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

Lifetime history of indoor tanning in young people: a retrospective assessment of initiation, persistence, and correlates

<p>Abstract</p> <p>Background</p> <p>Despite educational and public health campaigns to convey the risks of indoor tanning, many individuals around the world continue to engage in this behavior. Few descriptive studies of indoor tanning have collected information pertaining to the lifetime history of indoor tanning, thereby limiting our ability to understand indoor tanning patterns and potentially target interventions for individuals who not only initiate, but continue to persistently engage in indoor tanning.</p> <p>Methods</p> <p>In-person interviews elicited detailed retrospective information on lifetime history of indoor tanning among white individuals (n = 401) under age 40 seen by a dermatologist for a minor benign skin condition. These individuals were controls in a case-control study of early-onset basal cell carcinoma. Outcomes of interest included ever indoor tanning in both males and females, as well as persistent indoor tanning in females - defined as females over age 31 who tanned indoors at least once in the last three or all four of four specified age periods (ages 11-15, 16-20, 21-30 and 31 or older). Multivariate logistic regression was used to identify sociodemographic and lifestyle correlates of ever and persistent indoor tanning in females.</p> <p>Results</p> <p>Approximately three-quarters (73.3%) of females and 38.3% of males ever tanned indoors, with a median age of initiation of 17.0 and 21.5, respectively. Among indoor tanners, 39.3% of females and 21.7% of males reported being burned while indoor tanning. Female ever indoor tanners were younger, had darker color eyes, and sunbathed more frequently than females who never tanned indoors. Using unique lifetime exposure data, 24.7% of female indoor tanners 31 and older persistently tanned indoors starting as teenagers. Female persistent indoor tanners drank significantly more alcohol, were less educated, had skin that tanned with prolonged sun exposure, and sunbathed outdoors more frequently than non-persistent tanners.</p> <p>Conclusions</p> <p>Indoor tanning was strikingly common in this population, especially among females. Persistent indoor tanners had other high-risk behaviors (alcohol, sunbathing), suggesting that multi-faceted behavioral interventions aimed at health promotion/disease prevention may be needed in this population.</p

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

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

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

Ингаляционные глюкокортикостероиды в лечении хронической обструктивной болезни легких

The main objectives of chronic obstructive pulmonary disease (COPD) therapy are to reduce the severity of symptoms and the risk of exacerbations. The article discusses the role of local and systemic inflammation in the pathogenesis of COPD as well as various mechanisms of pharmacological influence on it. Approaches to prescribing basic therapy for patients with COPD, recommended by various national and global guidelines (clinical recommendations of the Russian respiratory society, criteria of the Global Initiative for Chronic Obstructive Lung Disease (GOLD), guidelines of the National Institute for Health and Clinical Excellence (NICE)), as well as recommendations on the therapy frequency review are considered. Currently, so-called triple combinations – fixed combinations of double bronchodilators with inhaled glucocorticosteroids – are being developed and registered in the world, and their place and significance in the treatment of COPD raise many discussions. The paper discusses the role of fixed triple combinations in reducing the incidence of COPD exacerbations, the impact on functional and patient-reported outcomes, and provides recommendations for the use of triple combinations in patients with COPD, taking into account the benefit/risk ratio.Основными задачами терапии хронической обструктивной болезни легких (ХОБЛ) являются уменьшение выраженности симптомов заболевания и снижение риска обострений. В статье обсуждается роль локального и системного воспаления в патогенезе ХОБЛ, а также различные механизмы фармакологического влияния на него. Рассмотрены подходы к назначению базисной терапии пациентам с ХОБЛ, рекомендуемые различными национальными и глобальными руководствами (клинические рекомендации Российского респираторного общества, критерии Глобальной стратегии по лечению хронической обструктивной болезни легких (Global Initiative for Chronic Obstructive Lung Disease – GOLD), руководство Национального института совершенствования здравоохранения Великобритании (National Institute for Health and Clinical Excellence – NICE)), а также рекомендации по периодичности пересмотра терапии. В настоящее время в мире разрабатываются и регистрируются т. н. тройные комбинации – фиксированные комбинации двойных бронхолитических препаратов с ингаляционными глюкокортикостероидами, при этом их место и значение в лечении ХОБЛ вызывает многочисленные дискуссии. В работе обсуждается роль фиксированных тройных комбинаций при снижении частоты обострений ХОБЛ, воздействии на функциональные и пациент-репортированные исходы, приведены рекомендации по применению тройных комбинаций у пациентов с ХОБЛ с учетом соотношения польза / риск

Problems and opportunities to improve diagnosis of asthma and chronic obstructive pulmonary disease in Russia: resolution of advisory board

Asthma and chronic obstructive pulmonary disease remain major problems of medicine, and still there is need to improve the level and quality of diagnosis of these diseases. Primary care physicians (general practitioners, therapists) should be involved widely and actively in this process. To simplify the diagnosis, special questionnaires have been developed, they can be used in a real clinical practice. Only this approach will bring statistical data closer to the true prevalence of these diseases and improve quality of their treatment.Бронхиальная астма и хроническая обструктивная болезнь легких остаются актуальными проблемами современной медицины, при этом сохраняется необходимость повышения уровня и качества диагностики данных заболеваний. Максимально широко и активно в диагностику должны быть вовлечены врачи первичного звена (терапевты, врачи общей практики). Для упрощения постановки диагноза разработаны специальные вопросники, которые могут использоваться в реальной клинической практике. Только такой подход позволит приблизить данные статистического учета к истинной распространенности этих заболеваний и улучшит их качество лечения

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