Downstaging Hepatocellular Carcinoma with Checkpoint Inhibitor Therapy Improves Access to Curative Liver Transplant.

PURPOSE: Liver transplantation is curative for hepatocellular carcinoma (HCC). Checkpoint inhibitor therapy (CPIT) has been used in unresectable HCC, but recent advances have demonstrated CPIT as an innovative method of downstaging advanced HCC with the caveat that CPIT prior to transplantation has risks including irreversible graft rejection. We report the outcomes of Mayo Clinic Arizona patients who underwent downstaging with CPIT. METHODS: This retrospective chart review was conducted for Mayo Clinic Arizona patients who were diagnosed with HCC who underwent downstaging with CPIT with the goal of meeting criteria for transplantation. RESULTS: We present nine cases with HCC outside Milan who underwent CPIT. Four received a transplant; one was delisted due to his exceptional therapeutic response. All received liver-directed therapy. Peak alpha-fetoprotein pre-CPIT ranged from 8-29,523 ng/mL, which decreased to 2.2-19.6 ng/mL on CPIT. CPIT included atezolizumab/bevacizumab, ipilimumab/nivolumab, nivolumab, and pembrolizumab; one patient received two regimens. CPIT was held prior to transplant at a median of 3 months. Three patients received methylprednisolone for immunosuppression induction; one received thymoglobulin. One patient developed acute cellular rejection at 5 weeks, 9 weeks, and 5 months post-transplant; given the late onset, these were not attributed to CPIT and were successfully treated. During an average follow-up of 16.5 months, no tumor recurrence has occurred. CONCLUSION: We describe nine patients with HCC outside Milan with inadequate response with liver-directed therapy, who achieved marked responses with CPIT, allowing for consideration of successful liver transplantation. Our case series supports the consideration of locoregional therapies and CPIT for downstaging to within transplant criteria.

Foveal avascular zone segmentation using deep learning-driven image-level optimization and fundus photographs.

The foveal avascular zone (FAZ) is a retinal area devoid of capillaries and associated with multiple retinal pathologies and visual acuity. Optical Coherence Tomography Angiography (OCT-A) is a very effective means of visualizing retinal vascular and avascular areas, but its use remains limited to research settings due to its complex optics limiting availability. On the other hand, fundus photography is widely available and often adopted in population studies. In this work, we test the feasibility of estimating the FAZ from fundus photos using three different approaches. The first two approaches rely on pixel-level and image-level FAZ information to segment FAZ pixels and regress FAZ area, respectively. The third is a training mask-free pipeline combining saliency maps with an active contours approach to segment FAZ pixels while being trained on image-level measures of the FAZ areas. This enables training FAZ segmentation methods without manual alignment of fundus and OCT-A images, a time-consuming process, which limits the dataset that can be used for training. Segmentation methods trained on pixel-level labels and image-level labels had good agreement with masks from a human grader (respectively DICE of 0.45 and 0.4). Results indicate the feasibility of using fundus images as a proxy to estimate the FAZ when angiography data is not available.

Advancing the Am Extractant Design through the Interplay among Planarity, Preorganization, and Substitution Effects.

Advancing the field of chemical separations is important for nearly every area of science and technology. Some of the most challenging separations are associated with the americium ion Am(III) for its extraction in the nuclear fuel cycle, 241Am production for industrial usage, and environmental cleanup efforts. Herein, we study a series of extractants, using first-principle calculations, to identify the electronic properties that preferentially influence Am(III) binding in separations. As the most used extractant family and because it affords a high degree of functionalization, the polypyridyl family of extractants is chosen to study the effects of the planarity of the structure, preorganization of coordinating atoms, and substitution of various functional groups. The actinyl ions are used as a structurally simplified surrogate model to quickly screen the most promising candidates that can separate these metal ions. The down-selected extractants are then tested for the Am(III)/Eu(III) system. Our results show that π interactions, especially those between the central terpyridine ring and Am(III), play a crucial role in separation. Adding an electron-donating group onto the terpyridine backbone increases the binding energies to Am(III) and stabilizes Am-terpyridine coordination. Increasing the planarity of the extractant increases the binding strength as well, although this effect is found to be rather weak. Preorganizing the coordinating atoms of an extractant to their binding configuration as in the bound metal complex speeds up the binding process and significantly improves the kinetics of the separation process. This conclusion is validated by the synthesized 1,2-dihydrodipyrido[4,3-b;5,6-b]acridine (13) extractant, a preorganized derivative of the terpyridine extractant, which we experimentally showed was four times more effective than terpyridine at separating Am3+ from Eu3+ (SFAm/Eu ∼ 23 ± 1).

The photobiology of the human circadian clock.

SignificanceThe function of our biological clock is dependent on environmental light. Rodent studies have shown that there are multiple colors that affect the clock, but indirect measures in humans suggest blue light is key. We performed functional MRI studies in human subjects with unprecedented spatial resolution to investigate color sensitivity of our clock. Here, we show that narrowband blue, green, and orange light were all effective in changing neuronal activity of the clock. While the clock of nocturnal rodents is excited by light, the human clock responds with a decrease in neuronal activity as indicated by a negative BOLD response. The sensitivity of the clock to multiple colors should be integrated in light therapy aimed to strengthen our 24-h rhythms.

Solid Organ Transplantation From SARS-CoV-2-infected Donors to Uninfected Recipients: A Single-center Experience.

BACKGROUND: The risk of donor-derived severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in solid organ (heart, lung, liver, kidney, pancreas, and intestine) transplant recipients is poorly understood. Since hematogenous transmission of SARS-CoV-2 has not been documented to date, nonlung solid organs might be suitable for transplantation since they likely portend a low risk of viral transmission. METHODS: Abdominal solid organs from SARS-CoV-2-infected donors were transplanted into uninfected recipients. RESULTS: Between April 18, 2021, and October 30, 2021, we performed transplants of 2 livers, 1 simultaneous liver and kidney, 1 kidney, and 1 simultaneous kidney and pancreas from SARS-CoV-2-infected donors into 5 uninfected recipients. None of the recipients developed SARS-CoV-2 infection or coronavirus disease 2019, and when tested, allograft biopsies showed no evidence of SARS-CoV-2 RNA. CONCLUSIONS: Transplanting nonlung organs from SARS-CoV-2-infected donors into uninfected recipients demonstrated no evidence of virus transmission.

Expanding Treatment Access for Chronic Hepatitis C with Task-shifting in the Era of Direct-acting Antivirals.

In the United States, the fight to eradicate hepatitis C virus (HCV) infection has been ongoing for many years, but the results have been less than ideal. Historically, patients with chronic hepatitis C (CHC) were treated with interferon-based regimens, which were associated with frequent adverse effects, suboptimal response rates, and long durations of treatment - of up to 48 weeks. Expertise from specialist-physicians, such as hepatologists and gastroenterologists, was needed to closely follow patients on these medications so as to monitor laboratory values and manage adverse effects. However, the emergence of direct-acting antiviral (DAA) agents against HCV infection have heralded outstanding progress in terms of safety, tolerability, lack of adverse effects, efficacy, and truncated duration of therapy - 12 weeks or less - thereby making the need for close monitoring by specialist-physicians obsolete. With the recent approval of DAA agents by the Food and Drug Administration, the treatment model for CHC no longer relies on the limited number of specialist-physicians, which represented a major barrier to treatment access in the past, especially in underserved areas of the United States. We propose and share our experiences in adapting a task-shifting treatment model, one that utilizes a relatively larger pool of non-specialist healthcare providers, such as nursing staff (medical assistants, vocational licensed nurses, registered nurses, etc.) and advanced practice providers (nurse practitioners and physician assistants), to perform a variety of important clinical functions in an effort to make DAA-based antiviral therapy widely available against HCV infection. Most recently, task-shifting was implemented by the United States and World Health Organization in the fight against the human immunodeficiency virus and showed encouraging results. Based on our experiences in implementing this model at our outreach clinics, the majority of HCV-infected patients treated with DAA agents can be easily monitored by non-specialist healthcare providers and physician extenders. Task-shifting can effectively address one of the major rate-limiting factors in expanding treatment access for HCV infection.

Sofosbuvir-based Regimens with Task Shifting Is Cost-effective in Expanding Hepatitis C Treatment Access in the United States.

Background and Aims: The current paradigm of specialist physician-managed treatment of chronic hepatitis C virus infection (HCV) is inefficient in absorbing the approximately 3 million patients awaiting treatment in the United States. Task shifting-whereby specialist physicians screen patients for treatment eligibility but on-treatment monitoring is devolved to more abundant non-physician clinicians-achieves non-inferior treatment outcomes with second generation direct-acting antivirals (2nd Gen DAAs), may increase treatment capacity, and may facilitate greater treatment access. We determined the cost effectiveness of 2nd Gen DAAs with respect to interferon-based first-generation DAAs (1st Gen DAAs) within a task-shifted treatment model. Methods: Using a previously described decision-analytic Markov structure, we modeled a hypothetical cohort of 1,000 patients with HCV genotype 1 infection over a lifetime horizon, based upon our outreach clinic's HCV treatment protocol. Treatment-naïve and treatment-experienced HCV cohorts were modeled separately, based upon our outr8each clinic's demographics. Treatment response to 2nd Gen DAAs was modeled based on our outreach clinic's data. Adverse events, utility, costing, and transition probabilities were sourced from the literature. Results: Driven by improved effectiveness and safety, as well as an expected increase in treatment capacity, 2nd Gen DAAs treatment monitored by non-physician clinicians was projected to improve health outcomes and be dominant from a cost-effective perspective versus that of 1st Gen DAAs. Trends were consistent across all assessed patient subpopulations. Conclusions: Based on an assumption of increased treatment capacity accompanying a task-shifted treatment model, 2nd Gen DAAs-based treatment was cost effective and cost saving as compared to 1st Gen DAAs-based treatment for all HCV patient subgroups assessed.

The Role of e-Health in Optimizing Task-Shifting in the Delivery of Antiviral Therapy for Chronic Hepatitis C.

PURPOSE: Recently, we reported the successful application of task-shifting to improve the management of patients with chronic hepatitis C virus (HCV) infection receiving treatment with direct-acting antiviral (DAA) agents in underserved areas of California. We assessed the impact of e-health on task-shifting in our treatment model. METHODS: In a retrospective analysis, we reviewed the impact of e-health on optimizing the delivery of DAA-based regimen to HCV-infected patients in outreach clinics in medically underserved areas of California. A nonphysician healthcare provider worked in close conjunction with a hepatologist to monitor the patients during the course of antiviral therapy. We exclusively used our institution-based, secured e-health portal as the means of communication with the local staff and patients in outreach clinics. RESULTS: From January 2015 to June 2016, we treated over 100 HCV-infected patients with DAA-based regimens using the task-shifting model. During the study period, we did not experience any delay in the care of our patients undergoing treatment with DAA agents. Communication with the patient and staff using e-health was prompt, secured, and documented in electronic medical records. Due to the optimization of task-shifting by e-health and safety/tolerability of DAA, 95% patients did not need a follow-up clinic visit during the treatment. Return clinic visits during the treatment were unrelated to DAA use or associated with ribavirin-related anemia. In addition, we noted improvement in access and capacity of our outreach clinic. CONCLUSIONS: We report a positive impact of e-health in optimizing task-shifting for DAA in HCV-infected patients in underserved outreach clinics. More importantly, a secondary improvement in access and capacity of our clinic was noted.

Task-Shifting: An Approach to Decentralized Hepatitis C Treatment in Medically Underserved Areas.

BACKGROUND: Despite the availability of safe and effective direct-acting antiviral drugs (DAAs), the vast majority of patients with chronic hepatitis C (HCV) in the USA remain untreated, in part due to lack of access to specialist providers. AIMS: To determine the effectiveness of DAA-based treatment in medically underserved areas in California, in a healthcare model dependent on task-shifting--wherein a visiting hepatologist assesses patients for treatment eligibility, but subsequent routine follow-up evaluation of patients prescribed treatment is devolved to a part-time licensed vocational nurse under remote supervision of the hepatologist. METHODS: We retrospectively determined rates of sustained virologic response 12 weeks after treatment completion (SVR-12), adverse events, and treatment discontinuations in patients who received sofosbuvir-based DAA regimens between December 2013 and November 2014. RESULTS: Despite limited specialist provider involvement in medically underserved areas, all but two of 58 patients completed treatment, and 88 % of patients achieved the curative endpoint of undetectable HCV RNA 12 weeks after completing treatment (sustained virologic response, SVR-12). Almost 80 % of patients with cirrhosis and 85 % of patients with prior treatment experience achieved SVR-12. CONCLUSIONS: Treatment effectiveness with sofosbuvir-based regimens in medically underserved areas utilizing task-shifting from a specialist to a mid-level provider is comparable to those achieved in pivotal clinical trials for these regimens, and to "real-world" experiences of tertiary care centers in the USA.

Factors affecting visual outcomes in patients with diabetic macular edema treated with ranibizumab.

PURPOSE: To identify factors associated with visual outcomes in patients with diabetic macular edema (DME) treated with ranibizumab (RBZ) in the Ranibizumab for Edema of the mAcula in Diabetes-Protocol 2 (READ-2) Study. PATIENTS AND METHODS: Optical coherence tomography scans, fundus photographs, and fluorescein angiograms (FAs) were graded and along with baseline characteristics were correlated with month (M) 24 visual outcome of best-corrected visual acuity (BCVA) ≤20/100 (poor outcome) vs >20/100 (better outcome). RESULTS: Of 101 patients with a M20 visit or beyond, 27 (27%) had BCVA ≤20/100. Comparison of patients with or without poor outcome showed mean baseline BCVA of 16.8 letters (20/125) in the former compared with 30.4 letters (20/63; P<0.001). Mean change in BCVA between baseline and M24 was -2.6 letters in the poor outcome group compared with +9.8 letters (P<0.001). Foveal thickness (FTH) at M24 was 374.1 µm in the poor outcome group compared with 268.8 µm (P<0.01), a difference driven by 14 patients with mean FTH of 450.3 µm. Foveal atrophy occurred in 65% (11/17) in the poor outcome group compared with 17%(12/71, P=0.001). Persistent edema was noted in 52% (14/27) of patients with poor outcome. Laser scars near foveal center were significantly more common in patients with poor outcome who did not have edema vs those who did (78% (7/9) vs 23% (3/13) P=0.03). CONCLUSION: Poor baseline BCVA (≤20/125) in DME patients predicts poor visual outcome (≤20/100) after 2 years of treatment with RBZ and/or focal/grid laser, often due to foveal atrophy and/or persistent edema.

Spectral- and time-domain optical coherence tomography measurements of macular thickness in normal eyes and in eyes with diabetic macular edema.

PURPOSE: To report macular thickness values in normal eyes and eyes with diabetic macular edema (DME) using time-domain (TD) and spectral-domain (SD) optical coherence tomography (OCT), and to derive a conversion equation. METHODS: The index study was a prospective investigation conducted on 80 eyes from 40 normal subjects and 130 eyes from 118 patients with DME seen in our clinic. Retinal thickness values from the central 1 mm of the macula and surrounding four ETDRS subfields were acquired using TD-OCT (Stratus OCT) and SD-OCT (SPECTRALIS HRA+OCT). Measurements of the central (C) subfield from both devices were used to derive a conversion equation. The equation was used to predict SD-OCT values using measurements from TD-OCT. Agreement between predicted and actual SD-OCT measurements was assessed. RESULTS: In normal eyes, the mean difference between TD-OCT and SD-OCT measurements of the C subfield was 76 µm (CI(95)=74 and 77, respectively). The conversion equation, y=1.029x+72.49, was derived. In eyes with DME, using the equation, SPECTRALIS-predicted values were 5% higher than actual measurements, with 95% of predicted values falling within 9% of the actual measurements. Relocating SD-OCT grids to match the location on TD-OCT resulted in predicted values falling within 7% of actual measurements. CONCLUSIONS: The percent difference between actual thickness measurements from SPECTRALIS and predicted thickness measurements, using the conversion equation, was within reported limits of repeatability of Stratus in eyes with DME. Our equation may help correlate OCT values from both devices in standard care and clinical trials for DME.

Development of melanoma-targeted polymer micelles by conjugation of a melanocortin 1 receptor (MC1R) specific ligand.

The incidence of malignant melanoma is rising faster than that of any other cancer in the United States. Because of its high expression on the surface of melanomas, MC1R has been investigated as a target for selective imaging and therapeutic agents against melanoma. Eight ligands were screened against cell lines engineered to overexpress MC1R, MC4R, or MC5R. Of these, compound 1 (4-phenylbutyryl-His-dPhe-Arg-Trp-NH(2)) exhibited high (0.2 nM) binding affinity for MC1R and low (high nanomolar) affinities for MC4R and MC5R. Functionalization of the ligand at the C-terminus with an alkyne for use in Cu-catalyzed click chemistry was shown not to affect the binding affinity. Finally, formation of the targeted polymer, as well as the targeted micelle formulation, also resulted in constructs with low nanomolar binding affinity.

Fluorescent and lanthanide labeling for ligand screens, assays, and imaging.

The use of fluorescent (or luminescent) and metal contrast agents in high-throughput screens, in vitro assays, and molecular imaging procedures has rapidly expanded in recent years. Here we describe the development and utility of high-affinity ligands for cancer theranostics and other in vitro screening -studies. In this context, we also illustrate the syntheses and use of heteromultivalent ligands as targeted imaging agents.