Virological and Parasitological Characterization of Mini-LEWE Minipigs Using Improved Screening Methods and an Overview of Data on Various Minipig Breeds

Minipigs play an important role in biomedical research and have also been used as donor animals in xenotransplantation. To serve as a donor in xenotransplantation, the animals must be free of potential zoonotic viruses, bacteria and parasites. Porcine endogenous retroviruses (PERVs) are integrated in the genome of all pigs and cannot be eliminated as most of the other pig viruses can. PERV-A and PERV-B infect human cells in cell culture and are integrated in all pigs, whereas PERV-C infects only pig cells and it is found in many, but not all pigs. Minipigs are known for a high prevalence of recombinant PERV-A/C viruses able to infect human cells (Denner and Schuurman, Viruses, 2021;13:1869). Here, Mini-LEWE minipigs are screened for the first time for pig viruses including PERV. Peripheral blood mononuclear cells (PBMCs) from 10 animals were screened using PCR-based methods (PCR, RT-PCR, and real-time PCR). In comparison with our previous screening assays, numerous improvements were introduced, e.g., the usage of gene blocks as a PCR standard and foreign RNA to control reverse transcription in RT-PCR. Using these improved detection methods, Mini-LEWE pigs were found to be negative for porcine cytomegalovirus (PCMV), porcine lymphotropic herpesviruses (PLHV-1, -2 and -3), porcine circoviruses (PCV1, 2, 3 and 4), porcine parvovirus (PPV) and hepatitis E virus (HEV). All animals carried PERV-A, PERV-B and PERV-C in their genome. PERV-A/C was not found. In contrast to all other minipig breeds (Göttingen minipigs, Aachen minipigs, Yucatan micropig, Massachusetts General Hospital miniature pigs), Mini-LEWE minipigs have less viruses and no PERV-A/C. Parasitological screening showed that none of the Mini-LEWE minipigs harbored ecto- and gastrointestinal parasites, but at least one animal tested positive for anti-Toxoplasma gondii antibodies.

Pre- and post-treatment image-based dosimetry in 90Y-microsphere radioembolization using the TOPAS Monte Carlo toolkit

Objective: To evaluate the pre-treatment and post-treatment imaging-based dosimetry of patients treated with 90Y-microspheres, including accurate estimations of dose to tumor, healthy liver and lung. To do so, the Monte Carlo (MC) TOPAS platform is in this work extended towards its utilization in radionuclide therapy. Approach: Five patients treated at the Massachusetts General Hospital were selected for this study. All patients had data for both pre-treatment SPECT-CT imaging using 99mTc-MAA as a surrogate of the 90Y-microspheres treatment and SPECT-CT imaging immediately after the 90Y activity administration. Pre- and post-treatment doses were computed with TOPAS using the SPECT images to localize the source positions and the CT images to account for tissue inhomoegeneities. We compared our results with analytical calculations following the voxel-based MIRD scheme. Main results: TOPAS results largely agreed with the MIRD-based calculations in soft tissue regions: the average difference in mean dose to the liver was 0.14 Gy/GBq (2.6%). However, dose distributions in the lung differed considerably: absolute differences in mean doses to the lung ranged from 1.2 Gy/GBq to 6.3 Gy/GBq and relative differences from 153% to 231%. We also found large differences in the intra-hepatic dose distributions between pre- and post-treatment imaging, but only limited differences in the pulmonary dose. Significance: Doses to lung were found to be higher using TOPAS with respect to analytical calculations which may significantly underestimate dose to the lung, suggesting the use of MC methods for 90Y dosimetry. According to our results, pre-treatment imaging may still be representative of dose to lung in these treatments.

Methodology for Low-Field, Portable Magnetic Resonance Neuroimaging at the Bedside

Neuroimaging is a critical component of triage and treatment for patients who present with neuropathology. Magnetic resonance imaging and non-contrast computed tomography are the gold standard for diagnosis and prognostication of patients with acute brain injuries. However, these modalities require intra-hospital transport to strict, access-controlled environments, which puts critically ill patients at risk for complications and secondary injuries. A novel, portable MRI (pMRI) device that can be deployed at the patient's bedside provides a needed solution. In a dual-center investigation, Yale New Haven Hospital has obtained regular neuroimaging on patients using the pMRI as part of routine clinical care in the Emergency Department and Intensive Care Unit (ICU) since August of 2020. Massachusetts General Hospital has begun using pMRI in the Neuroscience Intensive Care Unit since January 2021. This technology has expanded the population of patients who can receive MRI imaging by increasing accessibility and timeliness for scan completion by eliminating the need for transport and increasing the potential for serial monitoring. Here we describe our methods for screening, coordinating, and executing pMRI exams and provide further detail on how to scan specific patient populations.

Effect of electro-acupuncture on ovarian function of women with diminished ovarian reserve: study protocol for a randomized controlled trial

Background Diminished ovarian reserve (DOR) is the precursor state of ovarian failure and can cause the decline of women’s reproductive function. DOR also leads to poor outcome of in vitro fertilization and embryo transfer (IVF-ET) by affecting the oocytes, high qualified embryo rate, pregnancy rate, etc. Some studies have demonstrated that acupuncture can improve ovarian function. But to date, there is limited evidence indicating that acupuncture or electro-acupuncture is efficient to DOR. This trial aims to evaluate the efficiency and safety of electro-acupuncture for the ovarian function and the following outcome of IVF-ET in DOR patients. Methods This will be a multicenter randomized controlled clinical trial. A total of more than 338 women with DOR will be randomly allocated to treatment and control groups in 1:1 ratio receiving acupuncture before undergoing IVF-ET. The primary outcome will be the clinical pregnancy rate per cycle of IVF-ET after acupuncture. The secondary outcomes will be ovarian reserve function, outcomes of IVT-ET, blood biochemical index, Massachusetts General Hospital Acupuncture Sensation Scale (MASS), scores from the self-rating anxiety and depression scale, quality of life, and pregnancy outcomes. The safety of acupuncture will also be assessed. Discussion The results of this trial may provide high-quality evidence regarding the effectiveness of electro-acupuncture in the treatment of DOR and following outcomes of IVF-ET. This will also help patients with DOR and their physicians by offering a new treatment option. Trial registration Chinese Clinical Trial Registry ChiCTR1900024626. Registered on 19 July 2019.

Multi-Institutional Validation of a Mammography-Based Breast Cancer Risk Model

PURPOSE Accurate risk assessment is essential for the success of population screening programs in breast cancer. Models with high sensitivity and specificity would enable programs to target more elaborate screening efforts to high-risk populations, while minimizing overtreatment for the rest. Artificial intelligence (AI)-based risk models have demonstrated a significant advance over risk models used today in clinical practice. However, the responsible deployment of novel AI requires careful validation across diverse populations. To this end, we validate our AI-based model, Mirai, across globally diverse screening populations. METHODS We collected screening mammograms and pathology-confirmed breast cancer outcomes from Massachusetts General Hospital, USA; Novant, USA; Emory, USA; Maccabi-Assuta, Israel; Karolinska, Sweden; Chang Gung Memorial Hospital, Taiwan; and Barretos, Brazil. We evaluated Uno's concordance-index for Mirai in predicting risk of breast cancer at one to five years from the mammogram. RESULTS A total of 128,793 mammograms from 62,185 patients were collected across the seven sites, of which 3,815 were followed by a cancer diagnosis within 5 years. Mirai obtained concordance indices of 0.75 (95% CI, 0.72 to 0.78), 0.75 (95% CI, 0.70 to 0.80), 0.77 (95% CI, 0.75 to 0.79), 0.77 (95% CI, 0.73 to 0.81), 0.81 (95% CI, 0.79 to 0.82), 0.79 (95% CI, 0.76 to 0.83), and 0.84 (95% CI, 0.81 to 0.88) at Massachusetts General Hospital, Novant, Emory, Maccabi-Assuta, Karolinska, Chang Gung Memorial Hospital, and Barretos, respectively. CONCLUSION Mirai, a mammography-based risk model, maintained its accuracy across globally diverse test sets from seven hospitals across five countries. This is the broadest validation to date of an AI-based breast cancer model and suggests that the technology can offer broad and equitable improvements in care.

Effect modification by age of the association between obstructive lung diseases, smoking, and COVID-19 severity

IntroductionObstructive lung diseases (asthma and chronic obstructive pulmonary disease (COPD)) and smoking are associated with greater risk of respiratory infections and hospitalisations, but conflicting data exist regarding their association with severity of COVID-19, and few studies have evaluated whether these associations differ by age.ObjectivesTo examine the associations between asthma, COPD and smoking on the severity of COVID-19 among a cohort of hospitalised patients, and to test for effect modification by age.MethodsWe performed a retrospective analysis of electronic health record data of patients admitted to Massachusetts General Hospital, assigning the maximal WHO Clinical Progression Scale score for each patient during the first 28 days following hospital admission. Using ordered logistic regression, we measured the association between maximal severity score and asthma, COPD and smoking and their interaction with age.Measurements and main resultsAmong 1391 patients hospitalised with COVID-19, we found an increased risk of severe disease among patients with COPD and prior smoking, independent of age. We also found evidence of effect modification by age with asthma and current smoking; in particular, asthma was associated with decreased COVID-19 severity among older adults, and current smoking was associated with decreased severity among younger patients.ConclusionsThis cohort study identifies age as a modifying factor for the association between asthma and smoking on severity of COVID-19. Our findings highlight the complexities of determining risk factors for COVID-19 severity, and suggest that the effect of risk factors may vary across the age spectrum.

Evaluation of direct oral anticoagulant use for cancer-associated venous thromboembolism (VTE) in lung cancer.

243 Background: National Comprehensive Cancer Network recommends direct oral anticoagulants (DOACs) as preferred agents for treatment of cancer associated VTE in patients without gastric or gastroesophageal lesions. Currently at Massachusetts General hospital (MGH), DOACs are used in treatment of cancer associated VTE. This study was performed to evaluate the safety and efficacy of DOACs for treatment of VTE in patients with metastatic lung cancer. Methods: Retrospective chart review of patients at MGH with diagnosis of metastatic lung cancer who were prescribed edoxaban, rivaroxaban, or apixaban for treatment of VTE between January 2018 and January 2021 was performed. Patients were identified using electronic medical record reports. Data was collected on age, anticoagulation regimen, intent of anticoagulation therapy, presence of brain metastasis, renal function, liver function and platelet counts. The primary outcome was to assess the incidence of treatment failure, defined as VTE recurrence or major bleeding leading to a change in anticoagulation therapy. Results: 152 patients were evaluated, of which 57 received apixaban, 44 rivaroxaban, and 7 edoxaban. Most (n = 93) patients received enoxaparin for 14-90 days prior to transitioning to DOACs. Median age and creatinine clearance were 69 years and 63 mL/min, respectively. All patients had platelet count ≥ 50K/uL. Brain metastasis was present in n = 39 patients. Pulmonary embolism (PE)(n = 98), deep vein thrombosis (DVT) (n = 52), or both (n = 2) were the indication for DOAC therapy. Bleeding occurred in 14 patients including gastrointestinal bleeding (n = 5), hematuria (n = 4), epistaxis (n = 1), and hemoptysis (n = 4). Among patients with bleeding events, 7 received rivaroxaban and 7 received apixaban. Major recurrent VTE while on DOACs occurred in 5 of patients, including DVT (n = 2) and PE (n = 3). Patients with recurrent VTE received rivaroxaban (n = 7), apixaban (n = 3) and edoxaban (n = 1). All patient whom experienced bleeding and VTE were ≥ 60 years old. Brain metastasis was present in n = 2 of patients with bleeding events and n = 2 patients with recurrent VTE. Majority of patients (n = 93) received enoxaparin for 14-90 days prior to transitioning to DOACs. The median interval between initiation of DOACs and bleeding was 60 days (range 30-365) and recurrent VTE event was 90 days (range 60‐365). Conclusions: The results of this study suggest that outcomes of DOAC use for the treatment of cancer-associated VTE in patients with metastatic lung cancer are comparable to the results of large randomized controlled trials. DOAC therapy is a safe and effective anticoagulation option for lung cancer patients with cancer-associated thromboembolism.

Time burden and logistical intensity of early-phase clinical trials (EP-CTs).

84 Background: EP-CTs are increasingly important options for patients with cancer and often involve intensive monitoring. Thus, characterizing the time burden and logistical intensity of EP-CTs could help patients and clinicians make informed decisions regarding trial participation. Methods: We retrospectively reviewed the electronic health records of consecutive patients enrolled in EP-CTs at Massachusetts General Hospital from 2017-2019 to obtain baseline characteristics (demographics and clinical factors), EP-CT investigational agent (immunomodulatory therapy [IM], targeted inhibitor(s) [TI], antibody drug conjugate [ADC]/chemotherapy prodrug), and logistical intensity (trial visit frequency, presence of extended visits, distance traveled in one direction from home zip code to trial site). We defined visit frequency as the number of visits per protocol within the first 28 days on trial. We defined an extended visit as six or more hours in clinic on at least one day during the first 28 days on study. We investigated associations among patient characteristics, investigational agent, and logistical intensity. Results: Among 421 patients (median age=60.6 years, 55.8% female, 97.4% metastatic disease), most (73.6%) had two or more sites of metastatic disease. EP-CTs included 43.2% IM, 43.0% TI, and 13.8% ADC/chemotherapy prodrug. Patients enrolled in ADC/prodrug trials had the highest burden of metastatic disease (mean sites: 2.8 [ADC] vs 2.4 [TI] vs 2.3 [IM], p = 0.007) and oldest age (mean years: 64.0 [ADC] vs 61.7 [IM] vs 58.5 [TI], p = 0.003). Patients enrolled on TI trials had the highest visit frequency compared with those enrolled on other trials (mean visits: 5.5 [TI] vs 5.3 [ADC] vs 5.0 [IM], p = 0.027) and the fewest days spent on trial (mean days: 78.3 [TI] vs 102.2 [IM] vs 131.8 [ADC], p = 0.003). Patients enrolled on TI trials were also most likely to have an extended visit (82.3% [TI] vs 58.2% [IM] vs 29.3% [ADC], p < 0.001) and least likely to receive first in human therapy (38.1% [TI] vs 74.1% [ADC] vs 74.2% [IM], p < 0.001). Distance traveled from home to clinic did not significantly differ across trial type (median miles traveled: 35.1 [TI] vs 34.1 [IM] vs 33.2 [ADC], p = 0.884). Conclusions: In this cohort of patients participating in EP-CTs, we found that a plurality enrolled in IM studies. Those receiving ADC/prodrug regimens were older and had a higher burden of disease. On average, patients participating in EP-CTs had over five visits in the first month, with those enrolled on TI trials having the highest visit frequency and greatest likelihood of extended visits. Patients on TI trials also spent the fewest total days on trial. Despite the lack of significant differences in distance traveled, most patients were still traveling over 30 miles to get to the trial site. These data highlight the time burden and logistical intensity of various EP-CTs, which may help inform patient-clinician discussions about trial participation.