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Modern zoos are committed to environmental education and thus have a mandate to inform the public about biodiversity and conservation. Historically, zoos have avoided complex topics like biodiversity loss from overpopulation and overconsumption in their educational materials, for fear of being offensive or creating a sense of hopelessness. To measure visitor attitudes towards educating about such topics and to help determine effective presentation techniques, we assessed people's knowledge of and attitudes towards the commercial hunting and consumption of wildlife in West and Central Africa (the bushmeat crisis) and examined how the use of different types of images affected these variables. Zoo visitors were exposed to one of six series of photographs, each accompanied by the same text. Photos in three of the series contained explicit, disturbing images of dead animals. The other three series presented benign images related to the bushmeat crisis (i.e., logging, changes in hunting practices). While 83 percent of visitors had never heard of the bushmeat trade, 98 percent felt zoos should be educating about the topic. Ninety-seven percent felt the disturbing images were appropriate for zoo visitors except for children under the age of 12. While people spent significantly more time looking at the disturbing images, this did not lead to increases in knowledge (factual or conservation-related) on the topic. However, visitors who saw the disturbing images were significantly more likely to report being influenced by the images. While the type of image did not affect the frequency of conservation-related behaviors, significantly more people engaged in a conservation-related behavior when an opportunity was provided on-site rather than off-site. The results demonstrate that the public believes zoos should educate about bushmeat, and that realistic images influence people's perception of an issue. However, visitors' lack of knowledge gains, even when disturbing images are used, suggests that a static displays of text with photographs may not be the most effective method for educating about complex issues like bushmeat. Finally, the results show that zoos should provide on-site opportunities for people to turn their conservation interests into action. [ABSTRACT FROM AUTHOR]

Background: CD8+ tumor-infiltrating lymphocyte (TIL) predicts response to anti-PD-(L)1 therapy. However, there remains no standardized method to assess CD8+ TIL in melanoma, and developing a specific, cost-effective, reproducible, and clinically actionable biomarker to anti-PD-(L)1 remains elusive. We report on the development of automatic CD8+ TIL density quantification via whole slide image (WSI) analysis in advanced melanoma patients treated with front-line anti-PD-1 blockade, and correlation immunotherapy response., Methods: Seventy-eight patients treated with PD-1 inhibitors in the front-line setting between January 2015 and May 2023 at the University of Pittsburgh Cancer Institute were included. CD8+ TIL density was quantified using an image analysis algorithm on digitized WSI. Targeted next-generation sequencing (NGS) was performed to determine tumor mutation burden (TMB) in a subset of 62 patients. ROC curves were used to determine biomarker cutoffs and response to therapy. Correlation between CD8+ TIL density and TMB cutoffs and response to therapy was studied., Results: Higher CD8+ TIL density was significantly associated with improved response to front-line anti-PD-1 across all time points measured. CD8+ TIL density ≥222.9 cells/mm2 reliably segregated responders and non-responders to front-line anti-PD-1 therapy regardless of when response was measured. In a multivariate analysis, patients with CD8+ TIL density exceeding cutoff had significantly improved PFS with a trend toward improved OS. Similarly, increasing TMB was associated with improved response to anti-PD-1, and a cutoff of 14.70 Mut/Mb was associated with improved odds of response. The correlation between TMB and CD8+ TIL density was low, suggesting that each represented independent predictive biomarkers of response., Conclusions: An automatic digital analysis algorithm provides a standardized method to quantify CD8+ TIL density, which predicts response to front-line anti-PD-1 therapy. CD8+ TIL density and TMB are independent predictors of response to anti-PD-1 blockade., (© The Author(s) 2024. Published by Oxford University Press.)

The gut microbiome acts as a tumor-extrinsic regulator of responses to immune-checkpoint inhibitors (ICIs) targeting PD-1 and CTLA-4 receptors. Primary resistance to anti-PD-1 ICI can be reversed via responder-derived fecal microbiota transplant (FMT) in patients with refractory melanoma. Efforts to create stool banks for FMT have proved difficult. Therefore, we aimed to establish a novel donor-screening program to generate responder-derived FMT for use in PD-1 refractory melanoma. Candidate PD-1 responder donors and PD-1 refractory recipients were recruited via clinic-based encounters at the University of Pittsburgh Medical Center hospitals. Eligible donors and recipients underwent physician assessment and screening of serum, stool and nasopharynx for transmissible agents, which included SARS-CoV-2 modification. The cost of donor and recipient screening was calculated. Initially, 29 donors were screened with 14 eligible donors identified after exclusion; of the 14 donors, eight were utilized in clinical trials. The overall efficiency of screening was 48%. Seroprevalence rates for cytomegalovirus, Epstein-Barr virus, HSV-2, HHV-6, HTLV-1, HTLV-2, and syphilis were similar to published statistics from healthy blood donors in the USA. Donor stool studies indicated a 3.6% incidence of E. histolytica and norovirus, 3.7% incidence of giardia and 7.1% incidence of C. difficile. A single donor tested positive for SARS-CoV-2 in stool only. The cost for finding a single eligible donor was $2260.24 (pre-COVID) and $2,460.24 (post-COVID). The observed screening efficiency suggests that a well-resourced screening program can generate sufficient responder-derived donor material for clinical trial purposes. Eliminating testing for low-prevalence organisms may improve cost-effectiveness., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Anti-PD-1 immune checkpoint inhibitor (ICI) therapy has revolutionized the treatment of melanoma by producing durable long-term responses in a subset of patients. ICI-treated patients develop unique toxicities - immune related adverse events (irAEs) - that arise from unrestrained immune activation. The link between irAE development and clinical outcome in melanoma and other cancers is inconsistent; and little data exists on the occurrence of multiple irAEs. We sought to characterize development of single and multiple irAEs, and association of irAE(s) development with clinical variables and impact upon outcomes in advanced melanoma patients treated with anti-PD-1 ICIs., Methods: We conducted a retrospective study of 190 patients with metastatic melanoma treated with single-agent anti-PD-1 ICI therapy between June 2014 and August 2020 at a large integrated network cancer center identified through retrospective review of pharmacy records. irAEs were graded based on the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0., Results: 190 patients were evaluated of whom 114 patients (60.0%) experienced ≥1 irAE, including 30 (15.8%) with grade 3/4 irAEs. The occurrence of any irAE was strongly associated with the development of investigator-assessed response to anti-PD-1 therapy (p < 0.0001); whether evaluated by current (p=0.0082) or best (p=0.0001) response. In patients with ≥2 irAEs, distinct patterns were observed. Median progression-free survival (PFS) and overall survival (OS) were greater in those with any irAE compared to those without (PFS, 28 months vs . 5 months, p < 0.0001; OS, not reached vs . 9 months, p < 0.0001). Development of ≥2 irAEs had a trend towards improved PFS and OS compared to those who developed a single irAE, although this did not reach statistical significance (p=0.2555, PFS; p=0.0583, OS). Obesity but not age or gender was distinctly associated with irAE development., Conclusions: In this study, we demonstrated that irAE occurrence was significantly associated with response to anti-PD-1 therapy and improved PFS/OS. Those who developed multiple irAEs had a trend towards improved PFS and OS compared to those who developed only a single irAE. Increased BMI but neither age nor gender were associated with irAE development. Distinct patterns of irAEs observed suggest shared etiopathogenetic mechanisms., Competing Interests: YN: Research Funding (Merck, Pfizer, and Bristol-Myers Squibb). JL: Stock and Other Ownership Interests (RefleXion); Consulting/Advisory Role (7 Hills, Abbvie, Alnylam, Actym, Alphamab Oncology, Arch Oncology, Array, Bayer, Bristol-Myers Squibb, Checkmate Pharmaceuticals, Cstone, Eisai, EMD Serono, Flame,Fstar, Gilead, Kadmon, KSQ, Knaph, Janssen, Immunocore, Inzen, Macrogenics,Mavu, Merck, Mersana, Nektar, Novartis, Onc.AI, Pfizer, Pyxis, Regeneron, Ribon, Rubius, Silicon, Synlogic, TRex, Tempest, Werewolf, Xilio, Xencor); Research Funding (AbbVie, Agios, Array, Astellas, Bristol-Myers Squibb, Corvus, EMD Serono, Genmab, Ikena, Immatics, Incyte, Kadmon, KAHR, MAcrogenics, Merck, Moderna, Nektar, Numab, Replimmune, Rubius, Spring Bank, Synlogic, Takeda, Trishula, Tizona, Xencor). JK: Consulting/Advisory Role (Amgen, Bristol-Myers Squibb, Checkmate Pharmaceuticals, and Novartis); Research Funding (Amgen, Bristol-Myers Squibb, Castle Biosciences, Checkmate Pharmaceuticals, Immunocore LLC, Iovance, and Novartis). HZ: Consulting/Advisory Role (Bristol Myers Squibb, Checkmate Pharmaceuticals, GlaxoSmithKline/Tesaro and Vedanta Biosciences); Research Funding (Bristol Myers Squibb, Checkmate Pharmaceuticals, and GlaxoSmithKline/Tesaro). DD: Consulting/Advisory Role (Ascendis Pharma, Bristol Myers Squibb, Checkmate Pharmaceuticals, Shionogi, Vedanta Biosciences); Research Funding (Arcus, Checkmate Pharmaceuticals, Cellsight Technologies, GlaxoSmithKline/Tesaro, Merck Inc.). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Bastacky, Wang, Fortman, Rahman, Mascara, Brenner, Najjar, Luke, Kirkwood, Zarour and Davar.)

Newly synthesized Tc-99m dichlorobis(1,2-dimethylphosphino)ethane (DMPE) was investigated as a myocardial imaging agent with respect to its kinetics (dependent on both time and regional coronary blood flow), its percent organ uptake, and its imaging characteristics in the anesthetized dog. Most of these data are compared with those of Tl-201. Blood clearance of the two agents is essentially the same. Compared with Tl-201, Tc-99m DMPE shows faster overall kinetics, higher heart-to-lung ratio, equally good correlation with a wide range of regional blood flows, and higher liver uptake. At the time of peak myocardial uptake, the mean heart uptake of Tl-201 is 4.3%, compared with 2.9% for Tc-99m DMPE, yet only 0.9% uptake of Tc-99m DMPE is found in the lung as compared with 3.3% for Tl-201. These differences result in a heart-to-lung ratio of 2:1 for Tc-99m DMPE and 1:1 for Tl-201, based on the data obtained from the time-activity curve. The quantitative findings are supported by the superior quality of Tc-99m DMPE images of both normal and infarcted dog heart. The high hepatic uptake of Tc-99m DMPE is not a serious problem if images are obtained within 5-60 min after dose. These basic kinetic studies suggest that Tc-99m DMPE is a promising myocardial imaging agent.

After intravenous administration of Tc-99m DMPE the flow-dependent kinetics were studied in dogs during induced ischemia and during induced maximal reactive hyperemia. A control group was also studied. Mean time-activity curves obtained from the myocardial wall were compared within the same intervention group and also with other groups. During reactive hyperemia, there was a rapid and absolute increase in uptake followed by a rapid washout, whereas during ischemia there was a slow and decreased uptake followed by a slow washout. The magnitude of Tc-99m DMPE uptake during reactive hyperemia was slightly less than that of Tl-201, but the decreased uptake with ischemia was about equal for the two agents. Following maximal uptake in the myocardium the effective half-life of Tc-99m DMPE was one-third to one-fourth that of Tl-201. The similar kinetics of Tc-99m DMPE compared to Tl-201 suggests its usefulness in the evaluation of ischemic heart disease.

The cationic technetium-99 complex trans-[99TC(dmpe)2Cl2]+, where dmpe is bis(1,2-dimethylphosphino)ethane or (CH3)2P-CH2-P(CH3)2, has been prepared and characterized by single-crystal, x-ray structural analysis. The technetium-99m analog, trans-(99mTc(dmpe) 2Cl2]+, has also been prepared and shown to yield excellent gamma-ray images of the heart. The purposeful design, characterization, and synthesis of this technetium-99m radiopharmaceutical represents a striking application of fundamental inorganic chemistry to a problem in applied nuclear medicine.

All first metatarsophalangeal joint implants used at Sheridan Park Hospital from 1979 through 1984 were evaluated for postoperative infection and subsequent implant removal. Thirteen (1.3%) of 929 implants used were removed due to infection. Antibiotic prophylaxis was not determined to be necessary to avoid this complication. However, in all cases in which prophylaxis was used, no infection occurred.

Thallium-201, injected as thallous chloride, has been found to adhere to or be taken up by the vein into which it is injected, permitting images to be obtained of human veins up to 4 h following injection. A digoxin-insensitive rat vein model also retained 201Tl but for shorter periods of time. 201Tl uptake is independent of the solution into which it is introduced, whether 5% dextrose or 0.9% sodium chloride. This technique permits multiple delayed views of normal veins to be obtained but is of uncertain value in the evaluation of thrombophlebitis of the calf because of rather poor resolution and high cost.

Technetium-99m DMPE (99mTc-DMPE) is a newly synthesized myocardial perfusion imaging agent that shows intense myocardial accumulation in the dog. In the present study, dosimetry and potential clinical usefulness of this agent were assessed in four human subjects. Absorbed radiation doses were low, with the highest doses consisting of 200 mrad/mCi (54 microGy/MBq) to the gallbladder and 160 mrad/mCi (43 microGy/MBq) to the liver. No evidence of clinical toxicity was found. Technetium-99m DMPE did image the myocardium, but the ratio of target to nontarget activity was less favorable than that observed in the dog. Intense hepatic 99mTc-DMPE activity interfered with clinical imaging of the cardiac apex in two of the four subjects. We conclude that the prototype radiopharmaceutical, 99mTc-DMPE, is capable of myocardial perfusion imaging in man but the planar myocardial images produced are of inferior quality compared with 201Tl myocardial images. Further work is justified to develop related compounds to overcome the clinical limitations described.