Integrated frequency-modulated optical parametric oscillator.

Optical frequency combs have revolutionized precision measurement, time-keeping and molecular spectroscopy1-7. A substantial effort has developed around 'microcombs': integrating comb-generating technologies into compact photonic platforms5,7-9. Current approaches for generating these microcombs involve either the electro-optic10 or Kerr mechanisms11. Despite rapid progress, maintaining high efficiency and wide bandwidth remains challenging. Here we introduce a previously unknown class of microcomb-an integrated device that combines electro-optics and parametric amplification to yield a frequency-modulated optical parametric oscillator (FM-OPO). In contrast to the other solutions, it does not form pulses but maintains operational simplicity and highly efficient pump power use with an output resembling a frequency-modulated laser12. We outline the working principles of our device and demonstrate it by fabricating the complete optical system in thin-film lithium niobate. We measure pump-to-comb internal conversion efficiency exceeding 93% (34% out-coupled) over a nearly flat-top spectral distribution spanning about 200 modes (over 1 THz). Compared with an electro-optic comb, the cavity dispersion rather than loss determines the FM-OPO bandwidth, enabling broadband combs with a smaller radio-frequency modulation power. The FM-OPO microcomb offers robust operational dynamics, high efficiency and broad bandwidth, promising compact precision tools for metrology, spectroscopy, telecommunications, sensing and computing.

The Image Biomarker Standardization Initiative: Standardized Convolutional Filters for Reproducible Radiomics and Enhanced Clinical Insights.

Filters are commonly used to enhance specific structures and patterns in images, such as vessels or peritumoral regions, to enable clinical insights beyond the visible image using radiomics. However, their lack of standardization restricts reproducibility and clinical translation of radiomics decision support tools. In this special report, teams of researchers who developed radiomics software participated in a three-phase study (September 2020 to December 2022) to establish a standardized set of filters. The first two phases focused on finding reference filtered images and reference feature values for commonly used convolutional filters: mean, Laplacian of Gaussian, Laws and Gabor kernels, separable and nonseparable wavelets (including decomposed forms), and Riesz transformations. In the first phase, 15 teams used digital phantoms to establish 33 reference filtered images of 36 filter configurations. In phase 2, 11 teams used a chest CT image to derive reference values for 323 of 396 features computed from filtered images using 22 filter and image processing configurations. Reference filtered images and feature values for Riesz transformations were not established. Reproducibility of standardized convolutional filters was validated on a public data set of multimodal imaging (CT, fluorodeoxyglucose PET, and T1-weighted MRI) in 51 patients with soft-tissue sarcoma. At validation, reproducibility of 486 features computed from filtered images using nine configurations × three imaging modalities was assessed using the lower bounds of 95% CIs of intraclass correlation coefficients. Out of 486 features, 458 were found to be reproducible across nine teams with lower bounds of 95% CIs of intraclass correlation coefficients greater than 0.75. In conclusion, eight filter types were standardized with reference filtered images and reference feature values for verifying and calibrating radiomics software packages. A web-based tool is available for compliance checking.

Computed tomography-based radiomics decodes prognostic and molecular differences in interstitial lung disease related to systemic sclerosis.

BACKGROUND: Radiomic features calculated from routine medical images show great potential for personalised medicine in cancer. Patients with systemic sclerosis (SSc), a rare, multiorgan autoimmune disorder, have a similarly poor prognosis due to interstitial lung disease (ILD). Here, our objectives were to explore computed tomography (CT)-based high-dimensional image analysis ("radiomics") for disease characterisation, risk stratification and relaying information on lung pathophysiology in SSc-ILD. METHODS: We investigated two independent, prospectively followed SSc-ILD cohorts (Zurich, derivation cohort, n=90; Oslo, validation cohort, n=66). For every subject, we defined 1355 robust radiomic features from standard-of-care CT images. We performed unsupervised clustering to identify and characterise imaging-based patient clusters. A clinically applicable prognostic quantitative radiomic risk score (qRISSc) for progression-free survival (PFS) was derived from radiomic profiles using supervised analysis. The biological basis of qRISSc was assessed in a cross-species approach by correlation with lung proteomic, histological and gene expression data derived from mice with bleomycin-induced lung fibrosis. RESULTS: Radiomic profiling identified two clinically and prognostically distinct SSc-ILD patient clusters. To evaluate the clinical applicability, we derived and externally validated a binary, quantitative radiomic risk score (qRISSc) composed of 26 features that accurately predicted PFS and significantly improved upon clinical risk stratification parameters in multivariable Cox regression analyses in the pooled cohorts. A high qRISSc score, which identifies patients at risk for progression, was reverse translatable from human to experimental ILD and correlated with fibrotic pathway activation. CONCLUSIONS: Radiomics-based risk stratification using routine CT images provides complementary phenotypic, clinical and prognostic information significantly impacting clinical decision making in SSc-ILD.

High-bandwidth CMOS-voltage-level electro-optic modulation of 780 nm light in thin-film lithium niobate.

Integrated photonics operating at visible-near-infrared (VNIR) wavelengths offer scalable platforms for advancing optical systems for addressing atomic clocks, sensors, and quantum computers. The complexity of free-space control optics causes limited addressability of atoms and ions, and this remains an impediment on scalability and cost. Networks of Mach-Zehnder interferometers can overcome challenges in addressing atoms by providing high-bandwidth electro-optic control of multiple output beams. Here, we demonstrate a VNIR Mach-Zehnder interferometer on lithium niobate on sapphire with a CMOS voltage-level compatible full-swing voltage of 4.2 V and an electro-optic bandwidth of 2.7 GHz occupying only 0.35 mm2. Our waveguides exhibit 1.6 dB/cm propagation loss and our microring resonators have intrinsic quality factors of 4.4 × 105. This specialized platform for VNIR integrated photonics can open new avenues for addressing large arrays of qubits with high precision and negligible cross-talk.

Ultra-broadband mid-infrared generation in dispersion-engineered thin-film lithium niobate.

Thin-film lithium niobate (TFLN) is an emerging platform for compact, low-power nonlinear-optical devices, and has been used extensively for near-infrared frequency conversion. Recent work has extended these devices to mid-infrared wavelengths, where broadly tunable sources may be used for chemical sensing. To this end, we demonstrate efficient and broadband difference frequency generation between a fixed 1-µm pump and a tunable telecom source in uniformly-poled TFLN-on-sapphire by harnessing the dispersion-engineering available in tightly-confining waveguides. We show a simultaneous 1-2 order-of-magnitude improvement in conversion efficiency and ∼5-fold enhancement of operating bandwidth for mid-infrared generation when compared to equal-length conventional lithium niobate waveguides. We also examine the effects of mid-infrared loss from surface-adsorbed water on the performance of these devices.

High-efficiency second harmonic generation of blue light on thin-film lithium niobate.

The strength of interactions between photons in a χ(2) nonlinear optical waveguide increases at shorter wavelengths. These larger interactions enable coherent spectral translation and light generation at a lower power, over a broader bandwidth, and in a smaller device: all of which open the door to new technologies spanning fields from classical to quantum optics. Stronger interactions may also grant access to new regimes of quantum optics to be explored at the few-photon level. One promising platform that could enable these advances is thin-film lithium niobate (TFLN), due to its broad optical transparency window and possibility for quasi-phase matching and dispersion engineering. In this Letter, we demonstrate second harmonic generation of blue light on an integrated thin-film lithium niobate waveguide and observe a conversion efficiency of η0 = 33, 000%/W-cm2, significantly exceeding previous demonstrations.

CT radiomics and PET radiomics: ready for clinical implementation?

INTRODUCTION: Today, rapid technical and clinical developments result in an increasing number of treatment options for oncological diseases. Thus, decision support systems are needed to offer the right treatment to the right patient. Imaging biomarkers hold great promise in patient-individual treatment guidance. Routinely performed for diagnosis and staging, imaging datasets are expected to hold more information than used in the clinical practice. Radiomics describes the extraction of a large number of meaningful quantitative features from medical images, such as computed tomography (CT) and positron emission tomography (PET). Due to the non-invasive nature and ability to capture 3D image-based heterogeneity, radiomic features are potential surrogate markers of the cancer phenotype. Several radiomic studies are published per day, owing to encouraging results of many radiomics-based patient outcome models. Despite this comparably large number of studies, radiomics is mainly studied in proof of principle concept. Hence, a translation of radiomics from a hot topic research field into an essential clinical decision-making tool is lacking, but of high clinical interest. EVIDENCE ACQUISITION: Herein, we present a literature review addressing the clinical evidence of CT and PET radiomics. An extensive literature review was conducted in PubMed, including papers on robustness and clinical applications. EVIDENCE SYNTHESIS: We summarize image-modality related influences on the robustness of radiomic features and provide an overview of clinical evidence reported in the literature. Today, more evidence has been provided for CT imaging, however, PET imaging offers the promise of direct imaging of biological processes and functions. We provide a summary of future research directions, which needs to be addressed in order to successfully introduce radiomics into clinical medicine. In comparison to CT, more focus should be directed towards harmonization of PET acquisition and reconstruction protocols, which is important for transferable modelling. CONCLUSIONS: Both CT and PET radiomics are promising pre-treatment and intra-treatment biomarkers for outcome prediction. Most studies are performed in retrospective setting, however their validation in prospective data collections is ongoing.

SYN-004 (ribaxamase), an oral beta-lactamase, mitigates antibiotic-mediated dysbiosis in a porcine gut microbiome model.

AIM: To evaluate an antibiotic inactivation strategy to protect the gut microbiome from antibiotic-mediated damage. METHODS AND RESULTS: SYN-004 (ribaxamase) is an orally delivered beta-lactamase intended to degrade penicillins and cephalosporins within the gastrointestinal tract to protect the microbiome. Pigs (20 kg, n = 10) were treated with ceftriaxone (CRO) (IV, 50 mg kg-1 , SID) for 7 days and a cohort (n = 5) received ribaxamase (PO, 75 mg, QID) for 9 days beginning the day before antibiotic administration. Ceftriaxone serum levels were not statistically different in the antibiotic-alone and antibiotic + ribaxamase groups, indicating ribaxamase did not alter systemic antibiotic levels. Whole-genome metagenomic analyses of pig faecal DNA revealed that CRO caused significant changes to the gut microbiome and an increased frequency of antibiotic resistance genes. With ribaxamase, the gut microbiomes were not significantly different from pretreatment and antibiotic resistance gene frequency was not increased. CONCLUSION: Ribaxamase mitigated CRO-mediated gut microbiome dysbiosis and attenuated propagation of the antibiotic resistance genes in pigs. SIGNIFICANCE AND IMPACT OF THE STUDY: Damage of the microbiome can lead to overgrowth of pathogenic organisms and antibiotic exposure can promote selection for antibiotic-resistant micro-organisms. Ribaxamase has the potential to become the first therapy designed to protect the gut microbiome from antibiotic-mediated dysbiosis and reduce emergence of antibiotic resistance.

Metabolic engineering of Pseudomonas putida for production of docosahexaenoic acid based on a myxobacterial PUFA synthase.

Long-chain polyunsaturated fatty acids (LC-PUFAs) can be produced de novo via polyketide synthase-like enzymes known as PUFA synthases, which are encoded by pfa biosynthetic gene clusters originally discovered from marine microorganisms. Recently similar gene clusters were detected and characterized in terrestrial myxobacteria revealing several striking differences. As the identified myxobacterial producers are difficult to handle genetically and grow very slowly we aimed to establish heterologous expression platforms for myxobacterial PUFA synthases. Here we report the heterologous expression of the pfa gene cluster from Aetherobacter fasciculatus (SBSr002) in the phylogenetically distant model host bacteria Escherichia coli and Pseudomonas putida. The latter host turned out to be the more promising PUFA producer revealing higher production rates of n-6 docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA). After several rounds of genetic engineering of expression plasmids combined with metabolic engineering of P. putida, DHA production yields were eventually increased more than threefold. Additionally, we applied synthetic biology approaches to redesign and construct artificial versions of the A. fasciculatus pfa gene cluster, which to the best of our knowledge represents the first example of a polyketide-like biosynthetic gene cluster modulated and synthesized for P. putida. Combination with the engineering efforts described above led to a further increase in LC-PUFA production yields. The established production platform based on synthetic DNA now sets the stage for flexible engineering of the complex PUFA synthase.

Clinical trials in youth-onset type 2 diabetes: needs, barriers, and options.

Youth-onset type 2 diabetes (T2D) is increasingly recognized as a disorder with substantial risk for long-term metabolic, cardiovascular, and renal morbidity and mortality, as well as individual and societal burden. Recent studies suggest that the disorder differs from adult-onset T2D in a variety of ways and that there is an urgent need for an expanded set of treatment options. However, demographic, economic, and social challenges limit the number of eligible candidates for clinical trials in youth-onset T2D, and a growing number trials mandated by regulatory agencies have created a circumstance in which too many trials are chasing too few eligible participants. A solution to this situation will require novel approaches to clinical trial design incorporating collaboration among clinical investigators, pharmaceutical sponsors, and regulatory agencies. If successful, this approach could also serve as a model for clinical trials in other rare and understudied pediatric disorders.

Effect of colesevelam HCl monotherapy on lipid particles in type 2 diabetes mellitus.

PURPOSE: In addition to lowering hemoglobin A1C, colesevelam has been shown to improve the atherogenic lipoprotein profile of subjects with type 2 diabetes mellitus (T2DM) when used in combination with metformin and/or sulfonylureas. A recent study evaluated the effects of colesevelam as antidiabetes monotherapy in adults with T2DM who had inadequate glycemic control (hemoglobin A1C ≥7.5 to ≤9.5 %) with diet and exercise alone; we report here the effects on lipoprotein particle subclasses. METHODS: Subjects were randomized to receive oral colesevelam 3.75 g/day (n = 176) or placebo (n = 181) for 24 weeks. Changes in lipoprotein particle subclasses were determined by nuclear magnetic resonance spectroscopy. RESULTS: At Week 24 with last observation carried forward, colesevelam produced a reduction in total low-density lipoprotein (LDL) particle concentration (baseline: 1,611 nmol/L; least-squares [LS] mean treatment difference: -143 nmol/L, p < 0.0001) versus placebo; reductions were also seen in large, small, and very small LDL particle concentrations (all p < 0.05). There was also a reduction in total very low-density lipoprotein (VLDL) and chylomicron particle concentration (baseline: 88 nmol/L; LS mean treatment difference: -1 nmol/L, p = 0.82) that resulted from a lowering in small VLDL particle concentration (baseline: 45 nmol/L; LS mean treatment difference: -5 nmol/L, p = 0.03). In addition, with colesevelam there was an increase in total high-density lipoprotein (HDL) particle concentration versus placebo (baseline: 31 µmol/L; LS mean treatment difference: +0.6 µmol/L, p = 0.20), due to increases in the large (baseline: 5 µmol/L; LS mean treatment difference: +0.5 µmol/L, p = 0.007) and medium (baseline: 3 µmol/L; LS mean treatment difference: +0.8 µmol/L, p = 0.02) HDL subclasses. CONCLUSIONS: Colesevelam monotherapy in subjects with T2DM resulted in generally favorable changes in certain lipoprotein subclass profiles compared with placebo.

Quantum efficiency measurements of an x-ray charge-coupled device in the 2-10 keV spectral region by means of a double crystal monochromator coupled to an x-ray tube.

The Atomic Energy Commission has set up a laboratory dedicated to the calibration of x-ray cameras mainly used in the Laser MégaJoule Facility in the Bordeaux region of France. Thanks to a double crystal monochromator specifically designed to perform such calibration, we calibrated a thinned, back-illuminated x-ray CCD manufactured by Roper Scientific Inc. over the 2.2-8.9 keV spectral region. Quantum efficiency results are in good agreement with those of previous works. To explain slight differences, we studied the difference between monochromatization methods performed either using a crystal monochromator or filters. Results showed that the latter method appears to be too dependent on the x-ray source parameters to perform accurate and relevant calibration on x-ray cameras.

Inflammatory myofibroblastic tumor of the bladder in an adolescent: Case report.

Inflammatory myofibroblastic tumors of the bladder (IMTB) are rare neoplasms that can occur in children. These tumors have uncertain malignant potential and can present similarly to bladder sarcomas. It is important to differentiate between IMTB and bladder sarcomas using a careful immunohistochemical approach. We report a case of IMTB in a 12-year-old girl who presented with presyncope and gross hematuria. IMTB was diagnosed through immunohistochemical analysis, and clinical improvement was observed after resection of the tumor.

Effect of core preventative screening on kidney stone surgical patterns.

PURPOSE: In the surgical treatment of kidney stones, decreased access to healthcare has been shown to exacerbate stone burden, often requiring more invasive and extensive procedures. The objective of this study is to evaluate the effects of preventative health screening on kidney stone surgical treatment patterns. METHODS: We performed a retrospective analysis of data from the Healthcare Cost and Utilization Project (HCUP) Florida state-wide dataset and the PLACES Local Data for Better Health dataset from the Centers of Disease Control and Prevention (CDC). ZIP Code Tabulation Areas (ZCTAs) identified from the PLACES data were merged with the HCUP dataset to create a single dataset of community-level stone outcomes and community health measures. We included adult patients 18 years or older who underwent at least one urologic stone procedure from 2016 to 2020. RESULTS: 128,038 patients from 885 communities were included in the study. Patients underwent an average of 1.42 surgeries (Median = 1.39, SD = 0.16). Increased core preventative screening was associated with increased surgical frequency (Estimate: 0.51, P < 0.001). The low core preventative screening group had a higher prevalence of PNL than SWL while the high core preventative screening group had a low PNL prevalence compared to SWL. CONCLUSION: Increased core preventative screenings are associated with less invasive kidney stone surgeries, suggesting that preventative screenings detect stones at an earlier stage.

Radioproteomics stratifies molecular response to antifibrotic treatment in pulmonary fibrosis.

Antifibrotic therapy with nintedanib is the clinical mainstay in the treatment of progressive fibrosing interstitial lung disease (ILD). High-dimensional medical image analysis, known as radiomics, provides quantitative insights into organ-scale pathophysiology, generating digital disease fingerprints. Here, we used an integrative analysis of radiomic and proteomic profiles (radioproteomics) to assess whether changes in radiomic signatures can stratify the degree of antifibrotic response to nintedanib in (experimental) fibrosing ILD. Unsupervised clustering of delta radiomic profiles revealed two distinct imaging phenotypes in mice treated with nintedanib, contrary to conventional densitometry readouts, which showed a more uniform response. Integrative analysis of delta radiomics and proteomics demonstrated that these phenotypes reflected different treatment response states, as further evidenced on transcriptional and cellular levels. Importantly, radioproteomics signatures paralleled disease- and drug related biological pathway activity with high specificity, including extracellular matrix (ECM) remodeling, cell cycle activity, wound healing, and metabolic activity. Evaluation of the preclinical molecular response-defining features, particularly those linked to ECM remodeling, in a cohort of nintedanib-treated fibrosing ILD patients, accurately stratified patients based on their extent of lung function decline. In conclusion, delta radiomics has great potential to serve as a non-invasive and readily accessible surrogate of molecular response phenotypes in fibrosing ILD. This could pave the way for personalized treatment strategies and improved patient outcomes.

BCG Vaccination-Associated Lower HbA1c and Increased CD25 Expression on CD8+ T Cells in Patients with Type 1 Diabetes in Ghana.

BCG vaccination affects other diseases beyond tuberculosis by unknown-potentially immunomodulatory-mechanisms. Recent studies have shown that BCG vaccination administered during overt type 1 diabetes (T1D) improved glycemic control and affected immune and metabolic parameters. Here, we comprehensively characterized Ghanaian T1D patients with or without routine neonatal BCG vaccination to identify vaccine-associated alterations. Ghanaian long-term T1D patients (n = 108) and matched healthy controls (n = 214) were evaluated for disease-related clinical, metabolic, and immunophenotypic parameters and compared based on their neonatal BCG vaccination status. The majority of study participants were BCG-vaccinated at birth and no differences in vaccination rates were detected between the study groups. Notably, glycemic control metrics, i.e., HbA1c and IDAA1c, showed significantly lower levels in BCG-vaccinated as compared to unvaccinated patients. Immunophenotype comparisons identified higher expression of the T cell activation marker CD25 on CD8+ T cells from BCG-vaccinated T1D patients. Correlation analysis identified a negative correlation between HbA1c levels and CD25 expression on CD8+ T cells. In addition, we observed fractional increases in glycolysis metabolites (phosphoenolpyruvate and 2/3-phosphoglycerate) in BCG-vaccinated T1D patients. These results suggest that neonatal BCG vaccination is associated with better glycemic control and increased activation of CD8+ T cells in T1D patients.

Transurethral neo-orifice (TUNO) a novel technique for management of upper pole obstruction in infancy.

INTRODUCTION AND OBJECTIVE: Ureteral duplication is the most common urologic abnormality. The upper pole ureter can sometimes be associated with a ureterocele. In rare cases the ureteral insertion is extravesical and can result in significant hydroureteronephrosis. Patients can present with urinary tract infection, abdominal mass or urinary obstruction. Traditional procedures include ureteral reimplantation, ureteroureterostomy or heminephroureterectomy. These reconstructive procedures are technically challenging in small infants, especially when the hydroureteronephrosis is severe. In some cases a distal cutaneous ureterostomy is performed for immediate drainage followed by definitive surgery when the child is older. We describe our initial experience with a novel cystoscopic technique which provides drainage of the upper pole ureter and avoids the need for an incision or stoma. MATERIALS AND METHODS: A 3 month-old boy presented with urinary tract infections and failure to thrive. Ultrasound revealed severe upper pole hydroureteronephrosis. Voiding cystourethrography did not reveal vesicoureteral reflux or the presence of a ureterocele. The patient underwent cytoscopy. The ectopic ureteral orifice was not identified. A transurethral, transvesical needle puncture and confirmatory ureteropyelography was used to access the dilated upper pole ureter. Guidewire passage, followed catheter dilation then allowed creation of a new ureteral orifice using a holmium laser. RESULTS: The patient tolerated the procedure well. He was discharged after overnight observation. The hydronephrosis improved, urinary tract infections have not recurred and the patient rapidly improved feeding and weight gain. CONCLUSION: Trans-Urethral Neo-Orifice creation is a minimally invasive option for initial decompression for patients with obstructive ureteral ectopia.

Absolute calibration of the spectral sensitivity of an x-ray streak camera over the 0.1-10 keV spectral range equipped with CsI photocathode.

In this paper, we report the absolute measurement of the spectral sensitivity of a bilamellar tube x-ray streak camera (XRSC) over the 0.1-10 keV range equipped with a CsI photocathode for Laser MégaJoule (LMJ) fusion experiments. This calibration of the XRSC is performed in static mode by using two multi-anode x-ray generators. Two silicon drift detectors (SDDs) previously calibrated at the Physikalisch-Technische-Bundesanstalt radiometric laboratory are used as secondary standards. Both x-ray generators work with a specific monochromator for radiometric measurements. In the sub-keV region, a 1 m-grazing incidence Rowland geometry monochromator specifically developed to handle LMJ's x-ray camera is used, whereas for higher energies (>2 keV), a double-crystal monochromator is employed. The absolute spectral sensitivity of the XRSC is obtained by comparing the CCD counts of the XRSC output with the output counts in x-ray lines recorded by the SDD. The results obtained below 1.2 keV are, to our knowledge, the first measurements of the spectral sensitivity of an XRSC in the soft x-ray range with a CsI photocathode. Comparison with a model describing the spectral dependence of the sensitivity of the XRSC revealed that measurements obtained in the sub-keV region are greater than expected, whereas they agree with the model above 4.5 keV. There may be several contributors to this behavior, including the grain morphology of the CsI layer and exposure to air.

Integrated quantum optical phase sensor in thin film lithium niobate.

The quantum noise of light, attributed to the random arrival time of photons from a coherent light source, fundamentally limits optical phase sensors. An engineered source of squeezed states suppresses this noise and allows phase detection sensitivity beyond the quantum noise limit (QNL). We need ways to use quantum light within deployable quantum sensors. Here we present a photonic integrated circuit in thin-film lithium niobate that meets these requirements. We use the second-order nonlinearity to produce a squeezed state at the same frequency as the pump light and realize circuit control and sensing with electro-optics. Using 26.2 milliwatts of optical power, we measure (2.7 ± 0.2)% squeezing and apply it to increase the signal-to-noise ratio of phase measurement. We anticipate that photonic systems like this, which operate with low power and integrate all of the needed functionality on a single die, will open new opportunities for quantum optical sensing.

Hybrid balloon valvuloplasty for management of severe mitral stenosis in four symptomatic, adult dogs.

Four adult dogs weighing <10 kg presented for the evaluation of severe mitral valve stenosis with clinical signs. Owing to the size of the dogs, a hybrid surgical and interventional approach was utilized for balloon valvuloplasty. A left lateral thoracotomy was performed to allow direct entry through the left atrial wall. Transesophageal echocardiography was utilized for the entirety of the procedure in all dogs, and fluoroscopy was additionally used in two dogs. One dog had mild to moderate intra-operative bleeding from the left atrial wall during the procedure, but no other intra-operative complications were observed. No dogs developed a clinically relevant amount of worsened mitral regurgitation. Based on mitral leaflet mobility and transmitral flow profiles, there was perceived improvement in all four dogs. One dog died 6 h after extubation due to respiratory arrest. The remaining dogs survived to discharge and had resolution of clinical signs at home and discontinuation of heart failure medications. One dog died of an unknown cause at five months and another developed atrial fibrillation, and the owners elected to euthanize at ten months after the procedure. One dog continues to do well six months after the procedure as of the time of this writing. Hybrid balloon valvuloplasty can be a viable management option for small breed dogs with severe mitral stenosis exhibiting clinical signs, and both transesophageal echocardiography and fluoroscopy can be used intra-operatively to assist in successful procedural outcomes.