Immune checkpoint inhibitors and the risk of major atherosclerotic cardiovascular events in patients with high-risk or advanced melanoma: a retrospective cohort study.

BACKGROUND: Immune checkpoint inhibitors (ICI) are associated with immune-mediated adverse effects, potentially involving any organ. ICI has also been associated with an increased risk of cardiovascular disease in cancer populations. OBJECTIVE: To characterize the incidence and risk of major atherosclerotic cardiovascular events associated with ICI use in a high-risk and advanced melanoma population. METHODS: We conducted a retrospective cohort study of patients with high-risk or advanced melanoma (AJCC stage II, III or IV) presenting to an academic tertiary hospital between 2015-2020. The main outcome was major atherosclerotic cardiovascular events (MACE) including acute myocardial infarction, ischemic stroke, acute limb ischemia and coronary revascularization. RESULTS: The study cohort consisted of 646 patients, including 289 who had been treated with ICI. The incidence of MACE was higher in the ICI treated group (3.6 vs. 0.9 events per 100-person years). After adjusting for age, sex, smoking history and prior BRAF and/or MEK inhibitor use, ICI treatment was associated with an increased risk of MACE (HRadj 2.8, 95% CI 1.1-6.9, p = 0.03). Elevated risk was especially pronounced in patients with a past history of MACE (HR 14.4, 95% CI 1.9-112.3, p = 0.01). CONCLUSION: Patients with high-risk or advanced melanoma are at an increased risk of atherosclerotic cardiovascular events following ICI treatment, particularly those with a history of cardiovascular disease.

Association Between Low-Dose Methotrexate Exposure and Melanoma: A Systematic Review and Meta-analysis.

Importance: Methotrexate is widely used for the treatment of inflammatory disorders, including rheumatoid arthritis. Studies suggest that methotrexate may be associated with an increased risk of melanoma. Objective: To determine whether methotrexate exposure is associated with an increased risk of cutaneous melanoma. Data Sources: MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were searched from inception to May 12, 2022, for eligible studies. Study Selection: Case-control studies, cohort studies, or randomized clinical trials (RCTs) were included if they examined the odds or risk of cutaneous melanoma in individuals exposed to low-dose methotrexate in comparison with individuals unexposed. No language limitations were applied. Data Extraction and Synthesis: Two independent reviewers extracted data on study characteristics and outcome data. The Meta-analysis of Observational Studies in Epidemiology guidelines were followed. To assess study quality, the Cochrane risk of bias tool was used for RCTs, and the Joanna Briggs Institute Checklist was used for cohort and case-control studies. Odds ratio from case-control studies and relative risk or hazard ratio from cohort studies or RCTs were pooled, and a random-effects model meta-analysis was conducted. Main Outcomes and Measures: Prespecified outcome was the odds ratio, hazard ratio, or risk ratio of cutaneous melanoma comparing low-dose methotrexate exposure with nonexposure. Results: Seventeen studies (8 RCTs, 5 cohort studies, 4 case-control studies) were eligible for inclusion, and of these, 12 studies with 16 642 cases of melanoma were pooled in the primary analysis. Indications for methotrexate included rheumatoid arthritis, psoriasis, psoriatic arthritis, and inflammatory bowel disease and were unknown in 5 studies. Compared with unexposed individuals, study participants with methotrexate exposure had a small increased risk of melanoma (pooled relative risk, 1.15; 95% CI, 1.08-1.22), but this did not persist in a sensitivity analysis excluding the largest study (pooled relative risk, 1.11; 95% CI, 1.00-1.24). Subgroup analyses according to comparator group (comparing methotrexate exposure with either immunomodulator alone vs immunomodulator and methotrexate) or the indication for methotrexate being rheumatoid arthritis provided similar risk estimates. Using geographical population melanoma incidence rates, a number needed to harm of 18 630 was calculated in Australia, and 41 425 in North America. Conclusions and Relevance: In this systematic review and meta-analysis, low-dose methotrexate exposure was associated with an increased melanoma risk, but the absolute risk increase could be considered negligible.

A Statistical Overview of Fixed Wing Air Medical Transportation Operations in the United States (2019-2020).

Air medical transportation (AMT) services provide the transportation of patients, medical teams, and organs for the US health care system. Interfacility transfers account for 54% of air medical transports, and delivering specialty care and organs accounts for 13% of air medical transports. Interfacility transfer, specialty care, and organ delivery are predominantly conducted using fixed wing aircraft. The AMT fixed wing fleet has grown 2.2% per year over the last decade along with a 3.6% per year expansion in the number of AMT base airports with fixed wing operations. This article aims to characterize the operations of fixed wing AMT in the United States for the period of 2019 to 2020. This information can be used for aircraft design, airport and air traffic control infrastructure assessment and funding, and AMT industry sector analysis and strategic planning. Data from 12 databases were combined to identify AMT flights and generate operational statistics including the number of vehicles; ownership; flight distances; flight frequency; geographic distribution; and the types of airports, air traffic control, and navigation systems used.

A multi-axis robot-based bioprinting system supporting natural cell function preservation and cardiac tissue fabrication.

Despite the recent advances in artificial tissue and organ engineering, how to generate large size viable and functional complex organs still remains as a grand challenge for regenerative medicine. Three-dimensional bioprinting has demonstrated its advantages as one of the major methods in fabricating simple tissues, yet it still faces difficulties to generate vasculatures and preserve cell functions in complex organ production. Here, we overcome the limitations of conventional bioprinting systems by converting a six degree-of-freedom robotic arm into a bioprinter, therefore enables cell printing on 3D complex-shaped vascular scaffolds from all directions. We also developed an oil bath-based cell printing method to better preserve cell natural functions after printing. Together with a self-designed bioreactor and a repeated print-and-culture strategy, our bioprinting system is capable to generate vascularized, contractible, and long-term survived cardiac tissues. Such bioprinting strategy mimics the in vivo organ development process and presents a promising solution for in vitro fabrication of complex organs.

Cardiovascular disease and malignant melanoma.

In the last decade, systemic therapies such as immune checkpoint inhibitors and BRAF-MEK inhibitors have improved the prognosis of high-risk and advanced melanoma. With improved survival, melanoma survivorship is increasingly important, particularly in patients who have a good prognosis or are diagnosed at a younger age. It is increasingly recognized that cancer and its treatment is associated with increased cardiovascular morbidity and mortality. Indeed, data from observational studies and meta-analyses of randomized controls trials in melanoma show that systemic therapies may be associated with cardiac toxicities, such as myocardial infarction, heart failure, myocarditis and stroke. Our review will discuss cardiovascular disease and risk factors in the context of melanoma and outline the importance of cardiovascular risk modification in this population.

Rapid In Vivo Quantification of Creatine Kinase Activity by Phosphorous-31 Magnetic Resonance Spectroscopic Fingerprinting (31P-MRSF).

Creatine kinase (CK) plays an important role in tissue metabolism by providing a buffering mechanism for maintaining a constant supply of adenosine triphosphate (ATP) during metabolic perturbations. Phosphorous-31 magnetic resonance spectroscopy (31P-MRS) employing magnetization transfer techniques is the only noninvasive method for measuring the rate of ATP synthesis via creatine kinase. However, due to the low concentrations of phosphate metabolites, current 31P-MRS methods require long acquisition time to achieve adequate measurement accuracy. In this chapter, we present a new framework of data acquisition and parameter estimation, the 31P magnetic resonance spectroscopic fingerprinting (31P-MRSF) method, for rapid quantification of CK reaction rate constant in the hindlimb of small laboratory animals.

Biological Therapy Interruption and Re-Treatment in Chronic Plaque Psoriasis.

While biological treatments for chronic plaque psoriasis should be administered continuously to maximize and maintain efficacy, interruptions in therapy may be necessary for a number of reasons. We reviewed the evidence from clinical trials on efficacy, safety and immunogenicity in clinical trials for approved biologic agents for chronic plaque psoriasis. A systematic search of three major medical databases was performed and a total of 35 articles were included into the analysis, including 13 controlled trials. Trials assessing continuous therapy against dosing as-needed therapy (including infliximab, etanercept and secukinumab) have demonstrated superior efficacy for continuous regimes. However, randomized withdrawal trials for etanercept, adalimumab, ixekizumab, brodalumab, guselkumab, risankizumab and tildrakizumab, showed no significant impact on skin clearance rates in patients who are interrupted once and then re-treated. With the possible exception of infliximab, temporary interruption in biologic therapy appears to be safe and most agents will regain efficacy after re-introduction. J Drugs Dermatol. 2021;20(10):1063-1071. doi:10.36849/JDD.5716.

Utility of Routine Testing for Chlamydia and Gonorrhea in the Setting of Preterm Delivery or Premature Preterm Rupture of Membranes.

This study aimed to explore the rates of positive and negative Chlamydia trachomatis and Neisseria gonorrhoeae test results in patients screened for these infections and later experienced preterm delivery or preterm premature rupture of membranes. The team conducted a retrospective chart review of patients admitted for preterm premature rupture of membranes or who experienced preterm delivery between April 1, 2009, and April 30, 2015. Patients lacking chlamydia and gonorrhea screening before admission were excluded from the study. Four hundred and six patients met the inclusion criteria. The prevalence of chlamydia infection at initial prenatal screening before admission was 13.3%. Among those for whom the prenatal chlamydia test was negative, 1.7% of patients had a positive subsequent chlamydia test on admission screening. Among those for whom the prenatal chlamydia test was positive, 18.5% had a positive subsequent chlamydia test on admission screening. Positive prenatal test (P=.002) and age 25 years or less (P<.001) were associated with positive admission screening for chlamydia, though only a positive prenatal test remained significant in a logistic regression model (odds ratio, 8.56; 95% CI, 2.67-27.49; P=.003). The prevalence of gonorrhea was low at 0.2% of patients positive for gonorrhea at prenatal testing and 0.5% of patients positive for gonorrhea at admission testing. Our results suggest that individualization based on patient characteristics may be utilized to decrease re-testing. More research is needed to identify possible additional risk factors for new infection or re-infection and the most optimal timing for re-screening during the prenatal period.

SARS-CoV-2 (COVID-19) vaccination in dermatology patients on immunomodulatory and biologic agents: Recommendations from the Australasian Medical Dermatology Group.

As the phase III COVID-19 vaccine trials excluded patients on immunosuppressive treatments, or patients with significant autoimmunity, the Australasian Medical Dermatology Group make the following preliminary recommendations around COVID-19 vaccination in dermatology patients on immunomodulatory and/or biologic agents. Vaccination against COVID-19 is strongly encouraged for all patients on immunomodulatory drugs and/or biologic agents. There are currently insufficient data to recommend one COVID-19 vaccine or vaccine type (mRNA, recombinant, inactivated virus) over another. No specific additional risk in patients on immunomodulatory or biologic therapies has so far been identified. Data on vaccine efficacy in patients on immunomodulatory or biologic therapies are missing, so standard vaccination protocols are recommended until otherwise advised.

Quantification of creatine kinase reaction rate in mouse hindlimb using phosphorus-31 magnetic resonance spectroscopic fingerprinting.

The goal of this study was to evaluate the accuracy, reproducibility, and efficiency of a 31 P magnetic resonance spectroscopic fingerprinting (31 P-MRSF) method for fast quantification of the forward rate constant of creatine kinase (CK) in mouse hindlimb. The 31 P-MRSF method acquired spectroscopic fingerprints using interleaved acquisition of phosphocreatine (PCr) and γATP with ramped flip angles and a saturation scheme sensitive to chemical exchange between PCr and γATP. Parameter estimation was performed by matching the acquired fingerprints to a dictionary of simulated fingerprints generated from the Bloch-McConnell model. The accuracy of 31 P-MRSF measurements was compared with the magnetization transfer (MT-MRS) method in mouse hindlimb at 9.4 T (n = 8). The reproducibility of 31 P-MRSF was also assessed by repeated measurements. Estimation of the CK rate constant using 31 P-MRSF (0.39 ± 0.03 s-1 ) showed a strong agreement with that using MT-MRS measurements (0.40 ± 0.05 s-1 ). Variations less than 10% were achieved with 2 min acquisition of 31 P-MRSF data. Application of the 31 P-MRSF method to mice subjected to an electrical stimulation protocol detected an increase in CK rate constant in response to stimulation-induced muscle contraction. These results demonstrated the potential of the 31 P-MRSF framework for rapid, accurate, and reproducible quantification of the chemical exchange rate of CK in vivo.

3D magnetic resonance fingerprinting with quadratic RF phase.

PURPOSE: To implement 3D magnetic resonance fingerprinting (MRF) with quadratic RF phase (qRF-MRF) for simultaneous quantification of T1 , T2 , ΔB0 , and T2∗ . METHODS: 3D MRF data with effective undersampling factor of 3 in the slice direction were acquired with quadratic RF phase patterns for T1 , T2 , and T2∗ sensitivity. Quadratic RF phase encodes the off-resonance by modulating the on-resonance frequency linearly in time. Transition to 3D brings practical limitations for reconstruction and dictionary matching because of increased data and dictionary sizes. Randomized singular value decomposition (rSVD)-based compression in time and reduction in dictionary size with a quadratic interpolation method are combined to be able to process prohibitively large data sets in feasible reconstruction and matching times. RESULTS: Accuracy of 3D qRF-MRF maps in various resolutions and orientations are compared to 3D fast imaging with steady-state precession (FISP) for T1 and T2 contrast and to 2D qRF-MRF for T2∗ contrast and ΔB0 . The precision of 3D qRF-MRF was 1.5-2 times higher than routine clinical scans. 3D qRF-MRF ΔB0 maps were further processed to highlight the susceptibility contrast. CONCLUSION: Natively co-registered 3D whole brain T1 , T2 , T2∗ , ΔB0 , and QSM maps can be acquired in as short as 5 min with 3D qRF-MRF.

COVID-19 and the use of immunomodulatory and biologic agents for severe cutaneous disease: An Australian/New Zealand consensus statement.

Patients on immunomodulators, including biologic agents and new small molecular inhibitors, for cutaneous disease, represent a potentially vulnerable population during the COVID-19 pandemic. There is currently insufficient evidence to determine whether patients on systemic immunomodulators are at increased risk of developing COVID-19 disease or more likely to have severe disease. As such, clinicians need to assess the benefit-to-risk ratio on a case-by-case basis. In patients with suspected or confirmed COVID-19 disease, all immunomodulators used for skin diseases should be immediately withheld, with the possible exception of systemic corticosteroid therapy, which needs to be weaned. In patients who develop symptoms or signs of an upper respiratory tract infection, but COVID-19 is not yet confirmed, consider dose reduction or temporarily cessation for 1-2 weeks. In otherwise well patients, immunomodulators and biologics should be continued. In all patients, and their immediate close contacts, the importance of preventative measures to minimise human-to-human transmission cannot be overemphasised.

Late-onset malalignment of the great toenails.

Great toenail malalignment is characterised by lateral deviation of the longitudinal axis of the nail plate with respect to the hallux, and is usually post-traumatic, iatrogenic or due to congenital malalignment of the great toenails. We present cases of great toenail malalignment with onset in adolescence or young adulthood without preceding nail surgery or acute trauma. We postulate that this may represent a late-onset presentation of congenital malalignment of the great toenails.

Mesh-Based Computation for Solving Photometric Stereo With Near Point Lighting.

We tackle the problem of dense reconstruction with a practical system, in which near point lighting (NPL) is employed. Different from the conventional formulation of photometric stereo (PS) that assumes parallel lighting, PS under the NPL condition is a nonlinear problem as the local surface normals are coupled with its distance to the camera as well as the light sources. After obtaining the locations of point lights by a calibration process, we develop a new framework to solve this nonlinear reconstruction problem via mesh deformation, in which each facet is corresponding to a pixel in the image captured by the camera. In our framework, mesh deformation is decoupled into an iteration of interlaced steps of local projection and global blending. Experimental results verify that our method can generate accurate estimation of surface shape under NPL in a few iterations. Besides, this approach is robust to errors on the positions of light sources and is easy to be implemented.

Magnetic resonance fingerprinting with quadratic RF phase for measurement of T2* simultaneously with δf , T1 , and T2.

PURPOSE: This study explores the possibility of using a gradient moment balanced sequence with a quadratically varied RF excitation phase in the magnetic resonance fingerprinting (MRF) framework to quantify T2* in addition to δf , T1 , and T2 tissue properties. METHODS: The proposed quadratic RF phase-based MRF method (qRF-MRF) combined a varied RF excitation phase with the existing balanced SSFP (bSSFP)-based MRF method to generate signals that were uniquely sensitive to δf , T1 , T2 , as well as the distribution width of intravoxel frequency dispersion, Γ . A dictionary, generated through Bloch simulation, containing possible signal evolutions within the physiological range of δf , T1 , T2 , and Γ , was used to perform parameter estimation. The estimated T2 and Γ were subsequently used to estimate T2* . The proposed method was evaluated in phantom experiments and healthy volunteers (N = 5). RESULTS: The T1 and T2 values from the phantom by qRF-MRF demonstrated good agreement with values obtained by traditional gold standard methods (r2 = 0.995 and 0.997, respectively; concordance correlation coefficient = 0.978 and 0.995, respectively). The T2* values from the phantom demonstrated good agreement with values obtained through the multi-echo gradient-echo method (r2 = 0.972, concordance correlation coefficient = 0.983). In vivo qRF-MRF-measured T1 , T2 , and T2* values were compared with measurements by existing methods and literature values. CONCLUSION: The proposed qRF-MRF method demonstrated the potential for simultaneous quantification of δf , T1 , T2 , and T2* tissue properties.

Bas-Relief Modeling from Normal Layers.

Bas-relief is characterized by its unique presentation of intrinsic shape properties and/or detailed appearance using materials raised up in different degrees above a background. However, many bas-relief modeling methods could not manipulate scene details well. We propose a simple and effective solution for two kinds of bas-relief modeling (i.e., structure-preserving and detail-preserving) which is different from the prior tone mapping alike methods. Our idea originates from an observation on typical 3D models, which are decomposed into a piecewise smooth base layer and a detail layer in normal field. Proper manipulation of the two layers contributes to both structure-preserving and detail-preserving bas-relief modeling. We solve the modeling problem in a discrete geometry processing setup that uses normal-based mesh processing as a theoretical foundation. Specifically, using the two-step mesh smoothing mechanism as a bridge, we transfer the bas-relief modeling problem into a discrete space, and solve it in a least-squares manner. Experiments and comparisons to other methods show that (i) geometry details are better preserved in the scenario with high compression ratios, and (ii) structures are clearly preserved without shape distortion and interference from details.

Interactive Partitioning of 3D Models into Printable Parts.

In this paper, we present an easy, flexible and interactive tool for partitioning a 3D model, which is larger than 3D-printers working volume, into printable parts in an intuitive way. Our presented tool is based on the elegant partitioning optimization framework Chopper. Our tool aims at improving Chopper by providing users three easy-to-use interactive operations: no-go region painting, cutting plane specification and components re-union. With these operations, we show that (1) exhaustive search in the BSP tree --- the most time-consuming step in Chopper --- can be avoided, (2) more flexible geometric configurations can be provided, (3) users design intention is considered naturally and efficiently, and customized 3D partitioning results can be obtained. We test our tool on a wide range of 3D models and observe promising results. A preliminary user study also demonstrates its effectiveness and efficiency.