Browsing by Issue Date, starting with "2022-06-30"
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- Actionable secondary findings following exome sequencing of 836 non-obstructive azoospermia cases and their value in patient managementPublication . Kasak, Laura; Lillepea, Kristiina; Nagirnaja, Liina; Aston, Kenneth I.; Schlegel, Peter N.; Gonçalves, João; Carvalho, Filipa; Moreno-Mendoza, Daniel; Almstrup, Kristian; Eisenberg, Michael L.; Jarvi, Keith A.; O’Bryan, Moira K.; Lopes, Alexandra M.; Conrad, Donald F.; Nagirnaja, Liina; Aston, Kenneth I.; Carrell, Douglas T.; Hotaling, James M.; Jenkins, Timothy G.; McLachlan, Rob; O’Bryan, Moira K.; Schlegel, Peter N.; Eisenberg, Michael L.; Sandlow, Jay I.; Jungheim, Emily S.; Omurtag, Kenan R.; Lopes, Alexandra M.; Seixas, Susana; Carvalho, Filipa; Fernandes, Susana; Barros, Alberto; Laan, Maris; Punab, Margus; Rajpert-De Meyts, Ewa; Jørgensen, Niels; Almstrup, Kristian; Krausz, Csilla G.; Jarvi, Keith A.; Punab, Margus; Laan, MarisStudy question: What is the load, distribution and added clinical value of secondary findings (SFs) identified in exome sequencing (ES) of patients with non-obstructive azoospermia (NOA)? Summary answer: One in 28 NOA cases carried an identifiable, medically actionable SF. What is known already: In addition to molecular diagnostics, ES allows assessment of clinically actionable disease-related gene variants that are not connected to the patient's primary diagnosis, but the knowledge of which may allow the prevention, delay or amelioration of late-onset monogenic conditions. Data on SFs in specific clinical patient groups, including reproductive failure, are currently limited. Study design, size, duration: The study group was a retrospective cohort of patients with NOA recruited in 10 clinics across six countries and formed in the framework of the international GEMINI (The GEnetics of Male INfertility Initiative) study. Participants/materials, setting, methods: ES data of 836 patients with NOA were exploited to analyze SFs in 85 genes recommended by the American College of Medical Genetics and Genomics (ACMG), Geisinger's MyCode, and Clinical Genome Resource. The identified 6374 exonic variants were annotated with ANNOVAR and filtered for allele frequency, retaining 1381 rare or novel missense and loss-of-function variants. After automatic assessment of pathogenicity with ClinVar and InterVar, 87 variants were manually curated. The final list of confident disease-causing SFs was communicated to the corresponding GEMINI centers. When patient consent had been given, available family health history and non-andrological medical data were retrospectively assessed. Main results and the role of chance: We found a 3.6% total frequency of SFs, 3.3% from the 59 ACMG SF v2.0 genes. One in 70 patients carried SFs in genes linked to familial cancer syndromes, whereas 1 in 60 cases was predisposed to congenital heart disease or other cardiovascular conditions. Retrospective assessment confirmed clinico-molecular diagnoses in several cases. Notably, 37% (11/30) of patients with SFs carried variants in genes linked to male infertility in mice, suggesting that some SFs may have a co-contributing role in spermatogenic impairment. Further studies are needed to determine whether these observations represent chance findings or the profile of SFs in NOA patients is indeed different from the general population. Limitations, reasons for caution: One limitation of our cohort was the low proportion of non-Caucasian ethnicities (9%). Additionally, as comprehensive clinical data were not available retrospectively for all men with SFs, we were not able to confirm a clinico-molecular diagnosis and assess the penetrance of the specific variants. Wider implications of the findings: For the first time, this study analyzed medically actionable SFs in men with spermatogenic failure. With the evolving process to incorporate ES into routine andrology practice for molecular diagnostic purposes, additional assessment of SFs can inform about future significant health concerns for infertility patients. Timely detection of SFs and respective genetic counseling will broaden options for disease prevention and early treatment, as well as inform choices and opportunities regarding family planning. A notable fraction of SFs was detected in genes implicated in maintaining genome integrity, essential in both mitosis and meiosis. Thus, potential genetic pleiotropy may exist between certain adult-onset monogenic diseases and NOA.
- Rapidly adapting primary care sentinel surveillance across seven countries in Europe for COVID-19 in the first half of 2020: strengths, challenges, and lessons learnedPublication . Bagaria, Jayshree; Jansen, Tessa; Marques, Diogo F.P.; Hooiveld, Mariette; McMenamin, Jim; de Lusignan, Simon; Vilcu, Ana-Maria; Meijer, Adam; Rodrigues, Ana Paula; Brytting, Mia; Mazagatos, Clara; Cogdale, Jade; van der Werf, Sylvie; Dijkstra, Frederika; Guiomar, Raquel; Enkirch, Theresa; Valenciano, Marta; I-MOVE-COVID-19 study teamAs the COVID-19 pandemic began in early 2020, primary care influenza sentinel surveillance networks within the Influenza - Monitoring Vaccine Effectiveness in Europe (I-MOVE) consortium rapidly adapted to COVID-19 surveillance. This study maps system adaptations and lessons learned about aligning influenza and COVID-19 surveillance following ECDC / WHO/Europe recommendations and preparing for other diseases possibly emerging in the future. Using a qualitative approach, we describe the adaptations of seven sentinel sites in five European Union countries and the United Kingdom during the first pandemic phase (March–September 2020). Adaptations to sentinel systems were substantial (2/7 sites), moderate (2/7) or minor (3/7 sites). Most adaptations encompassed patient referral and sample collection pathways, laboratory testing and data collection. Strengths included established networks of primary care providers, highly qualified testing laboratories and stakeholder commitments. One challenge was the decreasing number of samples due to altered patient pathways. Lessons learned included flexibility establishing new routines and new laboratory testing. To enable simultaneous sentinel surveillance of influenza and COVID-19, experiences of the sentinel sites and testing infrastructure should be considered. The contradicting aims of rapid case finding and contact tracing, which are needed for control during a pandemic and regular surveillance, should be carefully balanced.
- The Preyssler-Type Polyoxotungstate Exhibits Anti-Quorum Sensing, Antibiofilm, and Antiviral ActivitiesPublication . Faleiro, Leonor; Marques, Ana; Martins, João; Jordão, Luísa; Nogueira, Isabel; Gumerova, Nadiia I.; Rompel, Annette; Aureliano, ManuelSimple Summary: Besides showing the antibacterial activity of the Preyssler-type polyoxotungstate (POT) P5W30 with the ability to affect MRSA cells, we demonstrated that P5W30 also displays other proprieties, such as anti-quorum sensing and antibiofilm. These are biological activities that are reported for a POT for the first time. Quorum sensing and biofilm facilitate the bacterial colonization, antibiotic resistance and persistence in both the environment and host, and its impairment by POTs can greatly contribute to the control of bacterial infections, such as those caused by multiresistant bacteria. Moreover, antiviral activity was also observed using the enterovirus Qβ. NMR stability studies of P5W30 demonstrate that it remains intact, suggesting its responsibility in the described biological activities. Taken together, our results emphasize the potential biomedical use of POTs, particularly the Preyssler-type POT, to fight antibiotic-resistant MRSA strains and their ability to form biofilm, besides being a promising antiviral agent.