Post-pandemic Recommendations: COVID-19 Continuity of Court Operations During a Public Health Emergency Workgroup

In this report, the COVID-19 Continuity of Court Operations During a Public Health Emergency Workgroup (Plan B Workgroup) makes recommendations about best practices and technologies that should be retained or adapted post-pandemic. The recommendations in this final Plan B Workgroup whitepaper are based on experience and feedback from Arizona’s courts addressing pandemic and post-pandemic practices. Although the original report, issued on June 2, 2021, included a May 2021 Survey of Arizona’s Courts, this updated report also includes information from a July 2021 State Bar of Arizona Survey and a September 2021 State of Arizona Public Opinion Survey addressing those practices. The workgroup’s findings and recommendations, which remain unchanged, can be summarized in five major categories: (1) Increasing Access to Justice, (2) Expanding Use of Technology, (3) Jury and Trial Management, (4) Communication Strategies and Disaster Preparedness, and (5) Health, Safety, and Security Protocols.

The Jewish Coins at Dura-Europos

The synagogue at Dura-Europos is undoubtedly the most prominent of the Jewish remains uncovered at the site. Dozens of Jewish coins found in excavations throughout the city have merited far less attention. Alfred Bellinger published a list of these coins in 1949; among the corpus of 14,017 coins found altogether at the site, 47 were identified as coins minted in Judea by Jewish rulers. This study offers the first comprehensive presentation and analysis of these Jewish coins. Following a review and analysis of the limited data on all 47 Jewish coins published in the original report, a full report is presented for the six coins from the Dura collection which are currently housed at the Yale University Art Gallery. This is followed by a discussion about the possible reasons why such a large assemblage of Jewish coins found its way in antiquity from Judea to distant Dura-Europos.

The Melt Enthalpy of Pu6Fe

Schwartz, et al., previously reported calorimetry measurements conducted on a Pu-Pu6Fe mixture, from which they derived a melt enthalpy of 31.2 J/g (46.6 kJ/mol) for Pu6Fe. This was the first—and remains the only—such value to appear in the literature. We reanalyze those results in light of two contributions to the measured heat flow not considered in the original report: the melt enthalpy of the excess Pu and the subsequent heating of the liquid mixture. These corrections yield a revised value of 24.4 J/g (36.3 kJ/mol), which we show to be consistent with the melt enthalpy of U6Fe.

Long-term outcomes in severe aplastic anemia patients treated with immunosuppression and eltrombopag: a phase 2 study

Patients with severe aplastic anemia (SAA) are either treated with bone marrow transplant (BMT) or immunosuppression (IST) depending on their age, comorbidities, and available donors. In 2017, our phase 2 trial reported improved hematologic responses with the addition of eltrombopag (EPAG) to standard IST for SAA when compared to a historical cohort treated with IST alone. However, the rates and characteristics of long-term complications, relapse, and clonal evolution, previously described in patients treated with IST alone are not yet known with this new regimen, IST and EPAG. Patients were accrued from 2012 to 2020 with a total of 178 subjects included in this secondary endpoint analysis. With double the sample size and a much longer median follow-up (4 years) since the original report in 2017, we report a cumulative relapse rate of 39% in responding patients who received CSA maintenance, and clonal evolution of 15% in all treated patients at 4 years. Relapse occurred at distinct timepoints: after cyclosporine dose reduction and EPAG discontinuation at six months, and after two years when cyclosporine was discontinued. Most relapsed patients were retreated with therapeutic doses of cyclosporine +/- EPAG, and two-thirds responded. Clonal evolution to a myeloid malignancy or chromosome 7 abnormality (high-risk) was noted in 5.7% of patients and conferred a poorer overall survival. Neither relapse nor high-risk evolution occurred at a higher rate than was observed in a historical comparator cohort but the median time to both events were earlier in IST and EPAG treated patients. Trial registered in clinicaltrials.gov (NCT01623167).

Supratentorial non-RELA, ZFTA-fused ependymomas: a comprehensive phenotype genotype correlation highlighting the number of zinc fingers in ZFTA-NCOA1/2 fusions

The cIMPACT-NOW Update 7 has replaced the WHO nosology of “ependymoma, RELA fusion positive” by “Supratentorial-ependymoma, C11orf95-fusion positive”. This modification reinforces the idea that supratentorial-ependymomas exhibiting fusion that implicates the C11orf95 (now called ZFTA) gene with or without the RELA gene, represent the same histomolecular entity. A hot off the press molecular study has identified distinct clusters of the DNA methylation class of ZFTA fusion-positive tumors. Interestingly, clusters 2 and 4 comprised tumors of different morphologies, with various ZFTA fusions without involvement of RELA. In this paper, we present a detailed series of thirteen cases of non-RELA ZFTA-fused supratentorial tumors with extensive clinical, radiological, histopathological, immunohistochemical, genetic and epigenetic (DNA methylation profiling) characterization. Contrary to the age of onset and MRI aspects similar to RELA fusion-positive EPN, we noted significant histopathological heterogeneity (pleomorphic xanthoastrocytoma-like, astroblastoma-like, ependymoma-like, and even sarcoma-like patterns) in this cohort. Immunophenotypically, these NFκB immunonegative tumors expressed GFAP variably, but EMA constantly and L1CAM frequently. Different gene partners were fused with ZFTA: NCOA1/2, MAML2 and for the first time MN1. These tumors had epigenetic homologies within the DNA methylation class of ependymomas-RELA and were classified as satellite clusters 2 and 4. Cluster 2 (n = 9) corresponded to tumors with classic ependymal histological features (n = 4) but also had astroblastic features (n = 5). Various types of ZFTA fusions were associated with cluster 2, but as in the original report, ZFTA:MAML2 fusion was frequent. Cluster 4 was enriched with sarcoma-like tumors. Moreover, we reported a novel anatomy of three ZFTA:NCOA1/2 fusions with only 1 ZFTA zinc finger domain in the putative fusion protein, whereas all previously reported non-RELA ZFTA fusions have 4 ZFTA zinc fingers. All three cases presented a sarcoma-like morphology. This genotype/phenotype association requires further studies for confirmation. Our series is the first to extensively characterize this new subset of supratentorial ZFTA-fused ependymomas and highlights the usefulness of ZFTA FISH analysis to confirm the existence of a rearrangement without RELA abnormality.

Unraveling the Wide Spectrum of Melanoma Biomarkers

The use of biomarkers in medicine has become essential in clinical practice in order to help with diagnosis, prognostication and prediction of treatment response. Since Alexander Breslow’s original report on “melanoma and prognostic values of thickness”, providing the first biomarker for melanoma, many promising new biomarkers have followed. These include serum markers, such as lactate dehydrogenase and S100 calcium-binding protein B. However, as our understanding of the DNA mutational profile progresses, new gene targets and proteins have been identified. These include point mutations, such as mutations of the BRAF gene and tumour suppressor gene tP53. At present, only a small number of the available biomarkers are being utilised, but this may soon change as more studies are published. The aim of this article is to provide a comprehensive review of melanoma biomarkers and their utility for current and, potentially, future clinical practice.

Ianula (1970) revisited. Lessons from a pioneering study

More than fifty years ago, G.E. Hutchinson published “Ianula: an account of the history and development of the Lago di Monterosi, Latium, Italy”, a detailed report of one of the first multi-disciplinary palaeolimnological studies. The main result of that study was that the last Glacial climate in peninsular Italy was not only cold but also dry, in contrast with the assumption prevalent at that time of wet "pluvials" in Glacial stages of the northern Mediterranean. These finding were confirmed by more recent studies on other volcanic lakes in Italy. Furthermore, the authors found a major change in ecosystem structure and concluded that it was caused by the building of a road in Roman time. Comparing Monterosi pollen profile with those obtained from cores in other lakes in Central Italy and in the Adriatic Sea, I suggest an alternative hypothesis linking the dramatic environmental change recorded to soil development during forest onset at the beginning of the Holocene. The original report made available a large share of the data set, as a pioneering example of Open Data, allowing a re-examination of the results and the formulation of new hypotheses, underlying the importance of open data in environmental science.

P–014 Effect of microsurgical varicocelectomy on fertility outcome and treatment plans of patients with severe oligozoospermia: An original report and meta-analysis

Study question Does microsurgical subinguinal varicocelectomy (MSV) improve semen parameters and fertility outcomes of patients with severe oligozoospermia (SO) and clinical varicocele? Summary answer MSV significantly improves semen parameters of patients with SO and can broaden their fertility treatment options. What is known already: Varicocele ligation has been proven to restore semen parameters and improve pregnancy rates in men with clinically palpable disease. However, its effect in men with SO is less clearly elucidated. Patients with SO are candidates for in vitro fertilization and intracytoplasmic sperm injection. Improvements in semen quality following varicocele ligation in this patient population may broaden their fertility options. While few studies indicate an improvement in semen parameters, reports revealing a negative outcome following surgery in this patient group were also published. Study design, size, duration This original report and meta-analysis examined the impact of MSV on semen parameters and fertility outcomes of men with SO. A retrospective chart review of 85 patients was conducted on patients with SO who underwent MSV. A literature search was carried out according to the PRISMA guidelines using the key words “severe oligozoospermia” and “varicocele”. 8 scientific articles (including the current study) reporting the impact of MSV on men with SO were included. Participants/materials, setting, methods Changes in semen parameters postoperatively were compared with pre-operative results. The reported natural pregnancy rates were also calculated. The Wilcoxon signed-rank test was used to compare semen and hormone values before and after varicocelectomy. The Chi-squared test was used to assess the changes in TMSC groups after surgery. The meta-analysis was performed using comprehensive meta-analysis software (Biostat, Englewood, NJ, USA). Statistical significance was set at α = 0.05. The random-effects model was used to adjust for heterogeneity. Main results and the role of chance The original study reported significant improvements in sperm concentration (p < 0.001), total motility (p = 0.003), progressive motility (p = 0.002) and TMSC (p < 0.001) was following the surgery. in semen parameters following surgery. 78 patients had a pre-operative TMSC < 5 million. Following surgery, 9 (11.5%) patients had a TMSC between 5–9 million, while 14 (17.9%) patients had a TMSC > 9 million. The meta-analysis shows a statistically significant increase in sperm count following surgery (MD 5.64, 95% CI, 4.195–7.090, p = 0.00) with an acceptable degree of heterogeneity (Q value= 8.75, p = 0.188, I²= 31.5%). Similarly, the total motility significantly increased by 7.77% (p = 0.001) following surgery (95% CI, 3.248–12.297), however, with considerable heterogeneity among the reported results (Q value= 34.4, p < 0.001). TMSC was assessed by three studies, including ours. The meta-analysis shows a significant increase in TMSC following surgery (MD 8.44 million sperm, 95% CI, 4.648–12.228, p < 0.001) (Q Value= 2.53, p = 283, I²=20.7%). A total of 6 studies reported the natural pregnancy rate of patients with SO who underwent surgery. Out of 530 patients with preoperative SO, 146 patients achieved natural pregnancy following surgery indicating that the reported pregnancy rate was 27.5%. Limitations, reasons for caution One limitation to the original study is its relatively small sample size. However, this was compensated by conducting a meta-analysis and reporting the outcome of 601 patients with SO who underwent varicocele ligation. Another limitation is the retrospective nature of the study design. Wider implications of the findings: 29.5% of SO patients in the original study became eligible for IUI following varicocelectomy. Meta-analysis showed that 27.5% of patients achieved natural conception following surgery. Such information is beneficial during patient counselling and needs to be measured against the financial and clinical implications in order to make sound treatment decisions. Trial registration number NA

Variant reclassification and its impact on clinical care in an Asian cancer center.

10583 Background: Genetic testing has demonstrated clinical utility in the identification and subsequent surveillance of patients with cancer predisposition syndromes. However, the increased likelihood of encountering a variant of uncertain significance (VUS) in individuals of non-European descent such as Asians may be challenging to both clinicians and patients in interpretation and management. VUS can be reclassified as more data becomes available. VUS reclassification is important, as it may have implications for surveillance and treatment. This study aims to evaluate the prevalence and patterns of variant reclassification in an Asian country and its impact on patient management. Methods: A prospective cohort of patients seen at the Cancer Genetics Service at the National Cancer Center Singapore between February 2014 to March 2020 was evaluated. The frequency, direction and time to variant reclassification was assessed by comparing the reclassified report against the original report. Results: A total of 1412 VUS were reported in 49.9% (845/1695) of patients. Over six-years, 6.7% (94/1412) of variants were reclassified. Most VUS (94.1%; 80/85) were downgraded to benign/likely benign variant, with a smaller proportion of VUS (5.9%; 5/85) upgraded to pathogenic/likely pathogenic variant. Actionable VUS upgrades and pathogenic/likely pathogenic variant downgrades, that resulted in management changes, happened in 31.0% (39/126) of patients. The median and mean time taken for reclassification were 1 and 1.62 year(s) respectively. Conclusions: Clinicians need to put in place a system for review of variants, as variant reclassification can lead to changes in management in nearly 1/3 of patients. Management should be based on the patient’s personal history, family history and variant interpretation. We propose a clinical guideline to standardize management of patients with VUS. For clinically relevant or suspicious VUS, follow-up is recommended every two years, as actionable reclassifications may happen during this period.