The Holocaust Is a Significant and Independent Risk Factor of Late-Onset Cancers: A Systematic Review of the Literature and Original Data on Jewish Israeli, Jewish Non-Israeli and Non-Jewish Non-Israeli Survivors.

BACKGROUND/AIM: Seventy-six years after Auschwitz Liberation, the Holocaust keeps on persecuting its surviving victims. As witnessed by the psychiatric and medical literature in the last decades, in fact, the Holocaust survivors (HS) appear to suffer from several Shoah-related late-onset diseases impacting their survival, such as internal illnesses and post-traumatic stress disorder (PTSD). Cancer represents a further severe pathology which seems to be connected with the Holocaust experience. Our aim was to review the existing knowledge of Holocaust-related cancer in HS in order to assess its real incidence and clinicoprognostic significance. MATERIALS AND METHODS: We systematically reviewed the literature dealing with Israeli Jewish and non-Jewish non-Israeli HS developing cancer. We also reviewed and analyzed the cancer data of noted Jewish HS not resident or having resided in Israel available as public information. RESULTS: We found 16 and 15 studies on Israeli Jews and non-Jewish non-Israeli survivors, respectively. A statistically significant association between the Holocaust and development of late-onset cancer in HS was seen in most studies with cancer adversely impacting the survival. We also selected 330 noted Jewish non-Israeli HS: genocide-related late-onset cancer resulted to be a significant and independent risk factor of poor prognosis (p<0.0001) imparting shorter survival in affected versus non-cancer subjects (57 versus 64 years, respectively, p=0.0001). CONCLUSION: Although 76 years have passed, our review shows how the Holocaust keeps on burdening its survivors. Moreover, we offered the first analysis of Jewish HS not resident or having resided in Israel in terms of genocide-related late-onset diseases focusing on cancer. Further studies on Jewish non-Israeli HS are needed in order to corroborate our findings on late-onset cancer occurring in this targeted population

Immunogenicity and reactogenicity of modified vaccinia Ankara pre-exposure vaccination against mpox according to previous smallpox vaccine exposure and HIV infection. Prospective cohort study

Background: Pre-exposure vaccination with MVA-BN has been widely used against mpox to contain the 2022 outbreak. Many countries have defined prioritized strategies, administering a single dose to those historically vaccinated for smallpox, to achieve quickly adequate coverage in front of low supplies. Using epidemiological models, real-life effectiveness was estimated at approximately 36%-86%, but no clinical trials were performed. Few data on MVA-BN immunogenicity are currently available, and there are no established correlates of protection. Immunological response in PLWH in the context of the 2022 outbreak was also poorly described. Methods: Blood samples were collected from participants eligible for pre-exposure MVA-BN vaccination before (T1) receiving a full course of vaccine (single-dose for vaccine-experienced or smallpox-primed and two-dose for smallpox vaccine-naïve or smallpox non-primed) and one month after the last dose (T2 and T3, respectively). MPXV-specific IgGs were measured by in-house immunofluorescence assay, using 1:20 as screening dilution, MPXV-specific nAbs by 50% plaque reduction neutralization test (PRNT50, starting dilution 1:10), and IFN-γ-producing specific T cells to MVA-BN vaccine, by ELISpot assay. Paired or unpaired t-test and Wilcoxon or Mann-Whitney test were used to analyse IgG and nAbs, and T-cell response, as appropriate. The probability of IgG and nAb response in vaccine-experienced vs. vaccine-naïve was estimated in participants not reactive at T1. The McNemar test was used to evaluate vaccination's effect on humoral response both overall and by smallpox vaccination history. In participants who were not reactive at T1, the proportion of becoming responders one month after full-cycle completion by exposure groups was compared by logistic regression and then analysed by HIV status strata (interaction test). The response was also examined in continuous, and the Average Treatment Effect (ATE) of the difference from baseline to schedule completion according to previous smallpox vaccination was estimated after weighting for HIV using a linear regression model. Self-reports of adverse effects following immunization (AEFIs) were prospectively collected after the first MVA-BN dose (T1). Systemic (S-AEFIs: fatigue, myalgia, headache, GI effects, chills) and local (L-AEFIs: redness, swelling, pain) AEFIs were graded as absent (grade 0), mild (1), moderate (2), or severe (3). The maximum level of severity for S-AEFIs and L-AEFIs ever experienced over the 30 days post-dose by vaccination exposure groups were analysed using a univariable multinomial logistic regression model and after adjusting for HIV status; for each of the symptoms, we also compared the mean duration by exposure group using an unpaired t-test. Findings: Among the 164 participants included, 90 (54.8%) were smallpox vaccine-experienced. Median age was 49 years (IQR 41-55). Among the 76 (46%) PLWH, 76% had a CD4 count &gt;500&nbsp;cells/μL. There was evidence that both the IgG and nAbs titers increased after administration of the MVA-BN vaccine. However, there was no evidence for a difference in the potential mean change in humoral response from baseline to the completion of a full cycle when comparing primed vs. non-primed participants. Similarly, there was no evidence for a difference in the seroconversion rate after full cycle vaccination in the subset of participants not reactive for nAbs at T1 (p&nbsp;=&nbsp;1.00 by Fisher's exact test). In this same analysis and for the nAbs outcome, there was some evidence of negative effect modification by HIV (interaction p-value&nbsp;=&nbsp;0.17) as primed people living with HIV (PLWH) showed a lower probability of seroconversion vs. non-primed, and the opposite was seen in PLWoH. When evaluating the response in continuous, we observed an increase in T-cell response after MVA-BN vaccination in both primed and non-primed. There was evidence for a larger increase when using the 2-dose vs. one-dose strategy with a mean difference of&nbsp;-2.01 log2 (p ≤ 0.0001), after controlling for HIV. No evidence for a difference in the risk of developing any AEFIs of any grade were observed by exposure group, except for the lower risk of grade 2 (moderate) fatigue, induration and local pain which was lower in primed vs. non-primed [OR 0.26 (0.08-0.92), p&nbsp;=&nbsp;0.037; OR 0.30 (0.10-0.88), p&nbsp;=&nbsp;0.029 and OR 0.19 (0.05-0.73), p&nbsp;=&nbsp;0.015, respectively]. No evidence for a difference in symptom duration was also detected between the groups. Interpretation: The evaluation of the humoral and cellular response one month after the completion of the vaccination cycle suggested that MVA-BN is immunogenic and that the administration of a two-dose schedule is preferable regardless of the previous smallpox vaccination history, especially in PLWH, to maximize nAbs response. MVA-BN was safe as well tolerated, with grade 2 reactogenicity higher after the first administration in vaccine-naïve than in vaccine-experienced individuals, but with no evidence for a difference in the duration of these adverse effects. Further studies are needed to evaluate the long-term duration of immunity and to establish specific correlates of protection. Funding: The study was supported by the National Institute for Infectious Disease Lazzaro Spallanzani IRCCS "Advanced grant 5&nbsp;×&nbsp;1000, 2021" and by the Italian Ministry of Health "Ricerca Corrente Linea 2"

Immunogenicity and reactogenicity of modified vaccinia Ankara pre-exposure vaccination against mpox according to previous smallpox vaccine exposure and HIV infection: prospective cohort study

BACKGROUND: Pre-exposure vaccination with MVA-BN has been widely used against mpox to contain the 2022 outbreak. Many countries have defined prioritized strategies, administering a single dose to those historically vaccinated for smallpox, to achieve quickly adequate coverage in front of low supplies. Using epidemiological models, real-life effectiveness was estimated at approximately 36%–86%, but no clinical trials were performed. Few data on MVA-BN immunogenicity are currently available, and there are no established correlates of protection. Immunological response in PLWH in the context of the 2022 outbreak was also poorly described. METHODS: Blood samples were collected from participants eligible for pre-exposure MVA-BN vaccination before (T1) receiving a full course of vaccine (single-dose for vaccine-experienced or smallpox-primed and two-dose for smallpox vaccine-naïve or smallpox non-primed) and one month after the last dose (T2 and T3, respectively). MPXV-specific IgGs were measured by in-house immunofluorescence assay, using 1:20 as screening dilution, MPXV-specific nAbs by 50% plaque reduction neutralization test (PRNT50, starting dilution 1:10), and IFN-γ-producing specific T cells to MVA-BN vaccine, by ELISpot assay. Paired or unpaired t-test and Wilcoxon or Mann–Whitney test were used to analyse IgG and nAbs, and T-cell response, as appropriate. The probability of IgG and nAb response in vaccine-experienced vs. vaccine-naïve was estimated in participants not reactive at T1. The McNemar test was used to evaluate vaccination's effect on humoral response both overall and by smallpox vaccination history. In participants who were not reactive at T1, the proportion of becoming responders one month after full-cycle completion by exposure groups was compared by logistic regression and then analysed by HIV status strata (interaction test). The response was also examined in continuous, and the Average Treatment Effect (ATE) of the difference from baseline to schedule completion according to previous smallpox vaccination was estimated after weighting for HIV using a linear regression model. Self-reports of adverse effects following immunization (AEFIs) were prospectively collected after the first MVA-BN dose (T1). Systemic (S-AEFIs: fatigue, myalgia, headache, GI effects, chills) and local (L-AEFIs: redness, swelling, pain) AEFIs were graded as absent (grade 0), mild (1), moderate (2), or severe (3). The maximum level of severity for S-AEFIs and L-AEFIs ever experienced over the 30 days post-dose by vaccination exposure groups were analysed using a univariable multinomial logistic regression model and after adjusting for HIV status; for each of the symptoms, we also compared the mean duration by exposure group using an unpaired t-test. FINDING: Among the 164 participants included, 90 (54.8%) were smallpox vaccine-experienced. Median age was 49 years (IQR 41–55). Among the 76 (46%) PLWH, 76% had a CD4 count >500 cells/μL. There was evidence that both the IgG and nAbs titers increased after administration of the MVA-BN vaccine. However, there was no evidence for a difference in the potential mean change in humoral response from baseline to the completion of a full cycle when comparing primed vs. non-primed participants. Similarly, there was no evidence for a difference in the seroconversion rate after full cycle vaccination in the subset of participants not reactive for nAbs at T1 (p = 1.00 by Fisher's exact test). In this same analysis and for the nAbs outcome, there was some evidence of negative effect modification by HIV (interaction p-value = 0.17) as primed people living with HIV (PLWH) showed a lower probability of seroconversion vs. non-primed, and the opposite was seen in PLWoH. When evaluating the response in continuous, we observed an increase in T-cell response after MVA-BN vaccination in both primed and non-primed. There was evidence for a larger increase when using the 2-dose vs. one-dose strategy with a mean difference of −2.01 log2 (p ≤ 0.0001), after controlling for HIV. No evidence for a difference in the risk of developing any AEFIs of any grade were observed by exposure group, except for the lower risk of grade 2 (moderate) fatigue, induration and local pain which was lower in primed vs. non-primed [OR 0.26 (0.08–0.92), p = 0.037; OR 0.30 (0.10–0.88), p = 0.029 and OR 0.19 (0.05–0.73), p = 0.015, respectively]. No evidence for a difference in symptom duration was also detected between the groups. INTERPRETATION: The evaluation of the humoral and cellular response one month after the completion of the vaccination cycle suggested that MVA-BN is immunogenic and that the administration of a two-dose schedule is preferable regardless of the previous smallpox vaccination history, especially in PLWH, to maximize nAbs response. MVA-BN was safe as well tolerated, with grade 2 reactogenicity higher after the first administration in vaccine-naïve than in vaccine-experienced individuals, but with no evidence for a difference in the duration of these adverse effects. Further studies are needed to evaluate the long-term duration of immunity and to establish specific correlates of protection

Post-intervention Status in Patients With Refractory Myasthenia Gravis Treated With Eculizumab During REGAIN and Its Open-Label Extension

OBJECTIVE: To evaluate whether eculizumab helps patients with anti-acetylcholine receptor-positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension. METHODS: Patients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study. RESULTS: A total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1-4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected. CONCLUSION: Eculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population. CLINICALTRIALSGOV IDENTIFIER: REGAIN, NCT01997229; REGAIN open-label extension, NCT02301624. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo

Minimal Symptom Expression' in Patients With Acetylcholine Receptor Antibody-Positive Refractory Generalized Myasthenia Gravis Treated With Eculizumab

The efficacy and tolerability of eculizumab were assessed in REGAIN, a 26-week, phase 3, randomized, double-blind, placebo-controlled study in anti-acetylcholine receptor antibody-positive (AChR+) refractory generalized myasthenia gravis (gMG), and its open-label extension

Mutations and polymorphism in bottlenose dolphin (Tursiops truncatus, Montagu 1821) albumin gene: First identification of mutations responsible for inherited bisalbuminemia

Hereditary bisalbuminemia is an asymptomatic and heterozygous condition in a range of species characterized by the presence of two serum albumin fractions with different electrophoretic mobility resulting in a bicuspid pattern on serum electrophoresis. Bisalbuminemia has been diagnosed by electrophoresis in two bottlenose dolphin (Tursiops truncatus) families, but causative mutations and the inheritance pattern have not been identified. The aims of this work are: to investigate polymorphisms of the bottlenose dolphin albumin gene and to identify mutations causative of bisalbuminemia; to identify the inheritance pattern in two bottlenose dolphin families. Coding regions of the albumin gene were screened for mutations in 15 bottlenose dolphins kept under human care from two distinct families. Eighteen albumin mutations (three synonymous and 15 non-synonymous) were identified. Two non-synonymous variations co-segregated with bisalbuminemic phenotype: p.Phe146Leu in exon 4 and p.Tyr163His in exon 5. The amino acid change in exon 5 was associated with the secondary and/or tertiary structure variation of the protein and has been reported as causative of bisalbuminemia in humans. Pedigree analysis of the dolphin families showed an autosomal codominant inheritance pattern. In this work, the mutations potentially responsible for bisalbuminemia were identified and confirmed the autosomal codominant trait in bottlenose dolphins

SERUM PARAOXONASE-1 (PON1) ACTIVITY IN BOTTLENOSE DOLPHINS (TURSIOPS TRUNCATUS): MEASUREMENT WITH DIFFERENT SUBSTRATES AND INFLUENCE OF GENETIC POLYMORPHISMS

Background: Paraoxonase-1 (PON1) is an HDL-bound esterase and lipolactonase involved in organophosphate detoxification, protection against oxidative damage. PON1 acts as negative acute phase reactant (APR). Based on the different PON1 functions, several substrates have been identified to evaluate PON1 activities, which are influenced by single-nucleotide polymorphisms (SNPs) such as Leu55Met and Gln192Arg. No data on PON1 activity and SNPs are available for dolphins. Objective: to evaluate the serum PON1 activity using different substrates and SNPs in bottlenose dolphins. Methods: Serum samples from under human-care bottlenose dolphins were used: in 42 healthy animals paraoxonase activity was evaluated using paraoxon as substrate. Arylesterase and lactonase activity were evaluated in samples from 6 healthy and 6 diseased animals using 4-nitrophenyl acetate (4-nPA), phenyl-acetate, and dihydrocoumarin. In 15 animals, PON1 gene was screened for Leu55Met and Gln192Arg SNPs. Results: paraoxonase activity showed mean values of 6.6\ub14.5 U/mL (median: 7.2 U/mL). Arylesterase activity using 4-nPA was 186.2\ub120.4 U/L (median: 187.2 U/L) in healthy dolphins and 177.5\ub114.3 U/L (median: 177.5 U/L) in diseased dolphins, while using phenyl-acetate, PON1 activity had high variability with no reaction or negative results. The lactonase activity was not detectable in any dolphins. All the animals showed homozygosis for Leu55 and Arg192. Conclusions: paraoxonase activity in bottlenose dolphins is lower compared to domestic animals, thus its use as a negative APR is hampered. Arylesterase activity was higher, but without significant differences between healthy and diseased animals. The SNPs seems not to be associated with an elevated paroxonase activity, as reported for humans

Detection of hereditary bisalbuminemia in bottlenose dolphins (Tursiops truncatus, Montagu 1821): comparison between capillary zone and agarose gel electrophoresis

Hereditary bisalbuminemia is a relatively rare anomaly characterized by the occurrence of two albumin fractions on serum protein separation by electrophoresis. In human medicine, it is usually revealed by chance, is not been clearly associated with a specific disease and the causative genetic alteration is a point mutation of human serum albumin gene inherited in an autosomal codominant pattern. This type of alteration is well recognizable by capillary zone electrophoresis (CZE), whilst agarose gel electrophoresis (AGE) not always produces a clear separation of albumin fractions. The aims of this study is to report the presence of this abnormality in two separate groups of related bottlenose dolphins and to compare the results obtained with capillary zone and agarose gel electrophoresis