mN/mm2). The changes in active tension coincided with a switch toward slow fiber types and, unexpectedly, faster kinetics of tension generation and relaxation. Functional overload (FO; ablation) and hindlimb suspension (HS; unloading) experiments were also conducted. TtnΔ219–225 mice showed increases in both longitudinal hypertrophy (increased number of sarcomeres in series) and cross-sectional hypertrophy (increased number of sarcomeres in parallel) in response to FO and attenuated cross-sectional atrophy in response to HS. In summary, slow- and fast-twitch muscles in a mouse model devoid of titin’s PEVK exons 219–225 have high passive tension, due in part to alterations elsewhere in splicing of titin’s spring region, increased kinetics of tension generation and relaxation, and altered trophic responses to both functional overload and unloading. This implicates titin’s C-terminal PEVK region in regulating passive and active muscle mechanics and muscle plasticity.

**Background:** The transition from pediatric to adult care in the US is often difficult for individuals with sickle cell disease (SCD). Young adults (18 to 25 years of age) have higher acute care utilization and an increased risk of poor outcomes. The current study was designed to provide greater insights into patients (16 to 18 years of age) with SCD prior to their transition to adult care. **Objectives:** To describe current treatment patterns, pain crises prevalence, SCD-related complications, and healthcare resource utilization (HCRU) in 16-to-18-year-old patients with SCD. **Methods:** From 1/1/2015-6/30/2017 using MarketScan Databases, patients were included if they were 16 to 18 years old at the index date, had ≥1 inpatient or 2 outpatient SCD diagnosis claims during the identification period, and were continuously enrolled in the database for at least one year prior (baseline) and post index date. Outcomes included medications, disease management interventions, Charlson Comorbidity Index (CCI), vaso-occlusive (VOC) crises requiring healthcare visits, HCRU, and SCD complications. **Results:** 1,186 patients were included; most (64.3%) were female. The mean CCI was 1.3 (SD: 0.7). In the overall cohort, patients experienced an average of 3.9 (SD: 4.2) VOCs and most patients (61.1%, n=725) had chronic complications during the one-year follow-up. Pulmonary disease (31.1%, n=369) was the most frequent complication; blood transfusions (mean: 8.4 [SD:7.0]) and iron-chelating therapies (mean: 8.6 [SD:10]) were the most common interventions and medications, respectively. In the 16 to 18 year old group, patients with SCD had 2.0 (SD = 2.3) hospital admissions, 3.4 (SD = 4.0) ER visits, and 5.0 (SD = 4.2) office visits. **Conclusions:** Prior to transition to adult care, adolescents with SCD already have significant acute and chronic disease-related complications, possibly contributing to frequent healthcare visits. Increased attention to this age group, including improvements in disease modifying therapy, are needed prior to transition to adult care systems to improve outcomes.

Abstract Background A pre-morbid mental health history is common in patients with severe burn injuries. This creates challenges in providing rehabilitation. The aim of this study is to cross examine the possible impact of psychological co-morbidities on outcomes. Methods A notes audit was carried out examining patients that were admitted to Concord Hospital Burns Unit in a 3-year period (2010–2012). Patients with total body surface area (TBSA) of 20% or greater and aged between 16 and 50 years were included. Subjects were divided into a mental health group and a control group. SPSS version 21 statistic program was used for analysis the data. Results Data collected included length of stay, time to achieve independence, %TBSA, types of burns and surgery required. Results of 69 files showed that the average length of stay per %TBSA was nearly double in the patients with a mental health problem (1.47 vs 0.88). They also had a higher rate of re-graft (52% vs 22%) due to infection and poor nutrition. The average time for patients to achieve independence in daily living activity was significantly higher (p = 0.046) in the mental health group (36.2 days) versus the control group (24.1 days). Conclusion Patients with a mental health history may have poorer general health. This may result in a higher failure rate of grafting, leading to a requirement of re-graft. Hence, it took a longer time to achieve independence, as well as a longer hospital stay. A mental health history in burn survivors can be a contributing factor for poorer outcomes in the adult population.

This survey aims to evaluate first aid knowledge for the management of burns cases amongst high risk groups. Methods: A survey was conducted on 674 workers including fire fighters, and workers in electrical power and oil industries. The contents of the survey focused on demographic criteria, first aid measure for burn accidents and source of information. Results: 29.5% of participants achieved the desirable score over 75%. The incidence of participants who reported knowing to use cool fresh water to reduce the temperature of the burn wound was 86.1%. In addition, a higher knowledge level was significantly seen in a sub-group of younger, male workers, as well as those who took part in training courses (p

Following the publication of this paper [1], it was brought to the authors’ attention that one of the contributing authors was left off of the paper. The authors apologize for the unfortunate oversight. In this correction paper, they have included Dr. Paola Tonino in the author list section.

Burn injury significantly impacts the victim's long-term quality of life, both physically and psychosocially. This prospective, observational study aimed to assess the physical and psychological health status in adult burn survivors in Sydney Australia using the Burns Specific Health Scale-Brief Version (BSHS-B) questionnaire, together with analysis of the baseline demographic data collected from medical records. A total of 24 adult acute burn victims admitted consecutively to the Burns Unit at Concord Repatriation General Hospital, Sydney, Australia between March 2007 and February 2009 fulfilled the inclusion criteria and participated in the study. The BSHS-B questionnaire (which includes nine domains or subscales) was administered to all 24 participants in person at time of discharge and by mail 6, 12, and 24 months post discharge. By 12 months, 11 participants dropped out and the final analysis was performed on the remaining 13 participants. The analyzed results showed that: 1) Perceived return to work was the only variable that continued to change with time at 12 months after discharge (P < 0.01); 2) At 12 months; return to work was significantly correlated with simple functional ability (P < 0.05), heat sensitivity (P < 0.01), and treatment regimes (P < 0.05), but no longer with affect and body image as demonstrated at 6 months. In summary, our findings have shown that the perception of returning to work changes significantly with time post discharge and this perception is affected by certain subscales of the BSHS-B. Given that return to work is one of the most important outcome concerns and issues of recovery for adult burn injury victims and families, it is essential that therapists be aware of the factors influencing return to work and address these factors through a comprehensive rehabilitation program.

Exercise is a key component of burn rehabilitation across all phases of care. Supervised outpatient exercise programs have been shown to improve outcomes following burn injury. However, little is known about the exercise behaviors of burn survivors who do not undertake such programs. This study aimed to investigate self-reported exercise behaviors and barriers to exercise in adult burn survivors. A short questionnaire survey was conducted on adult burn survivors attending the ambulatory burns clinic of a tertiary hospital over a 6-week period. The collected data were subjected to paired t-tests and Pearson's correlation test. A total of 63 adult burn survivors (mean age 36.5 years) completed the questionnaire. Participants reported exercising less frequently and engaged in fewer different types of exercise compared with pre-burn (P < 0.05). Poor physical conditions and low motivation and enthusiasm were the major barriers to exercise. Participation in supervised exercise programs can be limited by a range of factors including the availability of resources and access to facilities. This preliminary study suggests that there is a need to improve compliance with outpatient exercise programs. Burn survivors appear to exercise less frequently after burn injury. Barriers to exercise following burn injury include poor physical condition and reduced motivation. Further investigation into overall physical activity following burn injury and potential physical and psychological limitations is warranted. Burn clinicians should highly encourage injury survivors to participate in supervised exercise programs when available or to do exercises at home to maximize post-burn injury recovery.

Type 2 diabetes is characterized by impaired glucose homeostasis due to defects in insulin secretion, insulin resistance and the incretin response. GPR40 (FFAR1 or FFA1) is a G-protein-coupled receptor (GPCR), primarily expressed in insulin-producing pancreatic β-cells and incretin-producing enteroendocrine cells of the small intestine. Several GPR40 agonists, including AMG 837 and TAK-875, have been disclosed, but no GPR40 synthetic agonists have been reported that engage both the insulinogenic and incretinogenic axes. In this report we provide a molecular explanation and describe the discovery of a unique and potent class of GPR40 full agonists that engages the enteroinsular axis to promote dramatic improvement in glucose control in rodents. GPR40 full agonists AM-1638 and AM-6226 stimulate GLP-1 and GIP secretion from intestinal enteroendocrine cells and increase GSIS from pancreatic islets, leading to enhanced glucose control in the high fat fed, streptozotocin treated and NONcNZO10/LtJ mouse models of type 2 diabetes. The improvement in hyperglycemia by AM-1638 was reduced in the presence of the GLP-1 receptor antagonist Ex(9-39)NH(2).

Agonists of GPR40 (FFA1) have been proposed as a means to treat type 2 diabetes. Through lead optimization of a high throughput screening hit, we have identified a novel GPR40 agonist called AMG 837. The objective of these studies was to understand the preclinical pharmacological properties of AMG 837. The activity of AMG 837 on GPR40 was characterized through GTPγS binding, inositol phosphate accumulation and Ca(2+) flux assays. Activity of AMG 837 on insulin release was assessed on isolated primary mouse islets. To determine the anti-diabetic activity of AMG 837 in vivo, we tested AMG 837 using a glucose tolerance test in normal Sprague-Dawley rats and obese Zucker fatty rats. AMG 837 was a potent partial agonist in the calcium flux assay on the GPR40 receptor and potentiated glucose stimulated insulin secretion in vitro and in vivo. Acute administration of AMG 837 lowered glucose excursions and increased glucose stimulated insulin secretion during glucose tolerance tests in both normal and Zucker fatty rats. The improvement in glucose excursions persisted following daily dosing of AMG 837 for 21-days in Zucker fatty rats. Preclinical studies demonstrated that AMG 837 was a potent GPR40 partial agonist which lowered post-prandial glucose levels. These studies support the potential utility of AMG 837 for the treatment of type 2 diabetes.

Laser transmission spectroscopy (LTS) is a quantitative and rapid in vitro technique for measuring the size, shape, and number of nanoparticles in suspension. Here we report on the application of LTS as a novel detection method for species-specific DNA where the presence of one invasive species was differentiated from a closely related invasive sister species. The method employs carboxylated polystyrene nanoparticles functionalized with short DNA fragments that are complimentary to a specific target DNA sequence. In solution, the DNA strands containing targets bind to the tags resulting in a sizable increase in the nanoparticle diameter, which is rapidly and quantitatively measured using LTS. DNA strands that do not contain the target sequence do not bind and produce no size change of the carboxylated beads. The results show that LTS has the potential to become a quantitative and rapid DNA detection method suitable for many real-world applications.

The elucidation of distinct protein conformers or states by fluorine ((19)F) NMR requires fluorinated moieties whose chemical shifts are most sensitive to subtle changes in the local dielectric and magnetic shielding environment. In this study we evaluate the effective chemical shift dispersion of a number of thiol-reactive trifluoromethyl probes [i.e. 2-bromo-N-(4-(trifluoromethyl)phenyl)acetamide (BTFMA), N-(4-bromo-3-(trifluoromethyl)phenyl)acetamide (3-BTFMA), 3-bromo-1,1,1-trifluoropropan-2-ol (BTFP), 1-bromo-3,3,4,4,4-pentafluorobutan-2-one (BPFB), 3-bromo-1,1,1-trifluoropropan-2-one (BTFA), and 2,2,2-trifluoroethyl-1-thiol (TFET)] under conditions of varying polarity. In considering the sensitivity of the (19)F NMR chemical shift to the local environment, a series of methanol/water mixtures were prepared, ranging from relatively non-polar (MeOH:H2O = 4) to polar (MeOH:H2O = 0.25). (19)F NMR spectra of the tripeptide, glutathione ((2S)-2-amino-4-{[(1R)-1-[(carboxymethyl)carbamoyl]-2-sulfanylethyl]carbamoyl}butanoic acid), conjugated to each of the above trifluoromethyl probes, revealed that the BTFMA tag exhibited a significantly greater range of chemical shift as a function of solvent polarity than did either BTFA or TFET. DFT calculations using the B3LYP hybrid functional and the 6-31G(d,p) basis set, confirmed the observed trend in chemical shift dispersion with solvent polarity.