Impact of high-risk prenatal screening results for 22q11.2 deletion syndrome on obstetric and neonatal management: Secondary analysis from the SMART study

Objective One goal of prenatal genetic screening is to optimize perinatal care and improve infant outcomes. We sought to determine whether high-risk cfDNA screening for 22q11.2 deletion syndrome (22q11.2DS) affected prenatal or neonatal management. Methods This was a secondary analysis from the SMART study. Patients with high-risk cfDNA results for 22q11.2DS were compared with the low-risk cohort for pregnancy characteristics and obstetrical management. To assess differences in neonatal care, we compared high-risk neonates without prenatal genetic confirmation with a 1:1 matched low-risk cohort. Results Of 18,020 eligible participants enrolled between 2015 and 2019, 38 (0.21%) were high-risk and 17,982 (99.79%) were low-risk for 22q11.2DS by cfDNA screening. High-risk participants had more prenatal diagnostic testing (55.3%; 21/38 vs. 2.0%; 352/17,982, p < 0.001) and fetal echocardiography (76.9%; 10/13 vs. 19.6%; 10/51, p < 0.001). High-risk newborns without prenatal diagnostic testing had higher rates of neonatal genetic testing (46.2%; 6/13 vs. 0%; 0/51, P < 0.001), echocardiography (30.8%; 4/13 vs. 4.0%; 2/50, p = 0.013), evaluation of calcium levels (46.2%; 6/13 vs. 4.1%; 2/49, P < 0.001) and lymphocyte count (53.8%; 7/13 vs. 15.7%; 8/51, p = 0.008). Conclusions High-risk screening results for 22q11.2DS were associated with higher rates of prenatal and neonatal diagnostic genetic testing and other 22q11.2DS-specific evaluations. However, these interventions were not universally performed, and >50% of high-risk infants were discharged without genetic testing, representing possible missed opportunities to improve outcomes for affected individuals

Communications Biophysics

Contains research objectives, summary of research and reports on four research projects.National Institutes of Health (Grant 5 P01 GM14940-05)National Institutes of Health (Grant 5 TOl GM01555-05)National Aeronautics and Space Administration (Grant NGL 22-009-304)B-D ElectrodyneBoston City Hospital Purchase Order 1065

Performance of prenatal cfDNA screening for sex chromosomes.

PURPOSE: The aim of this study was to assess the performance of cell-free DNA (cfDNA) screening to detect sex chromosome aneuploidies (SCAs) in an unselected obstetrical population with genetic confirmation. METHODS: This was a planned secondary analysis of the multicenter, prospective SNP-based Microdeletion and Aneuploidy RegisTry (SMART) study. Patients receiving cfDNA results for autosomal aneuploidies and who had confirmatory genetic results for the relevant sex chromosomal aneuploidies were included. Screening performance for SCAs, including monosomy X (MX) and the sex chromosome trisomies (SCT: 47,XXX; 47,XXY; 47,XYY) was determined. Fetal sex concordance between cfDNA and genetic screening was also evaluated in euploid pregnancies. RESULTS: A total of 17,538 cases met inclusion criteria. Performance of cfDNA for MX, SCTs, and fetal sex was determined in 17,297, 10,333, and 14,486 pregnancies, respectively. Sensitivity, specificity, and positive predictive value (PPV) of cfDNA were 83.3%, 99.9%, and 22.7% for MX and 70.4%, 99.9%, and 82.6%, respectively, for the combined SCTs. The accuracy of fetal sex prediction by cfDNA was 100%. CONCLUSION: Screening performance of cfDNA for SCAs is comparable to that reported in other studies. The PPV for the SCTs was similar to the autosomal trisomies, whereas the PPV for MX was substantially lower. No discordance in fetal sex was observed between cfDNA and postnatal genetic screening in euploid pregnancies. These data will assist interpretation and counseling for cfDNA results for sex chromosomes

Cell-free DNA screening for prenatal detection of 22q11.2 deletion syndrome.

BACKGROUND: Historically, prenatal screening has focused primarily on the detection of fetal aneuploidies. Cell-free DNA now enables noninvasive screening for subchromosomal copy number variants, including 22q11.2 deletion syndrome (or DiGeorge syndrome), which is the most common microdeletion and a leading cause of congenital heart defects and neurodevelopmental delay. Although smaller studies have demonstrated the feasibility of screening for 22q11.2 deletion syndrome, large cohort studies with confirmatory postnatal testing to assess test performance have not been reported. OBJECTIVE: This study aimed to assess the performance of single-nucleotide polymorphism-based, prenatal cell-free DNA screening for detection of 22q11.2 deletion syndrome. STUDY DESIGN: Patients who underwent single-nucleotide polymorphism-based prenatal cell-free DNA screening for 22q11.2 deletion syndrome were prospectively enrolled at 21 centers in 6 countries. Prenatal or newborn DNA samples were requested in all cases for genetic confirmation using chromosomal microarrays. The primary outcome was sensitivity, specificity, positive predictive value, and negative predictive value of cell-free DNA screening for the detection of all deletions, including the classical deletion and nested deletions that are ≥500 kb, in the 22q11.2 low-copy repeat A-D region. Secondary outcomes included the prevalence of 22q11.2 deletion syndrome and performance of an updated cell-free DNA algorithm that was evaluated with blinding to the pregnancy outcome. RESULTS: Of the 20,887 women enrolled, a genetic outcome was available for 18,289 (87.6%). A total of 12 22q11.2 deletion syndrome cases were confirmed in the cohort, including 5 (41.7%) nested deletions, yielding a prevalence of 1 in 1524. In the total cohort, cell-free DNA screening identified 17,976 (98.3%) cases as low risk for 22q11.2 deletion syndrome and 38 (0.2%) cases as high risk; 275 (1.5%) cases were nonreportable. Overall, 9 of 12 cases of 22q11.2 were detected, yielding a sensitivity of 75.0% (95% confidence interval, 42.8-94.5); specificity of 99.84% (95% confidence interval, 99.77-99.89); positive predictive value of 23.7% (95% confidence interval, 11.44-40.24), and negative predictive value of 99.98% (95% confidence interval, 99.95-100). None of the cases with a nonreportable result was diagnosed with 22q11.2 deletion syndrome. The updated algorithm detected 10 of 12 cases (83.3%; 95% confidence interval, 51.6-97.9) with a lower false positive rate (0.05% vs 0.16%; P<.001) and a positive predictive value of 52.6% (10/19; 95% confidence interval, 28.9-75.6). CONCLUSION: Noninvasive cell-free DNA prenatal screening for 22q11.2 deletion syndrome can detect most affected cases, including smaller nested deletions, with a low false positive rate

Cell-free DNA screening for trisomies 21, 18 and 13 in pregnancies at low and high risk for aneuploidy with genetic confirmation.

BACKGROUND: Cell-free DNA (cfDNA) non-invasive prenatal screening for trisomy (T) 21, 18, and 13 has been rapidly adopted into clinical practice. However, prior studies are limited by lack of follow up genetic testing to confirm outcomes and accurately assess test performance, particularly in women at low-risk for aneuploidy. OBJECTIVE: To compare the performance of cfDNA screening for T21, T18 and T13 between women at low and high-risk for aneuploidy in a large, prospective cohort with genetic confirmation of results. STUDY DESIGN: A multicenter prospective observational study at 21 centers in 6 countries. Women who had SNP-based cfDNA screening for T21, T18 and T13 were enrolled. Genetic confirmation was obtained from prenatal or newborn DNA samples. Test performance and test failure (no-call) rates were assessed for the cohort and women with low and high prior risk for aneuploidy were compared. An updated cfDNA algorithm, blinded to pregnancy outcome, was also assessed. RESULTS: 20,194 were enrolled at median gestational age of 12.6 weeks (IQR:11.6, 13.9). Genetic outcomes were confirmed in 17,851 (88.4%): 13,043 (73.1%) low-risk and 4,808 (26.9%) high-risk for aneuploidy. Overall, 133 trisomies were diagnosed (100 T21; 18 T18; 15 T13). cfDNA screen positive rate was lower in low- vs. high-risk (0.27% vs. 2.2%, p<0.0001). Sensitivity and specificity were similar between groups. The positive predictive value (PPV) for the low and high-risk groups was 85.7% vs. 97.5%, p=0.058 for T21; 50.0% vs. 81.3%, p=0.283 for T18; and 62.5% vs. 83.3, p=0.58 for T13, respectively. Overall, 602 (3.4%) patients had no-call result after the first draw and 287 (1.61%) after including cases with a second draw. Trisomy rate was higher in the 287 with no-call results than patients with a result on a first draw (2.8% vs. 0.7%, p=0.001). The updated algorithm showed similar sensitivity and specificity to the study algorhitm with a lower no-call rate. CONCLUSIONS: In women at low-risk for aneuploidy, SNP-based cfDNA has high sensitivity and specificity, PPV of 85.7% for T21 and 74.3% for the three common trisomies. Patients who receive a no-call result are at increased risk of aneuploidy and require additional investigation

Direct and Inverse Computation of Jacobi Matrices of Infinite Homogeneous Affine I.F.S

We introduce a new set of algorithms to compute Jacobi matrices associated with measures generated by infinite systems of iterated functions. We demonstrate their relevance in the study of theoretical problems, such as the continuity of these measures and the logarithmic capacity of their support. Since our approach is based on a reversible transformation between pairs of Jacobi matrices, we also discuss its application to an inverse / approximation problem. Numerical experiments show that the proposed algorithms are stable and can reliably compute Jacobi matrices of large order.Comment: 20 pages 6 figure

Назначение / отмена ингаляционных глюкокортикостероидов у больных хронической обструктивной болезнью легких как терапевтический континуум в реальной клинической практике

Chronic obstructive pulmonary disease (COPD) is a progressing disease. Each exacerbation impairs the patient’s prognosis and increases burden for the healthcare system. The most common maintenance treatment options for COPD include long-acting bronchodilators – β2-agonists (LABA) and long-acting antimuscarinic agents (LAMA), and inhaled glucocorticosteroids (ICS), in fixed/opened double and triple combinations. Triple therapy in subjects with exacerbation history is the most effective way to prevent negative outcomes of the disease. It can reduce the frequency of exacerbations, slow down the disease progression, improve quality of life, and reduce mortality in the long run. On the other hand, the response to triple therapy may change over the time depending on airways inflammation level, infection activity, and exacerbation frequency. Current COPD guidelines propose different indications for therapy escalation and de-escalation (ICS addition/withdrawal) for more personalized and safe treatment. At the same time, many practical issues of this process are still unclear, e.g. how often treatment regimens should be reviewed and what escalation/de-escalation criteria should be prioritized. The authors strongly believe that COPD therapy should adapt a holistic treatment approach (continuum) with quick responses to any changes in the patient’s condition.The aim of our work was to create an algorithm for ICS administration/ withdrawal for COPD patients on long-acting dual bronchodilators maintenance therapy and to establish a therapeutic continuum that takes into account exacerbation history, symptoms severity, blood eosinophilia level, and concomitant asthma.Conclusion. This instrument can be a useful and convenient tool for long-term patient management when access to specialized medical care might be restricted. It takes into account the main current recommendations for COPD management and is easy to apply in real clinical practice.Хроническая обструктивная болезнь легких (ХОБЛ) является прогрессирующим заболеванием. При каждом обострении ухудшается прогноз, снижается качество жизни (КЖ) пациента, увеличивается нагрузка на систему здравоохранения. Наиболее часто для поддерживающей терапии ХОБЛ используются длительно действующие (ДД) бронхолитические препараты – β2-агонисты адренорецепторов (ДДБА) и ДД антихолинергические препараты, а также ингаляционные глюкокортикостероиды (иГКС) в виде двойных и тройных комбинаций. Тройная терапия у лиц с анамнезом обострений является наиболее эффективным методом предотвращения неблагоприятных исходов. При этом снижается число обострений, повышается КЖ, замедляется прогрессирование заболевания и снижается риск летальных исходов. С другой стороны, ответ на тройную терапию может изменяться с течением времени в зависимости от выраженности воспаления в дыхательных путях, активности инфекции и числа обострений. Для того чтобы сделать терапию конкретного больного персонализированной и более безопасной, современными руководствами по лечению ХОБЛ предлагаются различные показания для эскалации (добавление иГКС) и деэскалации (отмена иГКС) терапии. При этом многие практические вопросы, в частности, как часто следует пересматривать схему лечения и на какие показания для эскалации / деэскалации терапии следует обращать внимание в первую очередь, – остаются недостаточно разработанными. Современная терапия ХОБЛ должна представлять собой целостную последовательность действий врача (континуум), которая реагирует на изменения в состоянии пациента своевременной эскалацией и деэскалацией терапии (в первую очередь, речь идет о добавлении и отмене ГКС).Целью работы явилось создание алгоритма назначения / отмены иГКС у пациентов с ХОБЛ, получающих поддерживающую терапию ДД двойными бронходилататорами, а также разработка терапевтического континуума, при котором учитываются анамнез обострений, выраженность симптомов, уровень эозинофилии периферической крови, а также наличие сопутствующей бронхиальной астмы.Заключение. Эта схема может быть полезна как инструмент длительного ведения пациентов в условиях ограничения доступности специализированной медицинской помощи. При применении указанной схемы, легко применимой в реальной клинической практике, учитываются основные современные рекомендации по ведению пациентов с ХОБЛ

Бронхиальная астма: федеральные клинические рекомендации по диагностике и лечению

Bronchial asthma is a heterogeneous disease that requires identification of its phenotype and a personalized approach to therapy. At the same time, despite a wide range of therapeutic options, many patients with asthma cannot achieve control over the disease.Methodology. The target audience of these clinical recommendations are general practitioners, therapists, pediatricians, allergologists-immunologists, pulmonologists, and functional diagnostics doctors. Each thesis-recommendation about diagnostic and therapeutic procedures has been scored according to the scales of classes of recommendations from 1 to 5 and A, B, C scale of the levels of evidence. The clinical recommendations also contain comments and explanations to the theses, algorithms for the diagnosis and treatment of bronchial asthma, and reference materials.Conclusion. The presented clinical guidelines cover current information about the etiology and pathogenesis, classification, clinical manifestations, diagnosis, treatment, and prevention of bronchial asthma. These guidelines were approved by the Scientific and Practical Council of the Ministry of Health of the Russian Federation in 2021. Бронхиальная астма (БА) является гетерогенным заболеванием, при котором требуется выделение различных фенотипов и персонифицированный подход к терапии. При этом несмотря на широкий выбор терапевтических возможностей, у многих пациентов с БА не удается достичь контроля над заболеванием.Методы. Целевой аудиторией данных клинических рекомендаций являются врачи общей практики, терапевты, педиатры, аллергологи-иммунологи, пульмонологи и врачи функциональной диагностики. Каждый тезис-рекомендация по проведению диагностических и лечебных мероприятий оценивается по шкалам уровней достоверности доказательств от 1 до 5 и шкале оценки уровней убедительности рекомендаций по категориям А, В, С. Клинические рекомендации содержат также комментарии и разъяснения к указанным тезисам-рекомендациям, алгоритмы по диагностике и лечению БА, справочные материалы.Заключение. По данным представленных клинических рекомендаций освещаются современные сведения об этиологии и патогенезе, классификации, клинических проявлениях, диагностике, лечении и профилактике БА. Клинические рекомендации одобрены Научно-практическим Советом Министерства здравоохранения Российской Федерации (2021).

Clinical features of post-COVID-19 period. Results of the international register “Dynamic analysis of comorbidities in SARS-CoV-2 survivors (AKTIV SARS-CoV-2)”. Data from 6-month follow-up

Aim. To study the clinical course specifics of coronavirus disease 2019 (COVID-19) and comorbid conditions in COVID-19 survivors 3, 6, 12 months after recovery in the Eurasian region according to the AKTIV register. Material and methods.The AKTIV register was created at the initiative of the Eurasian Association of Therapists. The AKTIV register is divided into 2 parts: AKTIV 1 and AKTIV 2. The AKTIV 1 register currently includes 6300 patients, while in AKTIV 2 — 2770. Patients diagnosed with COVID-19 receiving in- and outpatient treatment have been anonymously included on the registry. The following 7 countries participated in the register: Russian Federation, Republic of Armenia, Republic of Belarus, Republic of Kazakhstan, Kyrgyz Republic, Republic of Moldova, Republic of Uzbekistan. This closed multicenter register with two nonoverlapping branches (in- and outpatient branch) provides 6 visits: 3 in-person visits during the acute period and 3 telephone calls after 3, 6, 12 months. Subject recruitment lasted from June 29, 2020 to October 29, 2020. Register will end on October 29, 2022. A total of 9 fragmentary analyzes of the registry data are planned. This fragment of the study presents the results of the post-hospitalization period in COVID-19 survivors after 3 and 6 months. Results. According to the AKTIV register, patients after COVID-19 are characterized by long-term persistent symptoms and frequent seeking for unscheduled medical care, including rehospitalizations. The most common causes of unplanned medical care are uncontrolled hypertension (HTN) and chronic coronary artery disease (CAD) and/or decompensated type 2 diabetes (T2D). During 3- and 6-month follow-up after hospitalization, 5,6% and 6,4% of patients were diagnosed with other diseases, which were more often presented by HTN, T2D, and CAD. The mortality rate of patients in the post-hospitalization period was 1,9% in the first 3 months and 0,2% for 4-6 months. The highest mortality rate was observed in the first 3 months in the group of patients with class II-IV heart failure, as well as in patients with cardiovascular diseases and cancer. In the pattern of death causes in the post-hospitalization period, following cardiovascular causes prevailed (31,8%): acute coronary syndrome, stroke, acute heart failure. Conclusion. According to the AKTIV register, the health status of patients after COVID-19 in a serious challenge for healthcare system, which requires planning adequate health system capacity to provide care to patients with COVID-19 in both acute and post-hospitalization period