Lower-extremity muscle wasting in patients with peripheral arterial disease: quantitative measurement and evaluation with CT.

OBJECTIVES: Lower-extremity peripheral arterial disease (PAD) results in limb ischemia and is strongly associated with sarcopenia. This study aimed to retrospectively evaluate the association between the quantity of muscle mass in the lower extremities and the severity of vascular stenosis in PAD patients. METHODS: Between January 2018 and August 2021, 128 patients with PAD and 53 individuals without PAD, diagnosed by computed tomography, were enrolled. The severity of stenosis of lower-extremity arteries was measured using a grading system. The muscle and fat mass areas were calculated in the abdomen at the L3 or L4 level, mid-thigh, and lower leg. Multivariable logistic regression was conducted to clarify the risk associated with low muscle mass. The difference in muscle mass between PAD and non-PAD patients was evaluated by using propensity score matching. RESULTS: A strong positive correlation between the abdomen muscle area and leg muscle area was observed. The muscle area and muscle index of the leg were lower in PAD patients. These changes occurred earlier than in the abdomen muscle area. The group with more severe artery stenosis had more muscle wasting in the lower extremities. Greater age, female, lower BMI, and PAD were associated with low muscle mass. After propensity score matching, the leg muscle area was still lower in PAD patients. CONCLUSIONS: There is a direct association between PAD and regional muscle wasting. This occurs earlier regionally in the lower extremities than in central muscles. Early diagnosis of PAD might prevent progressive muscle loss, improving disease outcome and quality of life. KEY POINTS: • Peripheral arterial disease is strongly associated with sarcopenia. • Muscle wasting in the lower extremities is earlier and more prominent than that in the abdomen. • More severe arterial stenoses are associated with higher muscle wasting in the lower extremities.

Development and internal validation of a multivariable risk prediction model for severe rebound pain after foot and ankle surgery involving single-shot popliteal sciatic nerve block.

BACKGROUND: Rebound pain occurs after up to 50% of ambulatory surgeries involving regional anaesthesia. To assist with risk stratification, we developed a model to predict severe rebound pain after foot and ankle surgery involving single-shot popliteal sciatic nerve block. METHODS: After ethics approval, we performed a single-centre retrospective cohort study. Patients undergoing lower limb surgery with popliteal sciatic nerve block from January 2016 to November 2019 were included. Exclusion criteria were uncontrolled pain in the PACU, use of a perineural catheter, or loss to follow-up. We developed and internally validated a multivariable logistic regression model for severe rebound pain, defined as transition from well-controlled pain in the PACU (numerical rating scale [NRS] 3 or less) to severe pain (NRS ≥7) within 48 h. A priori predictors were age, sex, surgery type, planned admission, local anaesthetic type, dexamethasone use, and intraoperative anaesthesia type. Model performance was evaluated using area under the receiver operating characteristic curve (AUROC), Nagelkerke's R2, scaled Brier score, and calibration slope. RESULTS: The cohort included 1365 patients (mean [standard deviation] age: 50 [16] yr). The primary outcome was abstracted in 1311 (96%) patients, with severe rebound pain in 652 (50%). Internal validation revealed poor model performance, with AUROC 0.632 (95% confidence interval [CI]: 0.602-0.661; bootstrap optimisation 0.021), Nagelkerke's R2 0.063, and scaled Brier score 0.047. Calibration slope was 0.832 (95% CI: 0.623-1.041). CONCLUSIONS: We show that a multivariable risk prediction model developed using routinely collected clinical data had poor predictive performance for severe rebound pain after foot and ankle surgery. Prospective studies involving other patient-related predictors are needed. CLINICAL TRIAL REGISTRATION: NCT05018104.

Machine learning combined with radiomics and deep learning features extracted from CT images: a novel AI model to distinguish benign from malignant ovarian tumors.

BACKGROUND: To develop an artificial intelligence (AI) model with radiomics and deep learning (DL) features extracted from CT images to distinguish benign from malignant ovarian tumors. METHODS: We enrolled 149 patients with pathologically confirmed ovarian tumors. A total of 185 tumors were included and divided into training and testing sets in a 7:3 ratio. All tumors were manually segmented from preoperative contrast-enhanced CT images. CT image features were extracted using radiomics and DL. Five models with different combinations of feature sets were built. Benign and malignant tumors were classified using machine learning (ML) classifiers. The model performance was compared with five radiologists on the testing set. RESULTS:  Among the five models, the best performing model is the ensemble model with a combination of radiomics, DL, and clinical feature sets. The model achieved an accuracy of 82%, specificity of 89% and sensitivity of 68%. Compared with junior radiologists averaged results, the model had a higher accuracy (82% vs 66%) and specificity (89% vs 65%) with comparable sensitivity (68% vs 67%). With the assistance of the model, the junior radiologists achieved a higher average accuracy (81% vs 66%), specificity (80% vs 65%), and sensitivity (82% vs 67%), approaching to the performance of senior radiologists. CONCLUSIONS:  We developed a CT-based AI model that can differentiate benign and malignant ovarian tumors with high accuracy and specificity. This model significantly improved the performance of less-experienced radiologists in ovarian tumor assessment, and may potentially guide gynecologists to provide better therapeutic strategies for these patients.

Bioelectronic silicon nanowire devices using functional membrane proteins.

Modern means of communication rely on electric fields and currents to carry the flow of information. In contrast, biological systems follow a different paradigm that uses ion gradients and currents, flows of small molecules, and membrane electric potentials. Living organisms use a sophisticated arsenal of membrane receptors, channels, and pumps to control signal transduction to a degree that is unmatched by manmade devices. Electronic circuits that use such biological components could achieve drastically increased functionality; however, this approach requires nearly seamless integration of biological and manmade structures. We present a versatile hybrid platform for such integration that uses shielded nanowires (NWs) that are coated with a continuous lipid bilayer. We show that when shielded silicon NW transistors incorporate transmembrane peptide pores gramicidin A and alamethicin in the lipid bilayer they can achieve ionic to electronic signal transduction by using voltage-gated or chemically gated ion transport through the membrane pores.

Adjunct diagnostic value of radiological findings in mucopolysaccharidosis type IVa-related thoracic spinal abnormalities: a pilot study.

BACKGROUND: In patients with mucopolysaccharidosis (MPS), systematic assessment and management of cervical instability, cervicomedullary and thoracolumbar junction spinal stenosis and spinal cord compression averts or arrests irreversible neurological damage, improving outcomes. However, few studies have assessed thoracic spinal involvement in MPS IVa patients. We aimed to evaluate thoracic spinal abnormalities in MPS IVa patients and identify associated image manifestations by CT and MRI study. RESULTS: Data of patients diagnosed and/or treated for MPS IVa at MacKay Memorial Hospital from January 2010 to December 2020 were extracted from medical records and evaluated retrospectively. Computed tomography (CT), plain radiography and magnetic resonance imaging (MRI) findings of MPS IVa-related spinal abnormalities were reviewed. Spine CT and plain radiography findings of 12 patients (6 males and 6 females with median age 7.5 years, range 1-28 years) revealed two subtypes of spinal abnormalities: thoracic kyphosis apex around T2 (subtype 1, n = 8) and thoracic kyphosis apex around T5 (subtype 2, n = 4). Spine CT and plain radiography clearly identified various degrees of thoracic kyphosis with apex around T2 or T5 in MPS IVa patients. Square-shaped to mild central beaking in middle thoracic vertebral bodies was observed in subtype 1 patients, while greater degrees of central beaking in middle thoracic vertebral bodies was observed in subtype 2 patients. CONCLUSIONS: Spine CT findings clearly identify new radiological findings of thoracic kyphosis apex around T2 or T5 in MPS IVa patients. The degrees of central beaking at middle thoracic vertebral bodies may be a critical factor associated with different image presentations of thoracic kyphosis.

Carbon nanotube transistor controlled by a biological ion pump gate.

We report a hybrid bionanoelectronic transistor that has a local ATP-powered protein gate. ATP-dependent activity of a membrane ion pump, Na(+)/K(+)-ATPase, embedded in a lipid membrane covering the carbon nanotube, modulates the transistor output current by up to 40%. The ion pump gates the device by shifting the pH of the water layer between the lipid bilayer and nanotube surface. This transistor is a versatile bionanoelectronic platform that can incorporate other membrane proteins.

Delayed manifestations of abdominal trauma: follow-up abdominopelvic CT in posttraumatic patients.

PURPOSE: Our study aims to investigate the frequency and patterns of delayed manifestations of abdominal and pelvic injuries which may not be identified or which fail to manifest on the initial abdominopelvic CT in posttraumatic patients. METHODS: For our institutional review board (IRB)-approved retrospective study, our hospital trauma registry was queried for patients with blunt multitrauma and Injury Severity Score (ISS) ≥ 16 between January 2010 and August 2016, yielding 3735 patients. A total of 203 patients received a follow-up abdominopelvic CT within six months from the initial scan and those with new findings on follow-up CT were identified. A retrospective blinded review of the initial CT examinations was performed by two experienced radiologists. The retrospective readings and original reports were compared to categorize the new abnormalities detected on follow-up CT scans. The categories included missed injuries, late presentations and sequelae of trauma, and complications of surgery, hospital admission, and invasive procedures. The patients' notes were reviewed for the clinical indications, time interval for repeat CT examination, and subsequent clinical management. The software used for statistical analysis of the extracted data was Microsoft Excel for Mac (version 15.33). RESULTS: Out of 3735 patients, 203 patients received 232 follow-up abdominopelvic CTs. The average elapsed time between the initial CT and the follow-up CT was 15 ± 27 days. Evaluation for an abdominal fluid collection was the most common clinical indication, accounting for 40% of the total number (n = 243) of indications. Delayed manifestations and complications of trauma were present in 41 patients due to 47 abnormalities, most commonly related to solid organ injury, followed by abdominal collections and hematoma. Twenty-nine CT findings (62%) were only detectable on follow-up CT, while nine injuries (19%) were missed on initial CT. The findings on repeated CT warranted eight surgical and 15 interventional procedures. CONCLUSION: A small percentage of traumatic injuries may be unidentified or fail to manifest on the initial CT, resulting in delayed manifestations of abdominopelvic trauma, which may lead to subsequent readmission, delayed management, and more severe medical complications.

Correction to: Delayed manifestations of abdominal trauma: follow-up abdominopelvic CT in posttraumatic patients.

The original version of this article unfortunately contained few mistakes. Under the subheading "Data extraction and review process", in line 12 the word "prospective" is incorrectly given by the author. The correct word is "retrospective". In Fig. 2D, the label should read as RA instead of LA. In Table 6, the word "ischemic/gangrenous" should read as "ischemia/gangrene" in 9th row, column 6. The revised Fig 2 and Table 6 are available in the correction article.

Time-domain and spectral-domain investigation of inflection-point slow-light modes in photonic crystal coupled waveguides.

We report on spectral-domain and time-domain measurements and numerical calculations of group velocities in a photonic crystal coupled waveguide, where the unique guided mode band structure has a flat band region within the photonic band gap allowing for slow light observation. The spectral dependence of group velocity, which is measured by interference method, indicates the existence of slow light modes around the inflection point of the unique flat band, rather than at the band edge. Time-domain observation of optical pulses propagating along two-dimension slab photonic crystal coupled waveguides is also demonstrated by using a high speed oscilloscope. By adjusting the wavelength of the input pulses toward the flat band of the coupled defect modes, an increasing duration time between reference and output pulses are clearly observed. An extremely small group velocity of 0.017c is thus obtained. Calculated group velocities show good agreement with our measured results.

Therapy-induced developmental reprogramming of prostate cancer cells and acquired therapy resistance.

Treatment-induced neuroendocrine transdifferentiation (NEtD) complicates therapies for metastatic prostate cancer (PCa). Based on evidence that PCa cells can transdifferentiate to other neuroectodermally-derived cell lineages in vitro, we proposed that NEtD requires first an intermediary reprogramming to metastable cancer stem-like cells (CSCs) of a neural class and we demonstrate that several different AR+/PSA+ PCa cell lines were efficiently reprogrammed to, maintained and propagated as CSCs by growth in androgen-free neural/neural crest (N/NC) stem medium. Such reprogrammed cells lost features of prostate differentiation; gained features of N/NC stem cells and tumor-initiating potential; were resistant to androgen signaling inhibition; and acquired an invasive phenotype in vitro and in vivo. When placed back into serum-containing mediums, reprogrammed cells could be re-differentiated to N-/NC-derived cell lineages or return back to an AR+ prostate-like state. Once returned, the AR+ cells were resistant to androgen signaling inhibition. Acute androgen deprivation or anti-androgen treatment in serum-containing medium led to the transient appearance of a sub-population of cells with similar characteristics. Finally, a 132 gene signature derived from reprogrammed PCa cell lines distinguished tumors from PCa patients with adverse outcomes. This model may explain neural manifestations of PCa associated with lethal disease. The metastable nature of the reprogrammed stem-like PCa cells suggests that cycles of PCa cell reprogramming followed by re-differentiation may support disease progression and therapeutic resistance. The ability of a gene signature from reprogrammed PCa cells to identify tumors from patients with metastasis or PCa-specific mortality implies that developmental reprogramming is linked to aggressive tumor behaviors.

A Patient Friendly Corifollitropin Alfa Protocol without Routine Pituitary Suppression in Normal Responders.

The release of corifollitropin alfa simplifies daily injections of short-acting recombinant follicular stimulating hormone (rFSH), and its widely-used protocol involves short-acting gonadotropins supplements and a fixed GnRH antagonist regimen, largely based on follicle size. In this study, the feasibility of corifollitropin alfa without routine pituitary suppression was evaluated. A total of 288 patients were stimulated by corifollitropin alfa on cycle day 3 following with routine serum hormone monitoring and follicle scanning every other day after 5 days of initial stimulation, and a GnRH antagonist (0.25 mg) was only used prophylactically when the luteinizing hormone (LH) was ≧ 6 IU/L (over half of the definitive LH surge). The incidence of premature LH surge (≧ 10 IU/L) was 2.4% (7/288) before the timely injection of a single GnRH antagonist, and the elevated LH level was dropped down from 11.9 IU/L to 2.2 IU/L after the suppression. Two hundred fifty-one patients did not need any antagonist (87.2% [251/288]) throughout the whole stimulation. No adverse effects were observed regarding oocyte competency (fertilization rate: 78%; blastocyst formation rate: 64%). The live birth rate per OPU cycle after the first cryotransfer was 56.3% (161/286), and the cumulative live birth rate per OPU cycle after cyrotransfers was 69.6% (199/286). Of patients who did and did not receive GnRH antagonist during stimulation, no significant difference existed in the cumulative live birth rates (78.4% vs. 68.3%, p = 0.25). The results demonstrated that the routine GnRH antagonist administration is not required in the corifollitropin-alfa cycles using a flexible and hormone-depended antagonist regimen, while the clinical outcome is not compromised. This finding reveals that the use of a GnRH antagonist only occasionally may be needed.

Functional integration of membrane proteins with nanotube and nanowire transistor devices.

Biological molecules perform a sophisticated array of transport and signaling functions that rival anything that the modern electronics industry can create. Incorporating such building blocks into nanoelectronic devices could enable new generations of electronic circuits that use biomimetics to perform complicated tasks. Such types of circuits could ultimately blur the interface between living biological organisms and synthetic structures. Our laboratory has recently developed a versatile and flexible platform for integrating ion channels and pumps into single-walled carbon nanotube (SWNT) and silicon nanowire (SiNW) transistor devices, in which membrane proteins are embedded in a lipid bilayer shell covering the nanotube or nanowire component. In this chapter, we provide details for the fabrication of these devices and outline procedures for incorporating biological molecules into them. In addition, we also provide several examples of the use of these devices to couple biological transport to electronic signaling.

Biofunctional subwavelength optical waveguides for biodetection.

We report a versatile biofunctional subwavelength photonic device platform for real-time detection of biological molecules. Our devices contain lipid bilayer membranes fused onto metal oxide nanowire waveguides stretched across polymeric flow channels. The lipid bilayers incorporating target receptors are submersed in the propagating evanescent field of the optical cavity. We show that the lipid bilayers in our devices are continuous, have very high mobile fraction, and are resistant to fouling. We also demonstrate that our platform allows rapid membrane exchange. Finally, we use this device to detect the hybridization of specific DNA target sequences in solution to complementary probe DNA strands anchored to the lipid bilayer. This evanescent wave sensing architecture holds great potential for portable, all-optical detection systems.

Formation, stability, and mobility of one-dimensional lipid bilayers on polysilicon nanowires.

Curved lipid membranes are ubiquitous in living systems and play an important role in many biological processes. To understand how curvature and lipid composition affect membrane formation and fluidity, we have assembled and studied mixed 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) supported lipid bilayers on amorphous silicon nanowires grown around carbon nanotube cores with controlled wire diameters ranging from 20 to 200 nm. We found that lipid vesicles fused onto nanowire substrates and formed continuous bilayers for all DOPC-DOPE mixtures tested (with the DOPE content of up to 30%). Our measurements demonstrate that nanowire-supported bilayers are mobile, exhibit fast recovery after photobleaching, and have a low concentration of defects. Lipid diffusion coefficients in these high-curvature tubular membranes are comparable to the values reported for flat supported bilayers and increase slightly with decreasing nanowire diameter. A free space diffusion model adequately describes the effect of bilayer curvature on the lipid mobility for nanowire substrates with diameters greater than 50 nm, but shows significant deviations from the experimental values for smaller diameter nanowires.

Persistence length control of the polyelectrolyte layer-by-layer self-assembly on carbon nanotubes.

We have studied layer-by-layer polyelectrolyte self-assembly on pristine individual single-wall carbon nanotubes as a function of solution ionic strength. We report the existence of an ionic strength threshold for the deposition, below which the majority of nanotubes remain uncoated. Once the ionic strength reaches the threshold value, the majority of the individual nanotubes become coated with polyelectrolytes. Our results indicate that the self-assembly process likely involves wrapping of polymer chains around nanotubes and that the polymer chain's ability to bend in order to accommodate the nanotube curvature is one of the critical parameters controlling layer-by-layer electrostatic self-assembly on these one-dimensional templates.