Patient actions and reactions after receiving negative results from expanded carrier screening.

With the expansion of carrier screening to general preconception and prenatal patient populations, most patients will receive negative results, which we define as indicating <25% risk of having a child with a genetic condition. Because there is limited experience with expanded carrier screening, it is important to understand how receiving negative results affects patients, especially as providers, payers, and policymakers consider whether to offer it. In this mixed-methods study, we asked preconception patients enrolled in the NextGen study about their expectations and experiences receiving negative expanded carrier screening results. Participants completed surveys at study enrollment (n = 110 women, 51 male partners), after receiving carrier results (n = 100 women, 38 male partners), after receiving secondary findings (n = 98 women, 36 male partners), and 6 months after receiving results (n = 95 women, 28 male partners). We also interviewed a subset of participants 12 to 24 months after receiving results (n = 24 women, 12 male partners). We found minimal negative emotional impact and privacy concerns, increased confidence in reproductive plans, and few changes to health behaviors, although some patients made health decisions based on misunderstandings of their results. These findings suggest that expanded carrier screening causes minimal psychosocial harms, but systems are needed to reduce the risk of misinterpreting results.

"I think we've got too many tests!": Prenatal providers' reflections on ethical and clinical challenges in the practice integration of cell-free DNA screening.

BACKGROUND: The recent introduction of cell-free DNA-based non-invasive prenatal screening (cfDNA screening) into clinical practice was expected to revolutionize prenatal testing. cfDNA screening for fetal aneuploidy has demonstrated higher test sensitivity and specificity for some conditions than conventional serum screening and can be conducted early in the pregnancy. However, it is not clear whether and how clinical practices are assimilating this new type of testing into their informed consent and counselling processes. Since the introduction of cfDNA screening into practice in 2011, the uptake and scope have increased dramatically. Prenatal care providers are under pressure to stay up to date with rapidly changing cfDNA screening panels, manage increasing patient demands, and keep up with changing test costs, all while attempting to use the technology responsibly and ethically. While clinical literature on cfDNA screening has shown benefits for specific patient populations, it has also identified significant misunderstandings among providers and patients alike about the power of the technology. The unique features of cfDNA screening, in comparison to established prenatal testing technologies, have implications for informed decision-making and genetic counselling that must be addressed to ensure ethical practice. OBJECTIVES: This study explored the experiences of prenatal care providers at the forefront of non-invasive genetic screening in the United States to understand how this testing changes the practice of prenatal medicine. We aimed to learn how the experience of providing and offering this testing differs from established prenatal testing methodologies. These differences may necessitate changes to patient education and consent procedures to maintain ethical practice. METHODS: We used the online American Congress of Obstetricians and Gynecologists Physician Directory to identify a systematic sample of five prenatal care providers in each U.S. state and the District of Columbia. Beginning with the lowest zip code in each state, we took every fifth name from the directory, excluding providers who were retired, did not currently practice in the state in which they were listed, or were not involved in a prenatal specialty. After repeating this step twice and sending a total of 461 invitations, 37 providers expressed interest in participating, and we completed telephone interviews with 21 providers (4.6%). We developed a semi-structured interview guide including questions about providers' use of and attitudes toward cfDNA screening. A single interviewer conducted and audio-recorded all interviews by telephone, and the interviews lasted approximately 30 minutes each. We collaboratively developed a codebook through an iterative process of transcript review and code application, and a primary coder coded all transcripts. RESULTS: Prenatal care providers have varying perspectives on the advantages of cfDNA screening and express a range of concerns regarding the implementation of cfDNA screening in practice. While providers agreed on several advantages of cfDNA, including increased accuracy, earlier return of results, and decreased risk of complications, many expressed concern that there is not enough time to adequately counsel and educate patients on their prenatal screening and testing options. Providers also agreed that demand for cfDNA screening has increased and expressed a desire for more information from professional societies, labs, and publications. Providers disagreed about the healthcare implications and future of cfDNA screening. Some providers anticipated that cfDNA screening would decrease healthcare costs when implemented widely and expressed optimism for expanded cfDNA screening panels. Others were concerned that cfDNA screening would increase costs over time and questioned whether the expansion to include microdeletions could be done ethically. CONCLUSIONS: The perspectives and experiences of the providers in this study allow insight into the clinical benefit, burden on prenatal practice, and potential future of cfDNA screening in clinical practice. Given the likelihood that the scope and uptake of cfDNA screening will continue to increase, it is essential to consider how these changes will affect frontline prenatal care providers and, in turn, patients. Providers' requests for additional guidance and data as well as their concerns with the lack of time available to explain screening and testing options indicate significant potential issues with patient care. It is important to ensure that the clinical integration of cfDNA screening is managed responsibly and ethically before it expands further, exacerbating pre-existing issues. As prenatal screening evolves, so should informed consent and the resources available to women making decisions. The field must take steps to maximize the advantages of cfDNA screening and responsibly manage its ethical issues.

CONTEXTE: L'introduction récente du dépistage prénatal non invasif (dépistage cfDNA) exempt de cellules à base d'ADN dans la pratique clinique devait révolutionner le dépistage prénatal. Le dépistage cfDNA de l'aneuploïdie fœtale a démontré une meilleure sensibilité et spécificité que le dépistage sérique classique et peut être effectué au début de la grossesse. Cependant, on ne sait pas si et comment les pratiques cliniques assimilent ce nouveau type de test dans leurs processus de consentement et de conseil éclairés. Depuis l'introduction du dépistage cfDNA dans la pratique en 2011, l'absorption et la portée ont augmenté de façon spectaculaire. Les professionnels sont sous pression pour rester à jour avec l'évolution rapide des échantillons cfDNA, gérer la demande croissante des patients, et suivre l'évolution des coûts de test, tout en essayant d'utiliser la technologie de manière responsable et éthique. Bien que la littérature clinique sur le dépistage cfDNA a montré des avantages pour les populations de patients spécifiques, elle a également identifié des malentendus importants entre les professionnels et les patients sur le pouvoir de la technologie. Les caractéristiques uniques du dépistage cfDNA, par rapport aux technologies de dépistage prénatal établies, ont des implications pour la prise de décisions éclairées et le conseil génétique qui rentrent en compte pour assurer une pratique éthique. OBJECTIFS: Cette étude a exploré les expériences des professionnels à la pointe du dépistage génétique non invasif aux États-Unis pour comprendre comment ce test modifie la pratique de la médecine prénatale. Nous avons cherché à savoir comment l'expérience de fournir et d'offrir ce test diffère des méthodes plus anciennes de dépistage prénatal. Ces différences peuvent nécessiter des changements dans l'éducation du patient et les procédures de consentement pour maintenir une pratique éthique. MÉTHODES: Nous avons utilisé l'annuaire en ligne du Congrès américain des médecins obstétriciens et gynécologues pour identifier un échantillon systématique de cinq fournisseurs de soins prénatals dans chaque État américain et le District de Columbia. En commençant par le code postal le plus bas dans chaque état, nous avons pris tous les cinquièmes noms de l'annuaire, à l'exclusion des prestataires qui étaient à la retraite, ne pratiquait pas actuellement dans l'état dans lequel ils ont été énumérés, ou ne sont pas impliqués dans une spécialité prénatale. Après avoir répété cette étape deux fois et l'envoi d'un total de 461 invitations, 37 professionnels ont exprimé leur intérêt à participer, et nous avons réalisé des entrevues téléphoniques avec 21 fournisseurs (4,6 %). Nous avons développé un entretien semi-dirigé comprenant des questions sur l'utilisation de fournisseurs de dépistage et les attitudes envers le cfDNA. Un seul intervieweur a mené et enregistré toutes les interviews par téléphone, les entretiens ont duré environ 30 minutes chacun. Nous avons développé en collaboration un dictionnaire par un processus itératif d'examen de la transcription et de l'application du code, et un codeur primaire a codé toutes les transcriptions. RÉSULTATS: Les professionnels de soins prénataux ont des points de vue variés sur les avantages du dépistage cfDNA et expriment une gamme de préoccupations concernant la mise en œuvre du dépistage cfDNA dans la pratique. S'ils ont convenu de plusieurs avantages de cfDNA, y compris une précision accrue, un retour plus rapide des résultats et une diminution de risque de complications, une préoccupation exprimée est qu'il n'y a pas suffisamment pour conseiller et éduquer les patients sur les options de dépistage et de dépistage prénatal. Les professionnels ont également convenu que la demande pour le dépistage cfDNA a augmenté et ont souhaité plus d'informations émanant des sociétés professionnelles, des laboratoires et des publications. Les fournisseurs étaient en désaccord au sujet des implications sur la santé et sur l'avenir du dépistage cfDNA. Certains fournisseurs prévoyaient que le dépistage cfDNA diminuerait les coûts des soins de santé lorsqu'ils seront appliqués largement et a exprimé son optimisme pour l'élargissement des échantillons de dépistage cfDNA. D'autres craignaient que le dépistage cfDNA augmenterait les coûts au fil du temps et se sont demandé si la possibilité d'y inclure les microdélétions pourrait être fait sur le plan éthique. CONCLUSIONS: Les perspectives et les expériences des fournisseurs dans cette étude permettent d'avoir un aperçu de l'avantage clinique, de la charge sur la pratique prénatale, et du futur potentiel du dépistage cfDNA dans la pratique clinique. Compte tenu de la probabilité que la portée et l'acceptation du dépistage cfDNA vont continuer à augmenter, il est essentiel d'examiner comment ces changements auront une incidence sur les fournisseurs de soins prénataux de première ligne et sur les patients. Les demandes de professionnels pour obtenir des conseils et des données supplémentaires ainsi que leurs préoccupations sur le manque de temps disponible pour expliquer aux patients les options de dépistage et de tests indiquent des problèmes potentiellement lourds. Il est important de veiller à ce que l'intégration clinique du dépistage cfDNA soit gérée de façon responsable et éthique avant qu'il ne se développe davantage, aggravant les problèmes préexistants. Comme le dépistage prénatal évolue, de même devrait évoluer le consentement éclairé et les ressources disponibles pour que les femmes puissent prendre leur décision. La discipline doit prendre des mesures pour maximiser les avantages du dépistage cfDNA et gérer de façon responsable les questions éthiques qui s'y rapportent.

Pulmonary capillaritis and alveolar hemorrhage. Update on diagnosis and management.

Pulmonary vascular inflammatory disorders may involve all components of the pulmonary vasculature, including capillaries. The principal histopathologic features of pulmonary capillaritis include capillary wall necrosis with infiltration by neutrophils, interstitial erythrocytes, and/or hemosiderin, and interalveolar septal capillary occlusion by fibrin thrombi. Immune complex deposition is variably present. Patients often present clinically with diffuse alveolar hemorrhage, which is characterized by dyspnea and hemoptysis; diffuse, bilateral, alveolar infiltrates on chest radiograph; and anemia. Pulmonary capillaritis has been reported with variable frequency and severity as a manifestation of Wegener's granulomatosis, microscopic polyarteritis, systemic lupus erythematosus, Goodpasture's syndrome, idiopathic pulmonary renal syndrome, Behçet's syndrome, Henoch-Schönlein purpura, IgA nephropathy, antiphospholipid syndrome, progressive systemic sclerosis, and diphenylhydantoin use. In addition to history, physical examination, and routine laboratory studies, certain ancillary laboratory tests, such as antineutrophil cytoplasmic antibodies, antinuclear antibodies, and antiglomerular basement membrane antibodies, may help diagnose an underlying disease. Diagnosis of pulmonary capillaritis can be made by fiberoptic bronchoscopy with transbronchial biopsy, but thoracoscopic biopsy is often employed. Since many disorders can result in pulmonary capillaritis with diffuse alveolar hemorrhage, it is crucial for clinicians and pathologists to work together when attempting to identify an underlying disease. Therapy depends on the disorder that gave rise to the pulmonary capillaritis and usually includes corticosteroids and cyclophosphamide or azathioprine. Since most diseases that result in pulmonary capillaritis are treated with immunosuppression, infection must be excluded aggressively.

Effect of blood and albumin on pulmonary hypertension and edema in perfused rabbit lungs.

Perfusate composition may alter pulmonary hemodynamics and edema formation in perfused lungs. Perfusion for 3 h with Krebs-Henseleit solution with 3% bovine serum albumin did not produce pulmonary hypertension, pulmonary edema (assessed by lung wet-to-dry wt ratio), or increased macromolecular permeability (assessed by 125I-albumin uptake). Addition of blood to hematocrit levels of 10 or 20% resulted in pulmonary hypertension during the final hour of perfusion but not pulmonary edema or increased macromolecular permeability. Pulmonary hypertension during blood perfusion was primarily due to increased precapillary resistance. Perfusion with buffer solution without albumin produced edema and increased macromolecular permeability but not pulmonary hypertension. In lungs perfused with blood (20% hematocrit), thromboxane B2 levels increased in parallel with the pulmonary hypertension, and inhibition of cyclooxygenase or thromboxane synthase with indomethacin or dazmegrel prevented pulmonary hypertension. Perfusion with leukopenic blood (from prior nitrogen mustard administration or from filtration) also prevented pulmonary hypertension. We conclude that blood perfusion produces pulmonary hypertension via thromboxane A2 generation, which depends on leukocyte activation, and that perfusion with buffer solutions without albumin produces edema and increased permeability without pulmonary hypertension.

Isoproterenol prevents oxidant-induced injury in isolated rabbit lungs.

Increased vascular permeability in the adult respiratory distress syndrome is due in part to toxic oxygen metabolites. In the present study, we produced lung injury in the isolated rabbit lung with hydrogen peroxide (H2O2) and examined its prevention with isoproterenol. Pulmonary arterial pressure (Ppa) and the fluid filtration coefficient (Kf) were measured as indices of lung injury. Rabbits were divided into two groups, and 7 mmol/l H2O2 was administered in both groups. In one group, isoproterenol (2 micrograms/ml) was administered 10 min before H2O2 injury. Ppa increased transiently after H2O2 administration in the control group but was unchanged in the isoproterenol group. Kf was significantly increased by H2O2 administration in the control group but not in the isoproterenol group. We conclude that H2O2 increases pulmonary vascular permeability and that isoproterenol may protect against H2O2-induced pulmonary injury.

Effect of hyperglycemia on neuronal changes in a rabbit model of focal cerebral ischemia.

In clinical medicine, cerebral ischemia is frequently due to a focal, rather than global, insult. The effect of hyperglycemia in focal cerebral ischemia is not well defined. We studied the effect of hyperglycemia on neuropathologic changes in a rabbit model of focal cerebral ischemia. Rabbits were randomized to receive saline (n = 12) or glucose (n = 12) infusions. The left anterior cerebral and left internal carotid arteries were clipped after the infusion began. After 6 hours of occlusion, the area of severe ischemic neuronal damage in the left neocortex and striatum on two standard sections of brain was calculated and expressed as a percentage of the total area of the left cortex or striatum. The mean +/- SEM cortical area of severe ischemic neuronal damage was 22.1 +/- 2.8% in the glucose-treated rabbits and 34.0 +/- 4.6% in the saline-treated rabbits (p less than 0.05). The cortical area of severe ischemic neuronal damage was inversely correlated with plasma glucose concentration at the time of arterial clipping (p less than 0.05). We conclude that hyperglycemia is associated with decreased histologic neuronal injury in this model of focal cerebral ischemia and may be protective when cerebral ischemia occurs from a focal insult.