Conflicting Interpretation of Genetic Variants and Cancer Risk by Commercial Laboratories as Assessed by the Prospective Registry of Multiplex Testing

Altres ajuts: Ambry Genetics, Myriad Genetics, Novartis (I), Pfizer (I)Massively parallel sequencing allows simultaneous testing of multiple genes associated with cancer susceptibility. Guidelines are available for variant classification; however, interpretation of these guidelines by laboratories and providers may differ and lead to conflicting reporting and, potentially, to inappropriate medical management. We describe conflicting variant interpretations between Clinical Laboratory Improvement Amendments-approved commercial clinical laboratories, as reported to the Prospective Registry of Multiplex Testing (PROMPT), an online genetic registry. Clinical data and genetic testing results were gathered from 1,191 individuals tested for inherited cancer susceptibility and self-enrolled in PROMPT between September 2014 and October 2015. Overall, 518 participants (603 genetic variants) had a result interpreted by more than one laboratory, including at least one submitted to ClinVar, and these were used as the final cohort for the current analysis. Of the 603 variants, 221 (37%) were classified as a variant of uncertain significance (VUS), 191 (32%) as pathogenic, and 34 (6%) as benign. The interpretation differed among reporting laboratories for 155 (26%). Conflicting interpretations were most frequently reported for CHEK2 and ATM, followed by RAD51C, PALB2, BARD1, NBN, and BRIP1. Among all participants, 56 of 518 (11%) had a variant with conflicting interpretations ranging from pathogenic/likely pathogenic to VUS, a discrepancy that may alter medical management. Conflicting interpretation of genetic findings from multiplex panel testing used in clinical practice is frequent and may have implications for medical management decisions

DYNAMIC SONOGRAPHY OF THE EQUINE METACARPO(TARSO)PHALANGEAL DIGITAL FLEXOR TENDON SHEATH

Palmar/plantar annular desmitis is a common disease that may be associated with adhesions and structures affecting the flexor tendons, which requires tenoscopy to diagnose. The purpose of this descriptive study was to develop a dynamic sonographic technique for evaluating the motion of normal equine flexor tendons in relation to the palmar/plantar annular ligament and to compare findings with horses previously diagnosed with palmar/plantar annular desmitis. Ten healthy adult horses were examined prospectively and the images of four horses diagnosed with palmar/plantar annular desmitis were retrospectively evaluated. Dynamic sonography was performed at the level of the metacarpo/metatarsophalangeal joint by maximally extending and flexing the interphalangeal joints. Palmar/plantar annular ligament thickness (mm), size of any gap between the flexor tendons, and subjectively increased angulation of the long linear echoes of the superficial digital flexor tendon were measured. The presence of gliding motion between the palmar/plantar annular ligament and superficial digital flexor tendon was determined by consensus. Twenty-eight healthy control limbs (16 hind/12 fore) and four with palmar/plantar annular desmitis (3 hind/1 fore) were evaluated. Controls had unrestricted gliding motion between the palmar/plantar annular ligament and flexor tendons and zero to 13° of angulation of the long linear echoes. The four affected horses had restricted gliding motion and between 20-35° angulation of the long linear echoes. Dynamic ultrasound is a feasible technique for detecting restricted flexor tendon and palmar/plantar annular ligament gliding motion, as well as subjectively increased angulation of the long linear echoes of the flexor tendon in affected horses compared with controls and warrants further investigation

A Case of Massive Hepatic Infarction in a Patient with HELLP Syndrome

Abstract Background Hepatic infarction is an exceedingly rare complication of hemolysis, elevated liver enzymes, and low platelets syndrome. Few cases have been described in the medical literature and the true incidence remains unknown. It can lead to fulminant liver failure, liver transplant, or death if not promptly addressed. Case Report A 22-year-old primigravida presented with right upper quadrant and epigastric pain at 28 weeks' gestation. She had severely elevated blood pressures requiring intravenous antihypertensives as well as proteinuria, thrombocytopenia, and mild transaminitis. Within 6 hours of admission, her rapidly rising liver function tests (LFTs) necessitated urgent delivery by primary cesarean section. Her liver enzymes continued to rapidly worsen postoperatively and immediate postpartum computed tomography of the abdomen and pelvis revealed massive hepatic infarction, 11 × 10 × 15 cm, of the right lobe of the liver. Her transaminases peaked at alanine transferase of 2,863 IU/L and aspartate transferase of 2,732 IU/L. She received supportive multidisciplinary intensive care, and LFTs returned to normal by postoperative day 20. Conclusion Hepatic infarction is an extraordinarily rare complication of pre-eclampsia. Early recognition and prompt multidisciplinary management are vital to prevent catastrophic bleeding, hepatic failure, and death

Determinant of Prenatal Diagnostic Testing among Women with Increased Risk of Fetal Aneuploidy and Genetic Disorders.

OBJECTIVE:  This study aimed to assess factors that influence patients decisions in accepting prenatal diagnostic testing following genetic counseling for increased risk of fetal aneuploidy. METHODS:  This is a retrospective cohort study of women at increased risk of fetal aneuploidy and genetic disorders who had genetic counseling from January 2012 to December 2016 at a single academic center. Demographics, indications for genetic counseling, and rates of diagnostic testing were collected and compared between those who accepted diagnostic testing and those who chose cell free DNA. The variables were analyzed using Chi-square, Fishers exact test, and multiple logistic regression. RESULT:  Of the 2,373 pregnant women who underwent genetic counseling for increased risk of fetal aneuploidy and genetic disorders during the study period, 321 women had diagnostic testing (13.5%). Women at 35 years and older accepted diagnostic testing more than women younger than 35 years (20.7 vs. 11.5%, p < 0.001). Asian women accepted diagnostic testing at 27.7% more than white, non-Hispanic Black, and Hispanic women at 18.0, 12.1, and 11.7%, respectively, p = 0.002. Number of indications for genetic counseling influenced the likelihood of accepting diagnostic testing. Women with one indication had 11.5% acceptance of diagnostic testing, and with two and three indications, it was 17.0 and 29.2%, respectively. The commonest indication for diagnostic testing was cystic hygroma (risk ratio [RR] = 7.5, 95% confidence interval [CI]: 3.12-8.76 p < 0.001). The relative risk of diagnostic testing for fetuses with shortened long bones, femur and humerus, thickened nuchal fold, echogenic bowel, single umbilical artery, and increased nuchal translucency were 4.0, 3.3, 3.1, 2.7, and 2.7, respectively. Abnormal serum analyte alone was associated with less acceptance of diagnostic testing (RR = 0.8, 95% CI: 0.7-0.96, p = 0.017). CONCLUSION:  Age, race, ethnicity, and cumulative number of indications for genetic counseling influenced acceptance of diagnostic testing in at-risk women of fetal aneuploidy and genetic disorders. KEY POINTS: · Genetic counseling.. · Fetal aneuploidy.. · Genetic disorders.. · Prenatal diagnostic testing. Prenatal diagnostic testing in women with increased risk of fetal aneuploidy and genetic disorders.

Determinant of prenatal diagnostic testing among women with increased risk of fetal aneuploidy and genetic disorders

Objective: This study aimed to assess factors that influence patients\u27 decisions in accepting prenatal diagnostic testing following genetic counseling for increased risk of fetal aneuploidy. Methods: A retrospective cohort study of women at increased risk of fetal aneuploidy who had genetic counseling from January 2012 to December 2016 at a single academic center. Demographics, indications for genetic counseling and rates of diagnostic testing were collected and compared between those who accepted diagnostic testing and those who chose cell free DNA. The variables were analyzed using chi-square, Fisher exact test, and multiple logistic regression. Result: Of the 2373 pregnant women who underwent genetic counseling for increased risk of fetal aneuploidy during the study period, 321 women had diagnostic testing (13.5%). Women at 35 years and older accepted diagnostic testing more than women younger than 35 years (20.7% versus 11.5%, p \u3c 0.001). Asian women accepted diagnostic testing at 27.7% more than white, non-Hispanic Black and Hispanic women at 18.0%, 12.1% and 11.7% respectively, p = 0.002. Number of indications for genetic counseling influenced the likelihood of accepting diagnostic testing. Women with one indication had 11.5% acceptance of diagnostic testing; and with two and three indications, it was 17.0% and 29.2% respectively. The commonest indication for diagnostic testing was cystic hygroma (RR 7.5, 95% CI 3.12-8.76 p \u3c 0.001). The relative risk of diagnostic testing for fetuses with shortened long bones; femur and humerus, thickened nuchal fold, echogenic bowel, single umbilical artery, increased nuchal translucency were 4.0, 3.3, 3.1, 2.7, and 2.7 respectively. Abnormal serum analyte alone was associated with less acceptance of diagnostic testing (RR 0.8, 95% CI 0.7 - 0.96, p = 0.017). Conclusion: Age, race, ethnicity and cumulative number of indications for genetic counseling influenced acceptance of diagnostic testing in at-risk women of fetal aneuploidy and genetic disorders

Agitation and Dementia: Prevention and Treatment Strategies in Acute and Chronic Conditions

International audienceAgitation is a behavioral syndrome characterized by increased, often undirected, motor activity, restlessness, aggressiveness, and emotional distress. According to several observations, agitation prevalence ranges from 30 to 50% in Alzheimer's disease, 30% in dementia with Lewy bodies, 40% in frontotemporal dementia, and 40% in vascular dementia (VaD). With an overall prevalence of about 30%, agitation is the third most common neuropsychiatric symptoms (NPS) in dementia, after apathy and depression, and it is even more frequent (80%) in residents of nursing homes. The pathophysiological mechanism underlying agitation is represented by a frontal lobe dysfunction, mostly involving the anterior cingulate cortex (ACC) and the orbitofrontal cortex (OFC), respectively, meaningful in selecting the salient stimuli and subsequent decision-making and behavioral reactions. Furthermore, increased sensitivity to noradrenergic signaling has been observed, possibly due to a frontal lobe up-regulation of adrenergic receptors, as a reaction to the depletion of noradrenergic neurons within the locus coeruleus (LC). Indeed, LC neurons mainly project toward the OFC and ACC. These observations may explain the abnormal reactivity to weak stimuli and the global arousal found in many patients who have dementia. Furthermore, agitation can be precipitated by several factors, e.g., the sunset or low lighted environments as in the sundown syndrome, hospitalization, the admission to nursing residencies, or changes in pharmacological regimens. In recent days, the global pandemic has increased agitation incidence among dementia patients and generated higher distress levels in patients and caregivers. Hence, given the increasing presence of this condition and its related burden on society and the health system, the present point of view aims at providing an extensive guide to facilitate the identification, prevention, and management of acute and chronic agitation in dementia patients