Citations

Abstract Idiopathic pulmonary fibrosis (IPF) is an aggressive and, thus far, incurable disease characterized by aberrant fibroblast-mediated extracellular matrix deposition. Our understanding of the disease etiology is incomplete; however, there is consensus that a reduction-oxidation (redox) imbalance plays a role. In this study, we use the autofluorescent properties of two redox molecules, NAD(P)H and FAD, to quantify changes in their relative abundance in living lung tissue of mice with experimental lung fibrosis and in freshly isolated cells from mouse lungs and humans with IPF. Our results identify cell population–specific intracellular redox changes in the lungs in experimental and human fibrosis. We focus particularly on redox changes within collagen-producing cells, where we identified a bimodal distribution of NAD(P)H concentrations, establishing NAD(P)Hhigh and NAD(P)Hlow subpopulations. NAD(P)Hhigh fibroblasts exhibited elevated profibrotic gene expression and decreased collagenolytic protease activity relative to NAD(P)Hlow fibroblasts. The NAD(P)Hhigh population was present in healthy lungs but expanded with time after bleomycin injury, suggesting a potential role in fibrosis progression. We identified a similar increased abundance of NAD(P)Hhigh cells in freshly dissociated lungs of subjects with IPF relative to control subjects, as well as similar reductions in collagenolytic activity in this cell population. These data highlight the complexity of redox state changes in experimental and human pulmonary fibrosis and the need for selective approaches to restore redox imbalances in the fibrotic lung.

ImportanceSince 2021, American College of Surgeons Commission on Cancer (CoC) accreditation standards require providing a survivorship program for patients with adult-onset cancer treated with curative intent. Since more than 70% of all patients with cancer in the US are treated at CoC-accredited facilities, this presents an opportunity for a landscape analysis of survivorship care availability.ObjectiveTo determine the prevalence, types, and outcomes of cancer survivorship services at CoC-accredited facilities.Design, Setting, and ParticipantsThis survey study used an anonymous, online, cross-sectional survey conducted from May 4 to 25, 2023. Participants were CoC-accredited facilities in the US representing diverse CoC program categories, institutional characteristics, geographic regions, and practice types. Department of Veterans Affairs cancer programs were excluded due to data usage restrictions. Data were analyzed from July to October 2023.ExposureCoC Survivorship Standard 4.8 was released in October 2019 and programs were expected to adhere to the Standard beginning January 1, 2021.Main Outcomes and MeasuresQuestions included self-reported survivorship program characteristics, availability of services aligned to CoC Survivorship Standard 4.8, and perceived program impacts. Response frequencies and proportions were determined in aggregate and by CoC program category.ResultsThere were 1400 eligible programs, and 384 programs participated (27.4% response rate). All regions and eligible program categories were represented, and most had analytic caseloads of 500 to 4999 patients in 2021. Most survivorship program personnel included nurses (334 programs [87.0%]) and social workers (278 programs [72.4%]), while physical (180 programs [46.9%]) and occupational (87 programs [22.7%]) therapists were less common. Services most endorsed as available for all survivors were screening for new cancers (330 programs [87.5%]), nutritional counseling (325 programs [85.3%]), and referrals to specialists (320 programs [84.7%]), while treatment summaries (242 programs [64.7%]), and survivorship care plans (173 programs [43.0%]), sexual health (217 programs [57.3%]), and fertility (214 programs [56.9%]) were less common. Survivorship services were usually delivered by cancer treatment teams (243 programs [63.3%]) rather than specialized survivorship clinics (120 programs [31.3%]). For resources needed, additional advanced practice clinicians with dedicated survivorship effort (205 programs [53.4%]) and electronic health record enhancements (185 programs [48.2%]) were most endorsed. Lack of referrals and low patient awareness were endorsed as the primary barriers. A total of 335 programs (87.2%) agreed that Survivorship Standard 4.8 helped advance their programs.Conclusions and RelevanceThese findings of this survey study of CoC-accredited programs establish a benchmark for survivorship care delivery in the US, identify gaps in specific services and opportunities for intervention, contribute to longitudinal reevaluation for tracking progress nationally, and suggest the value of survivorship care standards.

Neurostimulation is an increasingly common treatment option for medically intractable epilepsy. SANTE (Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy) and Responsive Neurostimulation (RNS) System are landmark neurostimulation trials that utilized either duty cycle or a responsive stimulation paradigm. A seizure-free outcome is rarely observed with responsive and duty cycle neurostimulation devices. Chronic subthreshold cortical stimulation (CSCS) is a promising treatment for adult drug-resistant epilepsy involving eloquent cortex and has demonstrated safety and efficacy. Herein, the authors describe the surgical technique as well as details of stimulation programming involved in CSCS placement to facilitate the adoption of this promising treatment. The video can be found here: https://stream.cadmore.media/r10.3171/2024.4.FOCVID2422

Pityriasis rubra pilaris (PRP) is a rare inflammatory skin disease with a poorly understood pathogenesis. Through a molecularly driven precision medicine approach and an extensive mechanistic pathway analysis in PRP skin samples, compared to psoriasis, atopic dermatitis, healed PRP, and healthy controls, we identified IL-1β as a key mediator, orchestrating an NF-κB–mediated IL-1β–CCL20 axis, including activation of CARD14 and NOD2. Treatment of three patients with the IL-1 antagonists anakinra and canakinumab resulted in rapid clinical improvement and reversal of the PRP-associated molecular signature with a 50% improvement in skin lesions after 2 to 3 weeks. This transcriptional signature was consistent with in vitro stimulation of keratinocytes with IL-1β. With the central role of IL-1β underscoring its potential as a therapeutic target, our findings propose a redefinition of PRP as an autoinflammatory keratinization disorder. Further clinical trials are needed to validate the efficacy of IL-1β antagonists in PRP.

A variety of advanced shear wave elastography techniques require the measurement of frequency-resolved phase velocity to properly characterize wave signals where factors such as tissue viscosity or guided wave effects are present. However, when applying these techniques in a dynamic environment where extrinsic motion cannot be limited, nonlinear and nonstationary trends can be expected in the motion signal used for phase velocity estimation. Because such extrinsic motion signals can contaminate a broad range of frequencies, they can produce significant errors in the phase velocity estimates. In this study, we propose a spatiotemporal detrending approach for elastography wave motion signals built from a 2D Whittaker smoother. This smoother has its origins in nonparametric regression and is well suited for fitting nonlinear curves of arbitrary shape. The resulting detrending filter was applied to Lamb wave signals from clinical ultrasound bladder vibrometry measurements. We found that the proposed detrending filter allowed for phase velocity estimates to be made in acquisitions that are otherwise be too corrupted by large motion. This works was supported by a grant from the NIH (DK131685)

Chronic lymphocytic leukemia (CLL) is characterized by multiple copy number alterations (CNAs) and somatic mutations that are central to disease prognosis, risk stratification, and mechanisms of therapy resistance. Fluorescence in situ hybridization (FISH) panels are widely used in clinical applications as the gold standard for screening prognostic chromosomal abnormalities in CLL. DNA sequencing is an alternative approach to identifying CNAs but is not an established method for clinical CNA screening. We sequenced DNA from 509 individuals with CLL or monoclonal B-cell lymphocytosis (MBL), the precursor to CLL, using a targeted sequencing panel of 59 recurrently mutated genes in CLL and additional amplicons across regions affected by clinically relevant CNAs [i.e., del(17p), del(11q), del(13q), and trisomy 12]. We used the PatternCNV algorithm to call CNA and compared the concordance of calling clinically relevant CNAs by targeted sequencing to that of FISH. We found a high accuracy of calling CNAs via sequencing compared to FISH. With FISH as the gold standard, the specificity of targeted sequencing was >95%, sensitivity was >86%, positive predictive value was >90%, and negative predictive value was >84% across the clinically relevant CNAs. Using targeted sequencing, we were also able to identify other common CLL-associated CNAs, including del(6q), del(14q), and gain 8q, as well as complex karyotype, defined as the presence of 3 or more chromosomal abnormalities, in 26 patients. In a single and cost-effective assay that can be performed on stored DNA samples, targeted sequencing can simultaneously detect CNAs, somatic mutations, and complex karyotypes, which are all important prognostic features in CLL.

Performing 3D ultrasound imaging at a real-time volume rate (e.g., >20 Hz) is a challenging task. While 2D array transducers remain the most practical approach for real-time 3D imaging, the large number of transducer elements (e.g., several thousand) that are necessary to cover an effective 3D field-of-view impose a fundamental constraint on imaging speed. Although solutions such as multiplexing and specialized transducers, including sparse arrays and row-column-addressing arrays, have been developed to address this limitation, they inevitably compromise imaging quality (e.g., SNR, resolution) in favor of speed. Coupled with the high equipment cost of 2D arrays, these compromises hinder the widespread adoption of 3D ultrasound imaging technologies in clinical settings. In this presentation, we introduce an innovative transducer clip-on device comprising a water-immersible, fast-tilting electromechanical acoustic reflector and a redirecting reflector to enable real-time 3D ultrasound imaging using common 1D array transducers. We will first introduce the principles underlying our novel technique, followed by validation studies incorporating simulation and experimental data. We will also demonstrate the feasibility of using the clip-on device to achieve a high 3D imaging volume rate that is suitable for advanced imaging modes such as shear wave elastography, blood flow imaging, and super-resolution ultrasound localization microscopy.

Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a liver disorder characterized by steatosis with underlying metabolic risk factors. The prevalence of MASLD continues to rise, leading to increased patient risk of various complications. Recent research has been focused on new therapeutic strategies to reduce the incidence of MASLD and provide effective treatment plans to prevent further irreversible liver damage. The treatment approach is multifactorial, with a primary focus on weight loss and management of underlying comorbidities through lifestyle modifications, pharmacotherapy, or surgical options. Ongoing research is exploring new pharmacological therapies that could enhance the treatment of MASLD.

Background There are limited data about the impact of timing of pulmonary valve replacement (PVR) on right heart reverse remodeling in patients with pulmonary regurgitation following intervention for isolated pulmonary valve stenosis (PS). This study compared differences in postprocedural right heart reverse remodeling after early versus late PVR (defined as PVR before versus after attainment of the conservative consensus criteria proposed by Bokma et al, 2018) in patients with prior intervention for PS, using patients with tetralogy of Fallot as the reference group. Method and Results Right atrial reservoir strain and right ventricular free wall strain was measured at baseline, 1 and 3 years after PVR. There were 114 patients with PS (early PVR, 87 [76%]; late PVR, 27 [24%]) and 291 patients with tetralogy of Fallot (early PVR, 197 [67%]; late PVR, 96 [33%]). The PS group had greater improvement in right atrial reservoir strain at 1 year (12%±4% versus 8%±4%; P <0.001) and 3 years (15%±6% versus 9%±6%; P <0.001), and a greater improvement in right ventricular free wall strain at 1 year (12%±4% versus 7%±3%, P =0.008) and 3‐years (16%±6% versus 12%±5%; P =0.01) after PVR compared with the tetralogy of Fallot group. There was no difference in right heart reverse remodeling between patients who underwent early versus later PVR within the PS group. In contrast, late PVR was associated with less right heart reverse remodeling within the tetralogy of Fallot group. Conclusions These data suggest that patients with palliated PS presenting pulmonary regurgitation have a more benign clinical course, and hence delaying PVR in this population may be appropriate.