High diagnosis rate for nonimmune hydrops fetalis with prenatal clinical exome from the Hydrops-Yielding Diagnostic Results of Prenatal Sequencing (HYDROPS) Study.

PURPOSE: Nonimmune hydrops fetalis (NIHF) presents as life-threatening fluid collections in multiple fetal compartments and can be caused by both genetic and non-genetic etiologies. We explored incremental diagnostic yield of testing with prenatal exome sequencing (ES) for NIHF following a negative standard NIHF workup. METHODS: Participants enrolled into the Hydrops-Yielding Diagnostic Results of Prenatal Sequencing (HYDROPS) study met a strict definition of NIHF and had negative standard-of-care workup. Clinical trio ES from fetal samples and parental blood was performed at a CLIA-certified reference laboratory with clinical reports returned by geneticists and genetic counselors. Negative exomes were reanalyzed with information from subsequent ultrasounds and records. RESULTS: Twenty-two fetal exomes reported 11 (50%) diagnostic results and five possible diagnoses (22.7%). Diagnosed cases comprised seven de novodominant disorders, three recessive disorders, and one inherited dominant disorder including four Noonan syndromes (PTPN11, RAF1, RIT1, and RRAS2), three musculoskeletal disorders (RYR1, AMER1, and BICD2), two metabolic disorders (sialidosis and multiple sulfatase deficiency), one Kabuki syndrome, and one congenital anemia (KLF1). CONCLUSION: The etiology of NIHF predicts postnatal prognosis and recurrence risk in future pregnancies. ES provides high incremental diagnostic yield for NIHF after standard-of-care testing and should be considered in the workup.

A systematic review of monogenic etiologies of nonimmune hydrops fetalis.

Hydrops fetalis (HF), accumulation of fluid in two or more fetal compartments, is life-threatening to the fetus. Genetic etiologies include many chromosomal and monogenic disorders. Despite this, the clinical workup typically evaluates limited genetic targets. To support broader molecular testing of pregnancies with HF, we cataloged the spectrum of monogenic disorders associated with nonimmune hydrops fetalis (NIHF). We performed a systematic literature review under PROSPERO tag CRD42018099495 of cases reporting NIHF meeting strict phenotypic criteria and well-defined genetic diagnosis. We ranked the evidence per gene based on number of reported cases, phenotype, and molecular/biochemical diagnosis. We identified 131 genes with strong evidence for an association with NIHF and 46 genes with emerging evidence spanning the spectrum of multisystem syndromes, cardiac disorders, hematologic disorders, and metabolic disorders. Several genes previously implicated with NIHF did not have any reported cases in the literature with both fetal hydrops and molecular diagnosis. Many genes with strong evidence for association with NIHF would not be detected using current sequencing panels. Nonimmune HF has many possible monogenic etiologies, several with treatment implications, but current diagnostic approaches are not exhaustive. Studies are needed to assess if broad sequencing approaches like exome sequencing are useful in clinical management of HF.

Intramuscular progesterone in women with twins and a prior singleton spontaneous preterm birth.

BACKGROUND: Although the use of 17-alpha-hydroxyprogesterone caproate is one of the most commonly used strategies to reduce the risk of preterm birth since its approval by the Food and Drug Administration in 2011, there has been controversy recently that there may be no benefit associated with its use in singleton pregnancies in women with a prior history of spontaneous preterm birth. However, very few of these investigations evaluated the use of intramuscular progesterone in twin pregnancies. A few studies that used 17-alpha-hydroxyprogesterone caproate in twin pregnancies had mainly included unselected twin pregnancies. Although a twin pregnancy is independently associated with an increased likelihood of preterm birth, the primary indication for the use of supplemental progesterone in pregnancy is prior history of spontaneous preterm birth. Therefore, our investigation of weekly intramuscular progesterone in twin pregnancies with this birth history best addresses this question using a selected cohort. OBJECTIVE: To assess whether weekly 17-alpha-hydroxyprogesterone caproate prevents recurrent preterm birth in women with a current twin pregnancy and a prior singleton spontaneous preterm birth. STUDY DESIGN: This was a retrospective cohort study of women with twin pregnancy and a prior singleton spontaneous preterm birth in 2 institutions between January 2005 and December 2016. One group (intervention group) consisted of women who received weekly 17-alpha-hydroxyprogesterone caproate, whereas the other (control group) did not. The primary outcome was twin spontaneous preterm birth <34 weeks compared with odds ratio and adjusted odds ratio, adjusting for potential confounders. Secondary outcomes included composite neonatal morbidity such as respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis, admission to the neonatal intensive care nursery, and fetal or neonatal death before hospital discharge. RESULTS: A total of 79 patients were included; 27 women received weekly 17-alpha-hydroxyprogesterone caproate and 52 did not. There were no statistically significant differences in maternal demographics except for age. Spontaneous preterm birth <34 weeks occurred in 16 patients (59%) in the intervention group vs 24 (46%) in the control group (odds ratio, 1.69; 95% confidence interval, 0.68-4.54). Composite neonatal morbidity occurred in 20 pregnancies (74%) in the intervention group and 41 pregnancies (79%) in the control group (odds ratio, 0.76; 95% confidence interval, 0.27-2.12). There remained no differences in outcomes after adjusting for potential confounders. CONCLUSION: In our study, weekly 17-alpha-hydroxyprogesterone caproate did not prevent spontaneous preterm birth or neonatal morbidity in women with twins and a prior singleton spontaneous preterm birth; however, further research with larger numbers and prospective design is needed.

Predictors of 30-day hospital readmission after mechanical thrombectomy for acute ischemic stroke.

OBJECTIVE: The 30-day readmission rate is of increasing interest to hospital administrators and physicians, as it is used to evaluate hospital performance and is associated with increased healthcare expenditures. The estimated yearly cost to Medicare of readmissions is $17.4 billion. The Centers for Medicare and Medicaid Services therefore track unplanned 30-day readmissions and institute penalties against hospitals whose readmission rates exceed disease-specific national standards. One of the most important conditions with potential for improvement in cost-effective care is ischemic stroke, which affects 795,000 people in the United States and is a leading cause of death and disability. Recent widespread adoption of mechanical thrombectomy has revolutionized stroke care, requiring reassessment of readmission causes and costs in this population. METHODS: The authors retrospectively analyzed a prospectively maintained database of stroke patients and identified 561 patients who underwent mechanical thrombectomy between 2010 and 2019 at the authors' institution. Univariate and multivariate analyses were conducted to identify clinical variables and comorbidities related to 30-day readmissions in this patient population. RESULTS: Of the 561 patients, 85.6% (n = 480) survived their admission and were discharged from the hospital to home or rehabilitation, and 8.8% (n = 42/480) were readmitted within 30 days. The median time to readmission was 10.5 days (IQR 6.0-14.3). The most common reasons for readmission were infection (33.3%) and acute cardiac or cerebrovascular events (19% and 20%, respectively). Multivariate analysis showed that hypertension (p = 0.030; OR 2.72) and length of initial hospital stay (p = 0.040; OR 1.032) were significantly correlated with readmission within 30 days, while hemorrhagic conversion (grades 3 and 4) approached significance (p = 0.053; OR 2.23). Other factors, such as unfavorable outcome at discharge, history of coronary artery disease, and discharge destination, did not predict readmission. CONCLUSIONS: The study data demonstrate that hypertension, length of hospital stay, and hemorrhagic conversion were predictors of 30-day hospital readmission in stroke patients after mechanical thrombectomy. Infection was the most common cause of 30-day readmission, followed by cardiac and cerebrovascular diagnoses. These results therefore may serve to identify patients within the stroke population who require increased surveillance following discharge to reduce complications and unplanned readmissions.

Endoscopic retrograde cholangiopancreatography in the elderly: results of a retrospective study and a geriatricians' point of view.

BACKGROUND: The incidence of biliary tract pathology is growing with an age-related trend, and progresses as the population ages. Endoscopic Retrograde Cholangiopancreatography (ERCP) represents the gold standard for treatment in these cases, but evidence about its safety in the elderly is still debated. METHODS: We retrospectively analyzed the clinical records of all patients aged ≥65 undergoing ERCP between July 2013 and July 2015. Of 387 ERCP cases, 363 (~ 94%) were completed entirely. The mean age of the study population (n = 363) was 79.9 years old (range 70-95), with 190 subjects aged 70-79 and 173 older than 80. We recorded demographics, Charlson Comorbidity index (CCI), American Society of Anesthesiologists (ASA) physical status classification score, indication for the use of the ERCP procedure, and clinical outcomes. Then, we tested all variables to identify the potential risk factors for complications associated with the procedure. RESULTS: The older group (those ≥80 years old) showed significantly more patients with ASA Classes III-IV than the younger one (those ≤79 years old). Interestingly, the CCI was higher in the younger group (p = 0.009). The overall complication rate was 17.3% without inter-group differences. Older age, sex, CCI and intra-ERCP procedures were not related to a higher risk of complications, and the multivariate regression did not identify any of the considered variables to be an independent risk factor for complications. CONCLUSION: ERCP appears as safe in the patients aged 80 years and older, as it is in those aged 70-79 years old in our study, however, a selection bias may affect these findings. A study including a comprehensive geriatric assessment will contribute to shedding light on this issue.

A Comprehensive Database and Analysis Framework To Incorporate Multiscale Data Types and Enable Integrated Analysis of Bioactive Polyphenols.

The development of a given botanical preparation for eventual clinical application requires extensive, detailed characterizations of the chemical composition, as well as the biological availability, biological activity, and safety profiles of the botanical. These issues are typically addressed using diverse experimental protocols and model systems. Based on this consideration, in this study we established a comprehensive database and analysis framework for the collection, collation, and integrative analysis of diverse, multiscale data sets. Using this framework, we conducted an integrative analysis of heterogeneous data from in vivo and in vitro investigation of a complex bioactive dietary polyphenol-rich preparation (BDPP) and built an integrated network linking data sets generated from this multitude of diverse experimental paradigms. We established a comprehensive database and analysis framework as well as a systematic and logical means to catalogue and collate the diverse array of information gathered, which is securely stored and added to in a standardized manner to enable fast query. We demonstrated the utility of the database in (1) a statistical ranking scheme to prioritize response to treatments and (2) in depth reconstruction of functionality studies. By examination of these data sets, the system allows analytical querying of heterogeneous data and the access of information related to interactions, mechanism of actions, functions, etc., which ultimately provide a global overview of complex biological responses. Collectively, we present an integrative analysis framework that leads to novel insights on the biological activities of a complex botanical such as BDPP that is based on data-driven characterizations of interactions between BDPP-derived phenolic metabolites and their mechanisms of action, as well as synergism and/or potential cancellation of biological functions. Out integrative analytical approach provides novel means for a systematic integrative analysis of heterogeneous data types in the development of complex botanicals such as polyphenols for eventual clinical and translational applications.

Association Between Preoperative Malnutrition and Postoperative Delirium After Hip Fracture Surgery in Older Adults.

OBJECTIVES: To determine whether poor nutritional status can predict postoperative delirium in elderly adults undergoing hip fracture surgery. DESIGN: Prospective observational cohort study. SETTING: Italian orthogeriatric unit. PARTICIPANTS: Individuals aged 70 and older (mean age 84.0 ± 6.6, 74.5% female) consecutively admitted for surgical repair of a proximal femur fracture between September 2012 and April 2016 (N = 415). MEASUREMENTS: Participants underwent a comprehensive geriatric assessment including nutritional status, which was evaluated using the Mini Nutritional Assessment Short Form (MNA-SF). The MNA-SF-based three-class stratification was tested using multivariable logistic regression to assess its role in predicting postoperative delirium (outcome). RESULTS: Seventy-eight malnourished individuals (MNA-SF score 0-7), 185 at risk of malnutrition (MNA-SF score 8-11), and 152 who were well nourished (MNA-SF score 12-14) were compared. On average, individuals with poor nutritional status were more disabled and more cognitively impaired than those who were well nourished and those at risk of malnutrition. Moreover, those who were malnourished were more likely to have postoperative delirium. Multivariate regression analysis adjusted for age, sex, comorbidity, functional impairment, preoperative cognitive status, and American Society of Anesthesiologists score showed that those who were at risk of malnutrition (odds ratio (OR) = 2.42, 95% confidence interval (CI) = 1.29-4.53) and those who were overtly malnourished (OR = 2.98, 95% CI = 1.43-6.19) were more likely to develop postoperative delirium. CONCLUSION: This is the first study in a Western population showing that risk of malnutrition and overt malnutrition, as assessed using the MNA-SF, are independent predictors of postoperative delirium. Accordingly, nutritional status should be assessed in individuals with hip fracture before surgery to determine risk of developing delirium.

Autonomic Nervous System Dysfunctions as a Basis for a Predictive Model of Risk of Neurological Disorders in Subjects with Prior History of Traumatic Brain Injury: Implications in Alzheimer's Disease.

Autonomic dysfunction is very common in patients with dementia, and its presence might also help in differential diagnosis among dementia subtypes. Various central nervous system structures affected in Alzheimer's disease (AD) are also implicated in the central autonomic nervous system (ANS) regulation. For example, deficits in central cholinergic function in AD could likely lead to autonomic dysfunction. We recently developed a simple, readily applicable evaluation for monitoring ANS disturbances in response to traumatic brain injury (TBI). This ability to monitor TBI allows for the possible detection and targeted prevention of long-term, detrimental brain responses caused by TBI that lead to neurodegenerative diseases such as AD. We randomly selected and extracted de-identified medical record information from subjects who have been assessed using the ANS evaluation protocol. Using machine learning strategies in the analysis of information from individual as well as a combination of ANS evaluation protocol components, we identified a novel prediction model that is effective in correctly segregating between cases with or without a documented history of TBI exposure. Results from our study support the hypothesis that trauma-induced ANS dysfunctions may contribute to clinical TBI features. Because autonomic dysfunction is very common in AD patients it is possible that TBI may also contribute to AD and/or other forms of dementia through these novel mechanisms. This study provides a novel prediction model to physiologically assess the likelihood of subjects with prior history of TBI to develop clinical TBI complications, such as AD.