The Significance of Short Latency in Mesothelioma for Attribution of Causation: Report of a Case with Predisposing Germline Mutations and Review of the Literature

Malignant mesothelioma is a tumour of the serosal membranes, related to asbestos exposure. Median latency is in the order of 40 years in various registries, but small numbers of cases with shorter latencies have long been reported and often dismissed as unrelated to asbestos exposure. However, emerging data regarding the significance of inherited mutations leading to a predisposition to mesothelioma suggest that the causative effect of asbestos may be associated with shorter latencies in a subset of patients. Here, we describe a male patient with germline mutations in RAD51 and p53 who developed peritoneal mesothelioma 8.5 years after well-documented asbestos exposure and discuss the current literature on the subject. Mesothelioma in situ is now a WHO-accepted diagnosis, but preliminary data reveal a potential lead time of 5 or more years to invasive disease, and this is also a factor which may affect the recording of latency (and potentially survival) in the future.

Genomics and transcriptomics landscapes associated to changes in insulin sensitivity in response to endurance exercise training

Despite good adherence to supervised endurance exercise training (EET), some individuals experience no or little improvement in peripheral insulin sensitivity. The genetic and molecular mechanisms underlying this phenomenon are currently not understood. By investigating genome-wide variants associated with baseline and exercise-induced changes (∆) in insulin sensitivity index (Si) in healthy volunteers, we have identified novel candidate genes whose mouse knockouts phenotypes were consistent with a causative effect on Si. An integrative analysis of functional genomic and transcriptomic profiles suggests genetic variants have an aggregate effect on baseline Si and ∆Si, focused around cholinergic signalling, including downstream calcium and chemokine signalling. The identification of calcium regulated MEF2A transcription factor as the most statistically significant candidate driving the transcriptional signature associated to ∆Si further strengthens the relevance of calcium signalling in EET mediated Si response.

An Unusual Case of “Conjugal” Polymyalgia Rheumatica after SARS-CoV-2 Vaccination

The rare occurrence of polymyalgia rheumatica (PMR) in married couples has been reported in the literature. Susceptibility to PMR is contributed by genetic and environmental factors and cases of PMR developing after influenza vaccine have also been described, in a debated phenomenon known as ‘ASIA’ syndrome. We report the case of two cohabitating married patients developing PMR few weeks after the first dose of ChAdOx1-S SARS-CoV-2 vaccine. Both patients presented with typical symptoms suggestive of PMR. Laboratory findings and ultrasound examination confirmed the diagnosis. Glucocorticoid therapy led to rapid improvment of symptoms. Anti-receptor-binding domain IgG titre was tested and, eight weeks after vaccination, both patients showed no antibody response. It has been suggested that vaccines might trigger autoimmune or inflammatory states in predisposed individuals and various hypotheses have been made regarding the pathogenesis of PMR. Although the causative effect of vaccines cannot be determined, the close temporal correlation observed in our case supports the potential role of environmental factors in triggering the onset of PMR. However, the literature indicates that post-COVID19 vaccination immune-mediated or inflammatory adverse events are extremely rare and vaccination should be encouraged since the benefit largely outweighs possible risks.

Acute corneal graft rejection after anti-severe acute respiratory syndrome-coronavirus-2 vaccination: A report of four cases

Purpose This study intends to add to previous reports on acute corneal graft rejection following anti-severe acute respiratory syndrome-coronavirus-2 vaccination, providing data to corroborate a possible causative relationship between anti-COVID-19 immunization and corneal graft rejection, regardless of vaccine or graft type. Methods and Results This report describes 4 cases of acute-onset rejection as early as 5 days following the first dose of anti-severe acute respiratory syndrome-coronavirus-2 vaccine types not yet referred for corneal allograft. Patients were individually given the Moderna messenger RNA-1273 COVID-19 vaccine (2 patients) and the AstraZeneca COVID-19 vaccine, Vaxzevria, AZD1222 (2 patients). Conclusions Even though a direct causative effect is hard to prove, temporal proximity between anti-severe acute respiratory syndrome-coronavirus-2 vaccines of different types and consecutive reports of corneal graft rejection indicates the need for further investigation. Consistent advice must be given to corneal transplant patients regarding such risk.

Causal Pathway Extraction from Web-Board Documents

This research aim is to extract causal pathways, particularly disease causal pathways, through cause-effect relation (CErel) extraction from web-board documents. The causal pathways benefit people with a comprehensible representation approach to disease complication. A causative/effect-concept expression is based on a verb phrase of an elementary discourse unit (EDU) or a simple sentence. The research has three main problems; how to determine CErel on an EDU-concept pair containing both causative and effect concepts in one EDU, how to extract causal pathways from EDU-concept pairs having CErel and how to indicate and represent implicit effect/causative-concept EDUs as implicit mediators with comprehension on extracted causal pathways. Therefore, we apply EDU’s word co-occurrence concept (wrdCoc) as an EDU-concept and the self-Cartesian product of a wrdCoc set from the documents for extracting wrdCoc pairs having CErel into a wrdCoc-pair set from the documents after learning CErel on wrdCoc pairs by supervised-machine learning. The wrdCoc-pair set is used for extracting the causal pathways by wrdCoc-pair matching through the documents. We then propose transitive closure and a dynamic template to indicate and represent the implicit mediators with the explicit ones. In contrast to previous works, the proposed approach enables causal-pathway extraction with high accuracy from the documents.

A maternally inherited Interstitial Xq21 deletion associated with deafness and mental retardation syndrome in a male patient

Клиническое значение делеции района q21 хромосомы X у мужчин все еще плохо изучено. Было показано, что делеция Xq21, включающая гены POU3F4, CHM и ZNF711, может приводить к глухоте, умственной отсталости и хороидеремии. Несмотря на тяжелые симптомы, наблюдаемые у пробандов-мужчин, большинство носителей женского пола бессимптомны или имеют незначительные фенотипические проявления. Представлена клиническая и молекулярно-цитогенетическая характеристика случая делеции района q21.1-q21.31 хромосомы X, выявленной при проведении хромосомного микроматричного анализа у пациента с задержкой психоречевого развития, лицевыми дизморфиями и тугоухостью. Такая же делеция была выявлена у практически здоровой матери. Наши данные способствуют дальнейшему пониманию корреляции между делецией Xq21 и аномальным фенотипом. Deletions on the X chromosome can lead to serious birth defects. Deletions in Xq21 cause various congenital defects in males including choroideremia, deafness and mental retardation, depending on their size and gene content. Only a limited number of patients with Xq21 deletions has been reported. It has been shown that deletions of the adjacent Xq21 genes, including the POU3F4, CHM and ZNF711 genes, can lead to deafness and mental retardation syndrome and choroideremia. Despite the severe symptoms exhibited by male probands, most female carriers are asymptomatic or exhibit only a mild phenotype. The article presents the clinical and molecular-cytogenetic characteristics of a case of deletion of the Xq21.1-q21.31 region of chromosome X, revealed during chromosomal microarray analysis in a patient with delayed psycho-speech development, facial dysmorphisms and hearing loss. The same deletion was found in an apparently healthy mother. Our study confirms the causative effect between the Xq21 deletion in males and choroideremia, deafness and mental retardation.

Investigating the Role of Functional Polymorphism of Maternal and Neonatal Vitamin D Binding Protein in the Context of 25-Hydroxyvitamin D Cutoffs as Determinants of Maternal-Neonatal Vitamin D Status Profiles in a Sunny Mediterranean Region

Recent results indicate that dysregulation of vitamin D-binding protein (VDBP) could be involved in the development of hypovitaminosis D, and it comprises a risk factor for adverse fetal, maternal and neonatal outcomes. Until recently, there was a paucity of results regarding the effect of maternal and neonatal VDBP polymorphisms on vitamin D status during pregnancy in the Mediterranean region, with a high prevalence of hypovitaminosis D. We aimed to evaluate the combined effect of maternal and neonatal VDBP polymorphisms and different maternal and neonatal 25-hydroxyvitamin D (25(OH)D) cut-offs on maternal and neonatal vitamin D profile. Blood samples were obtained from a cohort of 66 mother–child pairs at birth. Our results revealed that: (i) Maternal VDBP polymorphisms do not affect neonatal vitamin D status at birth, in any given internationally adopted maternal or neonatal cut-off for 25(OH)D concentrations; (ii) neonatal VDBP polymorphisms are not implicated in the regulation of neonatal vitamin D status at birth; (iii) comparing the distributions of maternal VDBP polymorphisms and maternal 25(OH)D concentrations, with cut-offs at birth, revealed that mothers with a CC genotype for rs2298850 and a CC genotype for rs4588 tended to demonstrate higher 25(OH)D (≥75 nmol/L) during delivery (p = 0.05 and p = 0.04, respectively), after adjustments for biofactors that affect vitamin D equilibrium, including UVB, BMI and weeks of gestation. In conclusion, this study from Southern Europe indicates that maternal and neonatal VDBP polymorphisms do not affect neonatal vitamin D status at birth, whereas mothers with CC genotype for rs2298850 and CC genotype for rs4588 demonstrate higher 25(OH)D concentrations. Future larger studies are required to establish a causative effect of these specific polymorphisms in the attainment of an adequate (≥75 nmol/L) maternal vitamin D status during pregnancy.

The use of drama and theatre in enhancing communication skills of psychiatry trainees: a pilot study

AimsVarious methods have been employed in the development of communication skills. This pilot study was designed to assess the acceptability, feasibility and cost-effectiveness of a specially designed workshop exploring the use of drama and theatre in enhancing the self-reported communication skills of psychiatry trainees. As a secondary aim, it assessed if the value of the improvements translated both into clinical practice and to training situations, including success in the Royal College of Psychiatrists (RCPsych) Clinical Assessment of Skills and Competencies (CASC) examination.MethodA three-day drama and theatre workshop was organised in the West Midlands Deanery in conjunction with specialist instructors from performing arts at the Hearth Centre, Birmingham. The Tension State technique developed by Jacques Lecoq and Forum Theatre approach, were some of the methods employed to enable participants to develop the softer, but essential communication skills required for effective practice. Work was also undertaken focussing on self-regulation. Fourteen trainees completed the first day of the workshop. This pilot study utilised a mixed methodology to evaluate participants’ views of the perceived impact of using drama and theatre to enhance their communication skills. Feedback was obtained from organisers and facilitators specifically relating to feasibility and cost effectiveness. Data were collected from participants using pre and post-workshop questionnaires and focus groups.ResultAll participants reported a positive and enjoyable experience, indicating that the approach was acceptable to those involved. The facilitators deemed this more novel approach to enhancing communication skills feasible, and cost effective and concluded that there was scope to incorporate it into routine psychiatry training in the area. It was however identified that the content of the workshop could be condensed, reducing the length therefore to two days. There was a notable increase in participants’ self-reported confidence in their communication skills post compared to pre-workshop. Trainees reported utilising the techniques in day-to-day practice. All of those participants who undertook the CASC examination during the workshop were successful, although it would be too presumptive to assume a causative effect. The workshop was completed without any adverse events and there were no concerns from a safety perspective.ConclusionDrama and theatre, as a novel approach, appears to have noticeable benefits in enhancing the communication skills of psychiatry trainees. The success of this pilot study in demonstrating acceptability, feasibility and cost effectiveness, suggests that drama and theatre techniques could be easily incorporated into psychiatry training and potentially other medical education programmes.

Is radiation necrosis in radiated melanoma brain metastasis increasing because immunotherapy is contributing to this or are patients just living longer?

e21518 Background: The use of immune checkpoint inhibitors, particularly combination ipilimumab and nivolumab, has drastically changed the management of patients with melanoma brain metastasis. Select patients also benefit from brain-directed stereotactic radiation. Radiation necrosis is a risk associated with stereotactic radiation that oncologists have been observing more frequently in the era of immunotherapy. Methods: Patients were identified who had a history of metastatic melanoma treated with stereotactic brain radiation who subsequently developed radiation necrosis. Brain tissue from those patients with a subsequent resection of their radiation necrosis was obtained and examined for immune infiltrate and other factors. The tissue obtained was evaluated by blinded pathologists who graded % viable tissue, % necrosis, % tumor and % fibrosis. In addition, they graded inflammation on a scale of 1-3. Results: Seven patients were identified who had surgery for radiation necrosis following radiation to melanoma brain metastasis. Tissue was available for five patients. Two patients had received no prior immunotherapy, one patient had received ipilimumab and two patients received combination ipilimumab and nivolumab. The samples obtained consisted of almost entirely viable brain tissue or necrosis. There was minimal inflammation seen in all patients’ samples including those who had not received immunotherapy and those who had. Conclusions: Radiation necrosis in patients on immunotherapy who receive brain-directed stereotactic radiation is a rising problem. On pathologic evaluation increased immune infiltrate is not observed in patients on immunotherapy with radiation necrosis compared to those who never received immunotherapy. This suggests that the increased rates of radiation necrosis may be more likely associated with longer survival as opposed to a direct causative effect from the immunotherapy although with our limited sample size this will need further exploration.[Table: see text]

Substantial anti-gout effect conferred by common and rare dysfunctional variants of URAT1/SLC22A12

Objectives Gout, caused by chronic elevation of serum uric acid levels, is the commonest form of inflammatory arthritis. The causative effect of common and rare variants of ATP-binding cassette transporter G2 (ABCG2/BCRP) on gout risk has been studied, but, little attention has been paid to the effect of common (rs121907892, p. W258X) and rare variants of urate transporter 1 (URAT1/SLC22A12) on gout, despite dysfunctional variants of URAT1 having been identified as pathophysiological causes of renal hypouricemia. Methods To address this important but overlooked issue, we investigated the effects of these URAT1 variants on gout susceptibility, using targeted exon sequencing on 480 clinically-defined gout cases and 480 controls of Japanese male in combination with a series of functional analyses of newly-identified URAT1 variants. Results Our results show that both common and rare dysfunctional variants of URAT1 markedly decrease the risk of gout (OR 0.0338, reciprocal OR 29.6, p = 7.66 × 1 0 −8). Interestingly, we also found that the URAT1-related protective effect on gout eclipsed the ABCG2-related causative effect (OR 2.30 – 3.32). Our findings reveal only one dysfunctional variant of URAT1 to have a substantial anti-gout effect, even in the presence of causative variants of ABCG2, a “gout gene”. Conclusion Our findings provide a better understanding of gout/hyperuricemia and its aetiology that is highly relevant to personalized health care. The substantial anti-gout effect of common and rare variants of URAT1 identified in the present study support the genetic concept of a ‘Common Disease, Multiple Common and Rare Variant’ model.