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Purpose/objectivesRecently a 1.5 Tesla MR Linac has been FDA approved and is commercially available. Clinical series describing treatment methods and outcomes for upper abdominal tumors using a 1.5 Tesla MR Linac are lacking. We present the first clinical series of upper abdominal tumors treated using a 1.5 Tesla MR Linac along with the acquisition of intra-treatment quantitative imaging.Materials/methods10 patients with abdominal tumors were treated at our institution. Each patient enrolled in an IRB approved advanced imaging protocol. Both daily real-time adaptive and non-adaptive methods were used, and selection criteria are described. Adaptive plans were based on pre-beam motion-averaged or mid-position images derived from respiratory-correlated 4D-MRI. Quantitative intravoxel incoherent motion diffusion-weighted imaging and T2 mapping were acquired during plan adaptation. Real-time motion monitoring using cine MRI was performed during beam-on.ResultsMedian patient age was 68.2, five patients were female. Tumor types included liver metastatic lesions from melanoma and sarcoma, primary liver hepatocellular carcinoma (HCC), and regional abdominal tumors included pancreatic metastatic lesions from renal cell carcinoma (RCC) along with two cases of recurrent pancreatic cancer. Doses included 30 Gy in 6 fractions, 33 Gy in 5 fractions, 50 Gy in 5 fractions, 45 Gy in 3 fractions, and 60 Gy in 3 fractions, depending on the location and clinical circumstances. Treatments were feasible and were successfully completed in all patients without significant acute toxicity, technical complications, or need for back up CT based treatment plans.ConclusionsWe present a first clinical series of patients treated for pancreatic tumors, primary liver tumors, and secondary liver tumors with a 1.5 Tesla MR Linear accelerator using adapt-to-position and adapt-to-shape strategies. Treatments were well tolerated by all patients. Acquisition of fully quantitative MR imaging was feasible during the course of the treatment delivery workflow without extending overall treatment times.

PURPOSE: Performance of anatomical metrics of Response Evaluation Criteria in Solid Tumors (RECIST1.1) versus Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST1.0) for neoadjuvant chemoradiation (nCR) of pancreatic adenocarcinoma was evaluated based on the pathological treatment response (PTR) data. METHODS AND MATERIALS: The pre- and post-nCR CT and PET data for 14 patients with resectable or borderline resectable pancreatic head adenocarcinoma treated with nCR followed by surgery were retrospectively analyzed. These data were compared with the PTR which were graded according to tumor cell destruction (cellularity), with Grade 0, 1, 2 or 3 (G0, G1, G2 or G3) for complete, moderate, minimal and poor responses, respectively. Maximum standardized uptake value (SUVmax) was defined using body-weight (SUVbw). PERCIST1.0 was defined using lean-body mass normalized SUV (SUVlb or SUL). RECIST1.1 was defined by contouring the whole pancreas head on the CT image. Pre- and post-SUL-peak and SUVmax, RECIST1.1 and PETRECIST1.0 were correlated with PTR using Pearson’s correlation coefficient test. RESULTS: The average mean and SD in SUL-peak for all patients analyzed were lower in post-nCR (3.63±1.06) compared to those at pre-nCR (4.29±0.89). Using PERCIST1.0, 62% of patients showed stable metabolic disease (SMD), 23% partial metabolic response (PMR), and 15% progressive metabolic disease (PMD). Using RECIST1.1, 85% of patients showed stable disease (SD), 8% partial response (PR), and 7% progressive diseases (PD). A poor insignificant correlation was established between PRT and PERECIST1.0 (r=0.121), whereas no correlation was seen with RECIST1.1. CONCLUSIONS: PERCIST1.0 appears to increase the chance of detecting patients with progressive disease compared to the conventional anatomical-based assessment of RECIST1.1. The integration of these additional radiographic metrics in assessing treatment response to nCR for pancreatic adenocarcinoma may provide a promising strategy to better select patients that are most suitable for therapeutic intensification.

Abstract Background Rotavirus B (RVB) causes diarrhea in humans and pigs. Although various RVB strains were identified in humans and various animals globally, little is known about the epidemiology RVB infection in Africa. In this study, we attempted to examine the prevalence of RVB infection in pig populations in Zambia. Methods Metagenomic analyses were conducted on pig feces collected in Zambia to detect double stranded RNA viruses, including RVB. To clarify the prevalence of RVB infection in pig populations in Zambia, 147 fecal samples were screened for the RVB detection by RT-qPCR. Full genome sequence of a detected RVB was determined by Sanger sequencing and genetically analyzed. Results The metagenomic analyses revealed that RVB sequence reads and contigs of RVB were detected from one fecal sample collected from pigs in Zambia. RT-qPCR screening detected RVB genomes in 36.7% (54/147) of fecal samples. Among 54 positive samples, 13 were positive in non-diarrheal samples (n = 48, 27.1%) and 41 in diarrheal samples (n = 99, 41.4%). Genetic analyses demonstrated that all the segments of ZP18-18, except for VP4, had high nucleotide sequence identities (80.6–92.6%) with all other known RVB strains detected in pigs. In contrast, the VP4 sequence of ZP18-18 was highly divergent from other RVB strains (

Abstract Rabies virus (RABV) is the causative agent of rabies, a lethal neurological disease in mammals. RABV strains can be classified into fixed strains (laboratory strains) and street strains (field/clinical strains), which have different properties including cell tropism and neuroinvasiveness. RABV Toyohashi strain is a street strain isolated in Japan from an imported case which had been bitten by rabid dog in the Philippines. In order to facilitate molecular studies of RABV, we established a reverse genetics (RG) system for the study of the Toyohashi strain. The recombinant virus was obtained from a cDNA clone of Toyohashi strain and exhibited similar growth efficiency as the original virus in cultured cell lines. Both the original and recombinant strains showed similar pathogenicity with high neuroinvasiveness in mice, and the infected mice developed a long and inconsistent incubation period, which is characteristic of street strains. We also generated a recombinant Toyohashi strain expressing viral phosphoprotein (P protein) fused with the fluorescent protein mCherry, and tracked the intracellular dynamics of the viral P protein using live-cell imaging. The presented reverse genetics system for Toyohashi strain will be a useful tool to explore the fundamental molecular mechanisms of the replication of RABV street strains.

Beiji nairovirus (BJNV), in the family Nairoviridae, the order Bunyavirales, was recently reported as a causative agent of an emerging tick-borne zoonotic infection in China. This study investigated the prevalence of BJNV in ticks in Japan. Screening of over 2,000 ticks from multiple regions revealed a widespread distribution of BJNV and BJNV-related viruses in Japan, particularly in the northern island, and in other high altitude areas with exclusive occurrence of Ixodes ticks. Phylogenetic analysis identified three distinct groups of nairoviruses in ticks in Japan: BJNV, Yichun nairovirus (YCNV) and a newly identified Mikuni nairovirus (MKNV). BJNV and YCNV variants identified in ticks in Japan exhibited high nucleotide sequence identities to those in China and Russia with evidence of non-monophyletic evolution among BJNVs, suggesting multiple cross-border transmission events of BJNV between the Eurasian continent and Japan. Whole genome sequencing of BJNV and MKNV revealed a unique GA-rich region in the S segment, the significance of which remains to be determined. In conclusion, the present study has shown a wide distribution and diversity of BJNV-related nairoviruses in Ixodes ticks in Japan and has identified unique genomic structures. The findings demonstrate the significance of BJNV as well as related viruses in Japan and highlight the necessity of monitoring emerging nairovirus infections and their potential risks to public health.

Background and purpose: Treatment planning for MR-guided stereotactic body radiotherapy (SBRT) for pancreatic tumors can be challenging, leading to a wide variation of protocols and practices. This study aimed to harmonize treatment planning by developing a consensus planning protocol for MR-guided pancreas SBRT on a 1.5 T MR-Linac. Materials and methods: A consortium was founded of thirteen centers that treat pancreatic tumors on a 1.5 T MR-Linac. A phased planning exercise was conducted in which centers iteratively created treatment plans for two cases of pancreatic cancer. Each phase was followed by a meeting where the instructions for the next phase were determined. After three phases, a consensus protocol was reached. Results: In the benchmarking phase (phase I), substantial variation between the SBRT protocols became apparent (for example, the gross tumor volume (GTV) D99% ranged between 36.8 – 53.7 Gy for case 1, 22.6 – 35.5 Gy for case 2). The next phase involved planning according to the same basic dosimetric objectives, constraints, and planning margins (phase II), which led to a large degree of harmonization (GTV D99% range: 47.9–53.6 Gy for case 1, 33.9–36.6 Gy for case 2). In phase III, the final consensus protocol was formulated in a treatment planning system template and again used for treatment planning. This not only resulted in further dosimetric harmonization (GTV D99% range: 48.2–50.9 Gy for case 1, 33.5–36.0 Gy for case 2) but also in less variation of estimated treatment delivery times. Conclusion: A global consensus protocol has been developed for treatment planning for MR-guided pancreatic SBRT on a 1.5 T MR-Linac. Aside from harmonizing the large variation in the current clinical practice, this protocol can provide a starting point for centers that are planning to treat pancreatic tumors on MR-Linac systems.

Background: KRAS wild-type (WT) pancreatic ductal adenocarcinoma (PDAC) represents a distinct entity with unique biology. The therapeutic impact of matched targeted therapy in these patients in a real-world setting, to date, is less established. Objectives: The aim of our study was to review our institutional database to identify the prevalence of actionable genomic alterations in patients with KRAS -WT tumors and to evaluate the therapeutic impact of matched targeted therapy in these patients. Design: We reviewed electronic medical records of patients with KRAS-WT PDAC and advanced disease ( n = 14) who underwent clinical-grade tissue ± liquid next-generation sequencing (315–648 genes for tissue) between years 2015 and 2021. Methods: Demographic and disease characteristics were summarized using descriptive parameters. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method. Results: Of 236 PDAC patients, 14 had advanced/metastatic disease with KRAS-WT tumors. Median age at diagnosis was 66 years. There was a high frequency of potentially actionable genomic alterations, including three (21%) with BRAF alterations, two (14%) with fusions [ RET-PCM1 and FGFR2-POC1B ( N = 1 each)]; and one with a druggable EGFR ( EGFR E746_A755delISERD) variant; two other patients had an STK11 and a MUTYH alteration. Five patients were treated with matched targeted therapy, with three having durable benefit: (i) erlotinib for EGFR -altered tumor, followed by osimertinib/capmatinib when MET amplification emerged (first-line therapy); (ii) pralsetinib for RET fusion (fifth line); and (iii) dabrafenib/trametinib for BRAF N486_P490del (third line). Duration of time on chemotherapy-free matched targeted therapy for these patients was 17+, 11, and 18+ months, respectively. Conclusion: Sustained therapeutic benefit can be achieved in a real-world setting in a subset of patients with advanced/metastatic KRAS-WT PDAC treated with chemotherapy-free matched targeted agents. Prospective studies are warranted.

Background and purpose: Magnetic Resonance Imaging (MRI) guided stereotactic body radiotherapy (SBRT) of liver metastases is an upcoming high-precision non-invasive treatment. Interobserver variation (IOV) in tumor delineation, however, remains a relevant uncertainty for planning target volume (PTV) margins. The aims of this study were to quantify IOV in MRI-based delineation of the gross tumor volume (GTV) of liver metastases and to detect patient-specific factors influencing IOV. Materials and methods: A total of 22 patients with liver metastases from three primary tumor origins were selected (colorectal(8), breast(6), lung(8)). Delineation guidelines and planning MRI-scans were provided to eight radiation oncologists who delineated all GTVs. All delineations were centrally peer reviewed to identify outliers not meeting the guidelines. Analyses were performed both in- and excluding outliers. IOV was quantified as the standard deviation (SD) of the perpendicular distance of each observer’s delineation towards the median delineation. The correlation of IOV with shape regularity, tumor origin and volume was determined. Results: Including all delineations, average IOV was 1.6 mm (range 0.6–3.3 mm). From 160 delineations, in total fourteen single delineations were marked as outliers after peer review. After excluding outliers, the average IOV was 1.3 mm (range 0.6–2.3 mm). There was no significant correlation between IOV and tumor origin or volume. However, there was a significant correlation between IOV and regularity (Spearman’s ρs = -0.66; p = 0.002). Conclusion: MRI-based IOV in tumor delineation of liver metastases was 1.3–1.6 mm, from which PTV margins for IOV can be calculated. Tumor regularity and IOV were significantly correlated, potentially allowing for patient-specific margin calculation.

Emerging and reemerging tick-borne virus infections caused by orthonairoviruses (family Nairoviridae), which are genetically distinct from Crimean-Congo hemorrhagic fever virus, have been recently reported in East Asia. Here, we have established a mouse infection model using type-I/II interferon receptor-knockout mice (AG129 mice) both for a better understanding of the pathogenesis of these infections and validation of antiviral agents using Yezo virus (YEZV), a novel orthonairovirus causing febrile illnesses associated with tick bites in Japan and China. YEZV-inoculated AG129 mice developed hepatitis with body weight loss and died by 6 days post infection. Blood biochemistry tests showed elevated liver enzyme levels, similar to YEZV-infected human patients. AG129 mice treated with favipiravir survived lethal YEZV infection, demonstrating the anti-YEZV effect of this drug. The present mouse model will help us better understand the pathogenicity of the emerging tick-borne orthonairoviruses and the development of specific antiviral agents for their treatment.

Abstract Mosquitoes interact with various organisms in the environment, and female mosquitoes in particular serve as vectors that directly transmit a number of microorganisms to humans and animals by blood-sucking. Comprehensive analysis of mosquito-borne viruses has led to the understanding of the existence of diverse viral species and to the identification of zoonotic arboviruses responsible for significant outbreaks and epidemics. In the present study on mosquito-borne bunyaviruses we employed a broad-spectrum RT-PCR approach and identified eighteen different additional species in the Phenuiviridae family and also a number of related but unclassified bunyaviruses in mosquitoes collected in Zambia. The entire RNA genome segments of the newly identified viruses were further analyzed by RNA sequencing with a ribonuclease R (RNase R) treatment to reduce host-derived RNAs and enrich viral RNAs, taking advantage of the dsRNA panhandle structure of the bunyavirus genome. All three or four genome segments were identified in eight bunyavirus species. Furthermore, L segments of three different novel viruses related to the Leishbunyaviridae were found in mosquitoes together with genes from the suspected host, the Crithidia parasite. In summary, our virus detection approach using a combination of broad-spectrum RT-PCR and RNA sequencing analysis with a simple virus enrichment method allowed the discovery of novel bunyaviruses. The diversity of bunyaviruses is still expanding and studies on this will allow a better understanding of the ecology of hematophagous mosquitoes.

The utilization of stereotactic body radiation therapy for the treatment of liver metastasis has been widely studied and has demonstrated favorable local control outcomes. However, several predictive factors play a crucial role in the efficacy of stereotactic body radiation therapy, such as the number and size (volume) of metastatic liver lesions, the primary tumor site (histology), molecular biomarkers (e.g., KRAS and TP53 mutation), the use of systemic therapy prior to SBRT, the radiation dose, and the use of advanced technology and organ motion management during SBRT. These prognostic factors need to be considered when clinical trials are designed to evaluate the efficacy of SBRT for liver metastases.

BackgroundMinority stress theory views social support as a protective factor against the effects of minority-specific stressors like internalized homophobia (IH) on mental health in sexual minority populations. However, much of the empirical validation of this theory has been conducted within predominantly White samples, resulting in a limited understanding of how the theory applies to Black sexual minority individuals. Current examinations of social support fail to capture the nuances of how Black sexual minority men may access support systems differently, resulting in a need to investigate how social support, IH, and mental health operate for Black sexual minority men. This study examined relationships between IH, depression, and different types of social support (i.e., family, friends, Black community, gay community) using a mediation model.MethodsWe used data from the POWER (Promoting Our Worth Equity and Resilience) Study, which recruited Black sexual minority men at Black Pride events across six cities in the United States from 2014 to 2017, to test four mediation pathways concurrently in Stata 17. Participants (N = 4,430) completed a questionnaire assessing a variety of health and life domains, including depression symptoms, internalized homophobia, and social support.ResultsIH was positively associated with depression. Lower levels of family, friend, and Black community support were all positively associated with depression symptoms. Additionally, IH was positively associated with all types of support. Finally, family, friend, and Black community support partially mediated the relationship between IH and depression.Conclusions and implicationsResults suggest that the relationship between social support and depression is complex for Black sexual minority men. Findings suggest family support is an important factor for clinical intervention efforts targeting depression, and that gay community support systems should assess how their environments can better support Black sexual minority men. Overall, findings demonstrate the necessity of future examination of how social support functions differently within Black sexual minority communities.

Abstract Purpose/Objectives Most patients with pancreatic adenocarcinoma (PDAC) will present with distant metastatic disease at diagnosis. We sought to identify clinical characteristics associated with prolonged overall survival (OS) in patients presenting with metastatic PDAC. Materials/Methods Patients presenting with metastatic PDAC that received treatment at our institution with FOLFIRINOX or gemcitabine‐based chemotherapies between August 1, 2011 and September 1, 2017 were included in the study. Metastatic disease burden was comprehensively characterized radiologically via individual diagnostic imaging segmentation. Landmark analysis was performed at 18 months, and survival curves were estimated using the Kaplan–Meier method and compared between groups via the log‐rank test. ECOG and Charlson Comorbidity Index (CCI) were calculated for all patients. Results 121 patients were included with a median age of 62 years (37–86), 40% were female, 25% had ECOG 0 at presentation. Of the 121 patients included, 33% (n = 41) were alive at 12 months and 25% (n = 31) were alive at 18 months. Landmark analysis demonstrated a significant difference between patients surviving 60 cc, p = 0.004), metastasis only in the liver (p = 0.04), and normalization of CA 19‐9 (p

Summary: Background: Pulmonary infection with SARS-CoV-2 stimulates host immune responses and can also result in the progression of dysregulated and critical inflammation. Throughout the pandemic, the management and treatment of COVID-19 has been continuously updated with a range of antiviral drugs and immunomodulators. Monotherapy with oral antivirals has proven to be effective in the treatment of COVID-19. However, treatment should be initiated in the early stages of infection to ensure beneficial therapeutic outcomes, and there is still room for further consideration on therapeutic strategies using antivirals. Methods: We studied the therapeutic effects of monotherapy with the oral antiviral ensitrelvir or the anti-inflammatory corticosteroid methylprednisolone and combination therapy with ensitrelvir and methylprednisolone in a delayed dosing model of hamsters infected with SARS-CoV-2. Findings: Combination therapy with ensitrelvir and methylprednisolone improved respiratory conditions and reduced the development of pneumonia in hamsters even when the treatment was started after 2 days post-infection. The combination therapy led to a differential histological and transcriptomic pattern in comparison to either of the monotherapies, with reduced lung damage and down-regulation of expression of genes involved in the inflammatory response. Furthermore, we found that the combination treatment is effective in case of infection with either the highly pathogenic delta or circulating omicron variants. Interpretation: Our results demonstrate the advantage of combination therapy with antiviral and corticosteroid drugs in COVID-19 treatment from the perspective of lung pathology and host inflammatory responses. Funding: Funding bodies are described in the Acknowledgments section.

Objectives: Human Leukocyte Antigen HLA-B*57:01 and B*58:01 are considered anti-HIV-1 protective alleles. HLA-B*57:01/58:01-restricted HIV-1 Gag TW10 (TSTLQEQIGW, Gag residues 240-249) epitope-specific CD8+ T cell responses that frequently select for a Gag escape mutation, T242N, with viral fitness cost are crucial for HIV-1 control. Although this finding has been observed in cohorts where HIV-1 subtype B or C predominates, the protective impact of HLA-B*57:01/58:01 has not been reported in Southeast Asian countries where HIV-1 CRF01_AE is the major circulating strain. Here, the effect of HLA-B*57:01/58:01 on CRF01_AE infection was investigated. Methods: The correlation of HLA-B*57:01/58:01 with viral load and CD4 counts were analyzed in the CRF01_AE-infected Vietnamese cohort (N = 280). The impact of the T242N mutation on CRF01_AE replication capacity was assessed. Results: HLA-B*57:01/58:01-positive individuals mostly had HIV-1 with T242N (62/63) but showed neither a significant reduction in viral load nor increased CD4 counts relative to B*57:01/58:01-negative participants. In vitro and in vivo analyses revealed a significant reduction in viral fitness of CRF01_AE with T242N. In silico analysis indicated reduced presentation of epitopes in the context of CRF01_AE compared to subtype B or C in 10/16 HLA-B*57:01/58:01-restricted HIV-1 epitopes. Conclusion: The protective impact of HLA-B*57:01/58:01 on CRF01_AE infection is impaired despite strong suppressive pressure by TW10-specific CD8+ T cells.

Background and purpose: The 1.5 Tesla (T) Magnetic Resonance Linear Accelerator (MRL) provides an innovative modality for improved cardiac imaging when planning radiation treatment. No MRL based cardiac atlases currently exist, thus, we sought to comprehensively characterize cardiac substructures, including the conduction system, from cardiac images acquired using a 1.5 T MRL and provide contouring guidelines. Materials and methods: Five volunteers were enrolled in a prospective protocol (NCT03500081) and were imaged on the 1.5 T MRL with Half Fourier Single-Shot Turbo Spin-Echo (HASTE) and 3D Balanced Steady-State Free Precession (bSSFP) sequences in axial, short axis, and vertical long axis. Cardiac anatomy was contoured by (AS) and confirmed by a board certified cardiologist (JR) with expertise in cardiac MR imaging. Results: A total of five volunteers had images acquired with the HASTE sequence, with 21 contours created on each image. One of these volunteers had additional images obtained with 3D bSSFP sequences in the axial plane and additional images obtained with HASTE sequences in the key cardiac planes. Contouring guidelines were created and outlined. 15–16 contours were made for the short axis and vertical long axis. The cardiac conduction system was demonstrated with eleven representative contours. There was reasonable variation of contour volume across volunteers, with structures more clearly delineated on the 3D bSSFP sequence. Conclusions: We present a comprehensive cardiac atlas using novel images acquired prospectively on a 1.5 T MRL. This cardiac atlas provides a novel resource for radiation oncologists in delineating cardiac structures for treatment with radiotherapy, with special focus on the cardiac conduction system.

IntroductionOnline adaptive magnetic resonance-guided radiotherapy (MRgRT) is a promising treatment modality for pancreatic cancer and is being employed by an increasing number of centers worldwide. However, clinical outcomes have only been reported on a small scale, often from single institutes and in the context of clinical trials, in which strict patient selection might limit generalizability of outcomes. This study presents clinical outcomes of a large, international cohort of patients with (peri)pancreatic tumors treated with online adaptive MRgRT.MethodsWe evaluated clinical outcomes and treatment details of patients with (peri)pancreatic tumors treated on a 1.5 Tesla (T) MR-linac in two large-volume treatment centers participating in the prospective MOMENTUM cohort (NCT04075305). Treatments were evaluated through schematics, dosage, delivery strategies, and success rates. Acute toxicity was assessed until 3 months after MRgRT started, and late toxicity from 3–12 months of follow-up (FU). The EORTC QLQ-C30 questionnaire was used to evaluate the quality of life (QoL) at baseline and 3 months of FU. Furthermore, we used the Kaplan–Meier analysis to calculate the cumulative overall survival.ResultsA total of 80 patients were assessed with a median FU of 8 months (range 1–39 months). There were 34 patients who had an unresectable primary tumor or were medically inoperable, 29 who had an isolated local recurrence, and 17 who had an oligometastasis. A total of 357 of the 358 fractions from all hypofractionated schemes were delivered as planned. Grade 3–4 acute toxicity occurred in 3 of 59 patients (5%) with hypofractionated MRgRT and grade 3–4 late toxicity in 5 of 41 patients (12%). Six patients died within 3 months after MRgRT; in one of these patients, RT attribution could not be ruled out as cause of death. The QLQ-C30 global health status remained stable from baseline to 3 months FU (70.5 at baseline, median change of +2.7 [P = 0.5]). The 1-year cumulative overall survival for the entire cohort was 67%, and that for the primary tumor group was 66%.ConclusionOnline adaptive MRgRT for (peri)pancreatic tumors on a 1.5 T MR-Linac could be delivered as planned, with low numbers of missed fractions. In addition, treatments were associated with limited grade 3–4 toxicity and a stable QoL at 3 months of FU.

Introduction Radiation therapy for head and neck squamous cell carcinoma is constrained by radiotoxicity to normal tissue. We demonstrate 100 nm theranostic nanoparticles for image-guided radiation therapy planning and enhancement in rat head and neck squamous cell carcinoma models. Methods PEG conjugated theranostic nanoparticles comprising of Au nanorods coated with Gadolinium oxide layers were tested for radiation therapy enhancement in 2D cultures of OSC-19-GFP-luc cells, and orthotopic tongue xenografts in male immunocompromised Salt sensitive or SS rats via both intratumoral and intravenous delivery. The radiation therapy enhancement mechanism was investigated. Results Theranostic nanoparticles demonstrated both X-ray/magnetic resonance contrast in a dose-dependent manner. Magnetic resonance images depicted optimal tumor-to-background uptake at 4 h post injection. Theranostic nanoparticle + Radiation treated rats experienced reduced tumor growth compared to controls, and reduction in lung metastasis. Conclusions Theranostic nanoparticles enable preprocedure radiotherapy planning, as well as enhance radiation treatment efficacy for head and neck tumors.

BackgroundQueer youth experience high rates of depression and suicidality. These disparities stem from stigma-based stressors, including internalized stigma (i.e., negative social views that minoritized individuals internalize about their own identity). Given the importance of this factor in understanding mental health disparities among queer youth, we completed a systematic review and meta-analysis examining the relationships between internalized stigma and outcomes of depression and suicide risk (i.e., suicidal ideation, non-suicidal self-injury, and suicidal behavior).MethodsWe followed the PRISMA standards. Six bibliographic databases were searched for studies in the United States from September 2008 to March 2022. Dual independent screening of search results was performed based on a priori inclusion criteria.ResultsA total of 22 studies were included for data extraction and review. Most studies examined general internalized homophobia, with few examining internalized biphobia or transphobia. Many studies examined depression as an outcome, few studies examined suicidal ideation or behavior, and no studies examined non-suicidal self-injury. Meta-analyses model results show the association between general internalized queer stigma and depressive symptoms ranged r = 0.19, 95% CI [0.14, 0.25] to r = 0.24, 95% CI [0.19, 0.29], the latter reflecting more uniform measures of depression. The association between internalized transphobia and depressive outcomes was small and positive (r = 0.21, 95% CI [−0.24, 0.67]). General internalized queer stigma and suicidal ideation had a very weak positive association (r = 0.07, 95% CI [−0.27, 0.41]) and an even smaller, weaker positive association with suicide attempt (r = 0.02, 95% CI [0.01, 0.03]).ConclusionImplications for clinical practice, policy, and future research are discussed.

Lesbian, gay, bisexual, and transgender (LGBT) individuals have a high prevalence of substance use disorders (SUDs) and experience unique barriers to treatment. Little is known about the characteristics of SUD treatment facilities providing LGBT-tailored programs at the outpatient and residential levels of care. The purpose of this study is to examine the availability of LGBT-tailored programs in outpatient and residential SUD treatment facilities. Using the National Survey of Substance Abuse Treatment Services 2020, we conducted logistic regression to examine facility characteristics, including ownership, pay assistance, region, outreach, and telehealth services, associated with having an LGBT-tailored program among SUD treatment facilities. Outpatient facilities that were for-profit, had pay assistance, had community outreach services, and provided telemedicine/telehealth were more likely to have an LGBT-tailored program. Those that were government-owned, in the Midwest, and that accepted Medicaid were less likely to have an LGBT-tailored program. Residential facilities that were in the West, for-profit, and had community outreach services were more likely to have an LGBT-tailored program. This study offers a national examination of the availability of LGBT-tailored programs in SUD treatment facilities. Differences in availability based on ownership, region, pay assistance, and outreach highlight potential gaps in treatment availability.

A novel multiplex loop-mediated isothermal amplification (LAMP) method combined with DNA chromatography was developed for the simultaneous detection of three important respiratory disease-causing viruses: severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), influenza A virus, and influenza B virus. Amplification was performed at a constant temperature, and a positive result was confirmed by a visible colored band. An in-house drying protocol with trehalose was used to prepare the dried format multiplex LAMP test. Using this dried multiplex LAMP test, the analytical sensitivity was determined to be 100 copies for each viral target and 100-1000 copies for the simultaneous detection of mixed targets. The multiplex LAMP system was validated using clinical COVID-19 specimens and compared with the real-time qRT-PCR method as a reference test. The determined sensitivity of the multiplex LAMP system for SARS-CoV-2 was 71% (95% CI: 0.62-0.79) for cycle threshold (Ct) ≤ 35 samples and 61% (95% CI: 0.53-0.69) for Ct ≤40 samples. The specificity was 99% (95%CI: 0.92-1.00) for Ct ≤35 samples and 100% (95%CI: 0.92-1.00) for the Ct ≤40 samples. The developed simple, rapid, low-cost, and laboratory-free multiplex LAMP system for the two major important respiratory viral diseases, COVID-19 and influenza, is a promising field-deployable diagnosis tool for the possible future 'twindemic, ' especially in resource-limited settings.

IntroductionSexual identity is mutable and evolving, particularly during adolescence. Sexual identity fluidity could be stressful for some adolescents and may differ by birth-sex. Evidence suggests chronic stress can lead to negative mental health outcomes. However, it is unknown if these two processes (stress and depression) differ by sexual identity fluidity.MethodsThis paper studied time-sequential associations between identity management stress and depression over time by sexual identity fluidity, in a national longitudinal data from sexual minority adolescents (SMA) aged 14–17 years using a multigroup autoregressive cross-lagged model (n = 1077).ResultsIn the sample, 40% of SMA reported at least one change in sexual identity over 18-month period. Greater number of cisgender females reported sexual identity fluidity compared to their male counterparts (46.9% vs. 26.6%). A temporal cross-lagged effect was reported between depression and identity management stress among cisgender females who reported fluidity in sexual identity; and no cross-lagged effect was reported among those females who did not report fluidity. However, among cisgender male sample depression predicted subsequent identity management stress, irrespective of their change sexual identity fluidity status.ConclusionPublic health programs and practice must be responsive to the sexual identity fluidity processes among adolescents, with particular attention to minority stress and depression. In addition, our results indicate that sexual identity development and fluidity processes differ between cisgender females and males; and the nuances associated with these processes of change need further investigation.

Summary: The amino acid residue at position 333 of the rabies virus (RABV) glycoprotein (G333) is a major determinant of RABV pathogenicity. Virulent RABV strains possess Arg333, whereas the attenuated strain HEP-Flury (HEP) possesses Glu333. To investigate the potential attenuation mechanism dependent on a single amino acid at G333, comparative analysis was performed between HEP and HEP333R mutant with Arg333. We examined their respective tropism for astrocytes and the subsequent immune responses in astrocytes. Virus replication and subsequent interferon (IFN) responses in astrocytes infected with HEP were increased compared with HEP333R both in vitro and in vivo. Furthermore, involvement of IFN in the avirulency of HEP was demonstrated in IFN-receptor knockout mice. These results indicate that Glu333 contributes to RABV attenuation by determining the ability of the virus to infect astrocytes and stimulate subsequent IFN responses.

Purpose: Magnetic resonance-guided online adaptive radiation therapy (MRgOART) requires accurate and efficient segmentation. However, the performance of current autosegmentation tools is generally poor for magnetic resonance imaging (MRI) owing to day-to-day variations in image intensity and patient anatomy. In this study, we propose a patient-specific autosegmentation strategy using multiple-input deformable image registration (DIR; PASSMID) to improve segmentation accuracy and efficiency for MRgOART. Methods and materials: Longitudinal MRI scans acquired on a 1.5T MRI-Linac for 10 patients with abdominal cancer were used. The proposed PASSMID includes 2 steps: applying a patient-specific image processing pipeline to longitudinal MRI scans, and populating all contours from previous sessions/fractions to a new fractional MRI using multiple DIRs and combining the resulted contours using simultaneous truth and performance level estimation (STAPLE) to obtain the final consensus segmentation. Five contour propagation strategies were compared: planning computed tomography to fractional MRI scans through rigid body registration (RDR), pretreatment MRI to fractional MRI scans through RDR and DIR, and the proposed multi-input DIR/STAPLE without preprocessing, and the PASSMID. Dice similarity coefficient (DSC) and mean distance to agreement (MDA) with ground truth contours were calculated slice by slice to quantify the contour accuracy. A quantitative index, defined as the ratio of acceptable slices, was introduced using a criterion of DSC > 0.8 and MDA < 2 mm. Results: The proposed PASSMID performed well with an average 2-dimensional DSC/MDA of 0.94/1.78 mm, 0.93/1.04 mm, 0.93/1.06 mm, 0.93/1.14 mm, 0.92/0.83 mm, 0.84/1.53 mm, 0.86/2.39 mm, 0.81/2.49 mm, 0.72/5.48 mm, and 0.70/5.03 mm for the liver, left kidney, right kidney, spleen, aorta, pancreas, stomach, duodenum, small bowel, and colon, respectively. Starting from the third fractions, the contour accuracy was significantly improved with PASSMID compared with the single-DIR strategy (P < .05). The mean ratio of acceptable slices were 13.9%, 17.5%, 60.8%, 70.6%, and 71.8% for the 5 strategies, respectively. Conclusions: The proposed PASSMID solution, by combining image processing, multi-input DIRs, and STAPLE, can significantly improve the accuracy of autosegmentation for intrapatient MRI scans, reducing the time required for further contour editing, thereby facilitating the routine practice of MRgOART.

Objective: The SARS-CoV-2 pathogen has established endemicity in humans. This necessitates the development of rapid genetic surveillance methodologies to serve as an adjunct to existing comprehensive, albeit though slower, genome sequencing-driven approaches. Methods: A total of 21,789 complete genomes were downloaded from GISAID on May 28, 2020, for analyses. We have defined the major clades and subclades of circulating SARS-CoV-2 genomes. A rapid sequencing-based genotyping protocol was developed and tested on SARS-CoV-2-positive RNA samples by next-generation sequencing. Results: We describe eleven major mutation events that defined five major clades (G614, S84, V251, I378, and D392) of globally-circulating viral populations. The clades can be specifically identified using an 11-nucleotide genetic barcode. An analysis of amino acid variation in SARS-CoV-2 proteins provided evidence of substitution events in the viral proteins involved in both host entry and genome replication. Conclusion: Globally-circulating SARS-CoV-2 genomes could be classified into five major clades based on mutational profiles defined by an 11-nucleotide barcode. We have successfully developed a multiplexed sequencing-based, rapid genotyping protocol for high-throughput classification of major clade types of SARS-CoV-2 in clinical samples. This barcoding strategy will be required to monitor genetic diversity decrease as treatment and vaccine approaches become widely available.

Abstract Background The objectives of this study were to investigate the relationships between polymorphisms at the interferon lambda (IFNL) locus and CD4+:CD8+ ratio normalisation in people living with HIV (PLWH) on effective antiretroviral therapy (ART); and to examine whether these polymorphisms influence the composition of T lymphocyte compartments in long-term treated HIV-1 infection. Methods A cross-sectional study in PLWH enrolled into the Mater Immunology study. We performed IFNL genotyping on stored samples and evaluated the association of IFNL single-nucleotide polymorphisms (rs368234815 and rs12979860) with CD4+:CD8+ ratio normalization (> 1) and expanded CD4+ and CD8+ T-cell subsets; CD45RO+CD62L+ (central-memory), CD45RO+ CD62L−(effector-memory) and CD45RO−CD62L+ (naïve), using logistic and linear regression models, respectively. Results 190 ambulatory PLWH recruited to the main study, 143 were included in the analysis (38 had no stored DNA and 9 no T-lymphocyte subpopulation). Of 143 included, the median age (IQR) was 45(39–48) years, 64% were male and 66% were of Caucasian ethnicity. Heterosexual-contact (36%), injecting drug-use (33%) and men who have sex with men (24%) were the most presented HIV-transmission risk groups. The majority of subjects (90.2%) were on ART with 79% of the cohort having an undetectable HIV-RNA (

In this article, we apply and combine elements from four theoretical frameworks (i.e., Minority Stress Theory, Person-in-Environment and Risk and Resilience Framework, Interpersonal-Psychological Theory of Suicide, and Intersectionality) to explain the problem of queer youth suicide through our integrated conceptual model, Queer Prevention of Youth Suicidality Model (Queer-PRYSM). The need for this conceptual model is based on the current state of the literature, including mixed empirical findings on factors related to queer youth suicidality, no scholarly consensus on specific contributing factors regarding high rates of suicidality among queer youth (including queer youth subgroups), and the absence of a unifying theory to explain the queer youth suicide risk. To address these limitations in theory, evidence, and scholarship explaining suicidality among queer youth we present our integrated model with growing, current, relevant research with queer youth. Queer-PRYSM includes minority stressors specific to queer youth, mental health problems, interpersonal-psychological factors, socioecological factors (i.e., family, school, peers, and community), and intersectionality concepts. Queer-PRYSM is essential to understanding the relationship of distal and proximal risk and protective factors in queer youth suicide and developing evidence-informed suicide preventive interventions that can be incorporated into practice, policy, and system structures.

Abstract Clinical outcomes for patients with pancreatic adenocarcinoma (PAC) remain dismal. Local recurrences, proportions of margin positive surgical resections, and overall survival outcomes remain inferior in PAC than any other solid tumor. This stems from a current standard of care management approach that needs to be inspired and transformed with modern treatment techniques and novel therapeutic options. Radiation therapy has historically been a central component in the treatment of pancreatic adenocarcinoma; however, the role of radiation therapy has been called into question based on the publication of clinical trials with conflicting results. We present an overview of the rationale for radiation therapy in resectable, borderline resectable, and unresectable pancreatic adenocarcinoma. We further present a summary of emerging clinical data and future directions to improve outcomes in this devastating malignancy.

Introduction/Background: Multimodal neoadjuvant therapy has resulted in increased rates of histologic response in pancreatic tumors and adjacent lymph nodes. The biologic significance of the collective response in the primary tumor and lymph nodes is not understood.Methods: Patients with localized PC who received neoadjuvant therapy and surgery with histologic assessment of the primary tumor and local-regional lymph nodes were included. Histopathologic response was classified using the modified Ryan score as follows: no viable cancer cells (CR), rare groups of cancer cells (nCR), residual cancer with evident tumor regression (PR), and extensive residual cancer with no evident tumor regression (NR). Nodal status was defined by number of lymph nodes (LN) with tumor metastases: N0 (0 LN), N1 (1–3), N2 (≥4).Results: Of 341 patients with localized PC who received neoadjuvant therapy and surgery, 107 (31%) received chemoradiation alone, 44 (13%) received chemotherapy alone, and 190 (56%) received chemotherapy and chemoradiation. Histopathologic response consisted of 15 (4%) CRs, 59 (17%) nCRs, 188 (55%) PRs, and 79 (23%) NRs. Patients who received chemotherapy alone had the worst responses (n = 21 for NR, 48%) as compared to patients who received chemoradiation alone (n = 25 for NR, 24%) or patients who received both therapies (n = 33 for NR, 17%) (Table 1; p = 0.001). Median overall survival for all 341 patients was 39 months; OS by histopathologic subtype was not reached (CR), 49 months (nCR), 38 months (PR), and 34 months (NR), respectively (p = 0.004). Of the 341 patients, 208 (61%) had N0 disease, 97 (28%) had N1 disease, and 36 (11%) had N2 disease. In an adjusted hazards model, modified Ryan score of PR or NR (HR: 1.71; 95% CI: 1.15–2.54; p = 0.008) and N1 (HR: 1.42; 95% CI: 1.1.02–2.01; p = 0.04), or N2 disease (HR: 2.54, 95% CI: 1.64–3.93; p < 0.001) were associated with increased risk of death.Conclusions: Neoadjuvant chemotherapy alone is associated with lower rates of pathologic response. Patients with CR or nCR have a significantly improved OS as compared to patients with PR or NR. Nodal status is the most important pathologic prognostic factor. Neoadjuvant chemoradiation may be an important driver of pathologic response.

PURPOSE: To investigate the feasibility of using apparent diffusion coefficient (ADC) to assesspathological treatment response in pancreatic ductal adenocarcinoma (PDAC) following neoadjuvant chemoradiation (nCR). MATERIALS/METHODS: MRI and pathological data collected for 25patients with resectable and borderline resectable PDAC following nCR were retrospectively analyzed. Pre- and post-nCR mean ADC values in the tumors were compared using Wilcoxon matched pairs test. Correlation of pathological treatment response and ADC values was assessed using Pearson’s correlation coefficient test and receiver-operating-curve (ROC) analysis. RESULTS: The average mean and standard deviation (SD) of the ADC values for all the patients analyzed were significantly higher in post-nCR (1.667±0.161×10-3) compared with those prior to nCR (1.395±0.136×10-3 mm2/sec), (P