Subjective and Objective Sonographic Assessment for the Prenatal Detection of Neonatal Coarctation of the Aorta.

INTRODUCTION: The objective of this study was to assess the performance of antenatal ultrasound markers in detecting neonatal coarctation of the aorta (CoA). METHODS: We performed a retrospective study including fetuses with suspected CoA and no other cardiac abnormalities. Data obtained from antenatal ultrasounds included subjective assessment of ventricular and arterial asymmetry, appearance of aortic arch, presence of a persistent left superior vena cava, and objective Z-score measurements of the mitral, tricuspid, aortic (AV), and pulmonary (PV) valves. Performance of antenatal ultrasound markers in predicting postnatal CoA was then assessed. RESULTS: Of the 83 fetuses referred for suspected CoA, 30 (36.1%) had confirmed CoA postnatally. The sensitivity and specificity for antenatal diagnosis were 83.3% (95% confidence interval [CI]: 65.3-94.4%) and 45.3% (95% CI: 31.6-59.6%), respectively. Neonates with confirmed CoA had lower mean AV Z-scores (-2.1 vs. -1.1, p = 0.01), higher PV Z-scores (1.6 vs. 0.8, p = 0.03), and a lower AV/PV ratio (0.5 vs. 0.6, p < 0.001). Subjective assessments of symmetry and the incidence of persistent left superior vena cava did not differ between groups. Among the variables studied, the most promising marker for CoA was the AV/PV ratio (area under the receiver operating characteristics curve 0.81, 95% CI: 0.67-0.94). CONCLUSION: The use of objective sonographic markers, in particular measurements of the AV and PV, shows a trend toward an improvement in prenatal detection of CoA. Confirmation in larger studies is required.

Trends in utilization of first-line palliative treatments for anal squamous cell carcinoma.

BACKGROUND: Anal squamous cell carcinoma patients often present with significant symptoms, including pain, bleeding, and obstructive symptoms. This requires palliation-directed therapy as a first-line treatment to alleviate symptoms. The proportion of patients receiving first-line palliative treatments is unknown. We aimed to study the factors associated with the use of first-line palliative treatments in stage II-IV anal squamous cell carcinoma patients. METHODS: We used the National Cancer Database to identify adult patients diagnosed with stage II-IV anal squamous cell carcinoma between 2004 and 2016. We performed univariable and multivariable logistic regression analysis to determine the clinical and sociodemographic variables associated with the utilization of palliative treatment in the first-line setting, including palliative radiotherapy, chemotherapy, surgery, and pain management. RESULTS: Among 16,944 patients diagnosed with stage II-IV anal squamous cell carcinoma, only a small proportion of 492 (2.9%) required first-line palliative treatments to control symptoms. The majority of these patients received palliative radiotherapy (32%), followed by palliative surgery (25%), palliative chemotherapy (19%), combination therapies (14%), and pain management (10%). On multivariable analysis, higher stage disease, lower income, Medicare and Medicaid insurance, and life expectancy <6 months were associated with higher odds of use of first-line palliative therapy. CONCLUSIONS: First-line use of palliative treatments to control symptoms is needed in a small proportion of anal squamous cell cancer patients. It was utilized in all stages, but it was most frequently observed in patients with stage IV disease and patients with <6 months life expectancy. First-line palliative therapy was also more frequent in lower-income patients and patients with Medicare and Medicaid insurance which highlights the disparities in anal cancer management.

Near-complete vision recovery from bilateral serous retinal detachment associated with thrombotic thrombocytopenic purpura.

Ocular manifestations of thrombotic thrombocytopenic purpura (TTP) are uncommon, and bilateral retinal detachment is a rare presentation of TTP. We report a rare case of bilateral retinal detachment from underlying TTP in a patient presenting with vision loss. A 56-year-old man presented with a 4-day history of bilateral vision loss. Bilateral serous retinal detachment was confirmed using dilated ophthalmoscope examination. Laboratory results were significant for severe thrombocytopenia, peripheral smear revealed numerous schistocytes and ADAMTS13 activity of less than 1%. The patient was treated with plasma exchange (PLEX), prednisone, rituximab and caplacizumab. This case report highlights that prompt treatment of TTP with PLEX, prednisone, rituximab and caplacizumab could result in significant vision recovery.

Outcomes and predictors of readmission after implantation of a percutaneous left atrial appendage occlusion device in the United States: A propensity score-matched analysis from The National Readmission Database.

BACKGROUND: Left atrial appendage occlusion (LAAO) devices have become a favorable alternative option among nonvalvular atrial fibrillation (AF) patients with long-term contraindication to anticoagulation. Real-world experience with postprocedural readmission rates and predictors of readmission in LAAO patients is limited. OBJECTIVE: To assess all-cause 30-day readmission rate and predictors of readmission after LAAO procedure in the United States. METHOD: This retrospective observational study included all AF patients undergoing percutaneous LAAO procedures in the United States from January 1, 2016, and December 31, 2017, in the National Readmission Database. The primary outcome measure was all-cause 30-day readmission. A propensity score-matched analysis compared outcomes with a non-LAAO AF cohort. RESULT: Among 14 024 LAAO procedures (age: 76 ± 8 years; 60.5% males), 9.4% were readmitted within 30-days and, 0.2% died during their index hospitalization. The most frequent primary diagnosis during readmission among LAAO was gastrointestinal bleeding (12%). The incidence of LAAO procedures increased by 102%. In the multivariate model, gender and CHA2 DS2 -VASc failed to predict readmission. Age 55-64 years had lower odds (adjusted odds ratios [aOR]: 0.41; 95% confidence interval [CI]: 0.18-0.94), while drug abuse (aOR: 4.1; 95% CI: 1.34-12.54), and deficiency anemia (aOR: 1.88; 95% CI: 1.12-3.18) had higher odds of readmission. In propensity-matched cohort, compared to non-LAAO AF, LAAO patients had lower 30-day readmission (9.4% vs. 10.98%, p = .002) and all-cause in-hospital mortality (0.19% vs. 0.57%, p < .001). CONCLUSION: The readmission rate following the LAAO procedure is substantial (approximately 10%), and largely attributable to gastrointestinal bleeding. Factors such as drug abuse and anemia must be explored further to minimize readmission risk.

Cannabis-induced basal-mid-left ventricular stress cardiomyopathy: A case report.

Cannabis, popularly known as marijuana, is a recreational drug derived from the plant Cannabis Sativa. It has been recognized as the most widely used mood-altering substance in the world and is falsely perceived as a safe substance by the public at large. This is mostly due to lack of awareness of its adverse effects as well as successful attempts for legalization of its use in many states. We present a unique case of a 56-year-old man who presented with neurological deficits concerning for stroke. Soon after presentation, he required endotracheal intubation for airway protection due to worsening mental status changes and pulmonary edema. Echocardiogram revealed severe hypokinesis of the basal and mid-left ventricular (LV) walls with hyperdynamic motion of the apex (reverse takotsubo). Coronary angiography revealed no obstructive disease. Urine toxicology screen was positive for Δ-9-tetrahydrocannabinol. The patient then stated to have used excess marijuana before the symptom onset, while denying any recent emotional stressors. The findings were consistent with stress cardiomyopathy (SC) triggered by marijuana use. Myocardial infarction, stroke, and peripheral arteriopathy have been increasingly reported in younger individuals using marijuana. SC appears to be another unique complication of marijuana use triggered through its effects on the autonomic nervous and endocannabinoid systems.

Cardiac transplantation for hypertrophic cardiomyopathy in the United States 2003-2011.

BACKGROUND: Cardiac transplant (CT) is the sole option in a minority of hypertrophic cardiomyopathy (HC) adults with refractory symptoms or end-stage disease. AIMS/METHODS: We aimed to examine the trends and hospital outcomes of CT in HC using 2003-2011 Nationwide Inpatient Sample database. RESULTS: HC comprised 1.1% of CT (151 of 14,277) performed during this time period (age 45±12 years, 67% male, 79% Caucasians). Number of HC CT increased from 2003 to 2011 (odds ratio=1.174; 95% confidence interval=1.102-1.252; P< 0.001). Comorbidities included congestive heart failure (76%), hypertension (23%), chronic kidney disease (23%), hyperlipidemia (19%), diabetes (13%), and coronary artery disease (10%). Acute in-hospital major adverse events occurred in 1 in 4 (23%) patient and 1 in 25 (3.8%) patients died perioperatively. Other major adverse events included allograft rejection or vasculopathy (23%), postoperative stroke or transient ischemic attack (3.5%), acute renal failure (43%), respiratory failure requiring mechanical ventilation (13%), sepsis (10%) or need for blood transfusion (10%). Compared to 1990-2004 United Network of Organ Sharing registry data (n=303), patients in current cohort had more comorbid conditions [diabetes (13%-vs-0%); chronic obstructive lung disease (9%-vs-1%); P < 0.001 for both), were more likely to be male (66%-vs-48% P< 0.001), were less likely to be Caucasian (79%-vs-86%; P < 0.001) or smokers (3%-vs-17%; P < 0.001) and less often required perioperative circulatory support or hemodialysis (17%-vs-49%, P < 0.001 and 3.2%-vs-8.3%, P = 0.04, respectively). CONCLUSION: HC comprises a small proportion of patients undergoing CT. The annual number of CT in HC has increased in recent years at least in part due to inclusion of patients with more comorbid conditions. Transplant recipients in the current cohort, however, required less postoperative circulatory support or renal replacement therapy.

Influence of comorbidity on survival after out-of-hospital cardiac arrest in the United States.

AIM: Association between survival rate and Elixhauser Comorbidity Index (ECI) among individuals suffering an out-of-hospital cardiac arrest (OHCA) in the United States (US). METHODS: We utilized the US National Emergency Department Sample (NEDS) dataset to retrospectively identify individuals experiencing OHCA between January 1, 2006 to December 31, 2015; using the International Classification of Diseases, Ninth Revision-Clinical Modification (ICD-9-CM) and Tenth Revision-Clinical Modification (ICD-10-CM) codes. Logistic regression analysis with twenty-nine ECIs as predictor variables were performed to compute for odds ratio (OR), after controlling for age and gender. Linear regression analysis performed to assess survival trend after clustering based on ECI. We also assessed the association of ECI with survival rate after stratifying patients based on cardiac rhythm (shockable versus non-shockable). RESULTS: We identified 1,282,520 (16.4%, survived-to-discharge) weighted observations presenting primarily after OHCA in the US during the study period. Annual percentage change (APC) in survival rate among OHCA patients with no ECI and those with >3 ECI was -1.53% (95% CI: -1.98% to -1.09%, Ptrend < 0.001) and 1.2% (95% CI: 0.69%-1.7%, Ptrend = 0.001), respectively. Adjusted OR for ECI was 1.31 (95% CI: 1.3-1.31, P < 0.001). Percentage change in the survival rate among shockable and non-shockable rhythm was 5.6% (95% CI: -3.9% to 15.13%, Ptrend = 0.127) and 1.04% (95% CI: 0.01%-2.07%, Ptrend = 0.05), respectively, with a unit increase in ECI. CONCLUSION: In the US, OHCA patients with higher ECI have greater survival-to-discharge rate, demonstrating "comorbidity paradox".

Postoperative infections in women undergoing hysterectomy for benign indications: a cohort study.

BACKGROUND: There is limited data on the incidence of postoperative infections following hysterectomy by route of surgery. We hypothesize that vaginal hysterectomy has lower rates of postoperative infection than laparoscopic and abdominal hysterectomies. METHODS: A retrospective cohort study and independent hand review of charts of participants undergoing hysterectomy at five hospitals from September 2011 through May 2015 was performed. Cases were identified using International Classification of Diseases, Ninth Revision, Clinical Modification codes and were reviewed by the investigators. The primary outcome was the development of Clostridium difficile infection, urinary tract infection, surgical site infection, or yeast vaginitis within 60 days following surgery. RESULTS: In total, 2742 women underwent hysterectomy: abdominal 17.5% (AH), laparoscopic 65.8% (LH), and vaginal 16.7% (VH). The composite postoperative infection rate for the four specified variables was 8.5% (232). In comparing surgical route, AH was most commonly associated with CDI (0.6%, p <0.001), SSI (6.0%, P=0.001), and yeast vaginitis (1.9%, p <0.001), while VH was most commonly associated with UTI (8.1%, P=0.002). After controlling for demographic and operative factors, multivariable analysis showed that hysterectomy route was not associated with infection. Independent predictors for postoperative infection were increasing age, American Society of Anesthesiologists physical status classification, operative time, and hospital type. CONCLUSIONS: Infectious complications after hysterectomy are uncommon, accounting for 8.5% of cases. Multivariable analysis showed that demographic and operative variables were more likely to serve as independent predictors of development of infection than hysterectomy route.

Dynamic left ventricular changes in patients with gestational diabetes: A speckle tracking echocardiography study.

PURPOSE: The left ventricle (LV) undergoes physiologic remodeling in adaptation to the hemodynamic changes that occur in pregnancy. Speckle tracking echocardiography (STE) is a novel and reliable tool to evaluate subtle myocardial alterations that have been utilized to assess myocardial changes in patients with diabetes mellitus (DM) but not in patients with gestational DM (GDM). We seek to evaluate changes in LV function using STE in patients with GDM compared with women with normal pregnancy. METHODS: This was a single-center retrospective cohort study. A total of 312 pregnant patients that underwent transthoracic echocardiogram (TTE) between 2009 and 2014 were screened. After excluding patients with comorbidities or insufficient data, 90 women were included. TTE from the second and third trimester for each patient were then reviewed, and STE analysis was performed. RESULTS: Of the 90 subjects, 72 had normal pregnancies and 18 developed GDM. There was no difference in LV end-diastolic diameter (4.73 ± 0.40 versus 4.60 ± 0.56, p = 0.25), LV end-systolic diameter (3.12 ± 0.35 versus 2.91 ± 0.61, p = 0.152), or ejection fraction (62.26 ± 4.12 versus 63.50 ± 5.24, p = 0.314) between the two groups. Global longitudinal strain was lower (-19.8 ± 3.34 versus -17.2 ± 2.18, p < 0.001) in patients with GDM, while time-to-peak strain was greater (0.43 ± 0.05 versus 0.50 ± 0.06, p < 0.001). Circumferential and radial strains were preserved in both groups. CONCLUSIONS: Although conventional TTE variables show preserved LV size and function, LV longitudinal strain suggests subclinical myocardial dysfunction in patients with GDM. © 2016 Wiley Periodicals, Inc. J Clin Ultrasound 45:20-27, 2017.

Protective effect of cytomegalovirus reactivation on relapse after allogeneic hematopoietic cell transplantation in acute myeloid leukemia patients is influenced by conditioning regimen.

Cytomegalovirus (CMV) reactivation after allogeneic hematopoietic cell transplant (allo-HCT) has been associated with a reduced risk of relapse in patients with acute myeloid leukemia (AML). However, the influence of the conditioning regimen on this protective effect of CMV reactivation after allo-HCT is relatively unexplored. To address this, we evaluated the risk of relapse in 264 AML patients who received T cell-replete, 6/6 HLA matched sibling or 10/10 HLA matched unrelated donor transplantation at a single institution between 2006 and 2011. Of these 264 patients, 206 received myeloablative (MA) and 58 received reduced-intensity conditioning (RIC) regimens. CMV reactivation was observed in 88 patients with MA conditioning and 37 patients with RIC. At a median follow-up of 299 days, CMV reactivation was associated with significantly lower risk of relapse in patients who received MA conditioning both in univariate (P = .01) and multivariate analyses (hazard ratio, .5246; P = .006); however, CMV reactivation did not significantly affect the risk of relapse in our RIC cohort. These results confirm the protective effect of CMV reactivation on relapse in AML patients after allo-HCT reported by previous studies but suggest this protective effect of CMV reactivation on relapse is influenced by the conditioning regimen used with the transplant.

Photocontrolled nanoparticles for on-demand release of proteins.

We describe here light-regulated swelling and degradation features of polymeric nanoparticles that are produced using an inverse microemulsion polymerization method. We demonstrate the phototriggered release characteristics of the nanoparticles by sequestering protein molecules and releasing them using light as a trigger. Furthermore, the intracellular translocation of the nanoparticles, along with its fluorescent protein payload, was achieved using a cell-penetrating peptide-based surface modification. We expect that the noncovalent encapsulation of proteins using nanoparticles and their photo triggered release using an external light would provide opportunities for achieving intracellular release of molecular therapeutics for on-demand requirements.

Quantitative neuropathological changes in presymptomatic Huntington's disease.

Morphometric studies of the tail of the caudate nucleus, the site where the pathology is first seen, were performed on 16 brain specimens collected from individuals at risk for inheriting Huntington's disease (HD). Medical records and information obtained from immediate family members indicated that all had died without symptoms of HD. Six individuals had 37 or more CAG repeats and were designated HD gene carriers, whereas 10 were determined to be non-carriers. Cell counts of the tail of the caudate nucleus revealed an increased density of oligodendrocytes among the presymptomatic HD gene carriers (mean cells/field: carriers = 40.0, noncarrier = 21.3; age, sex, repeated measure adjusted F[126] = 11.7, p = 0.0008). No statistically significant differences were found between HD carriers and noncarriers in the density of neurons (carriers = 16.9, noncarriers = 15.5), astrocytes (carriers = 27.8, noncarriers = 21.3) or microglial cells (carriers = 7.9, noncarriers = 5.6). Ubiquitin immunostaining performed in 3 gene carriers revealed intranuclear inclusions in all 3 cases, including 1, with 37 repeats, who died 3 decades before the expected age for onset of the clinical syndrome. Normal densities of other cell types and careful macroscopic examination suggest that the increase in oligodendroglial density is not a consequence of atrophy and may instead reflect a developmental effect of the HD gene.

Analysis of germline mutation spectra at the Huntington's disease locus supports a mitotic mutation mechanism.

Trinucleotide repeat disease alleles can undergo 'dynamic' mutations in which repeat number may change when a gene is transmitted from parent to offspring. By typing >3500 sperm, we determined the size distribution of Huntington's disease (HD) germline mutations produced by 26 individuals from the Venezuelan cohort with CAG/CTG repeat numbers ranging from 37 to 62. Both the mutation frequency and mean change in allele size increased with increasing somatic repeat number. The mutation frequencies averaged 82% and, for individuals with at least 50 repeats, 98%. The extraordinarily high mutation frequency levels are most consistent with a mutation process that occurs throughout germline mitotic divisions, rather than resulting from a single meiotic event. In several cases, the mean change in repeat number differed significantly among individuals with similar somatic allele sizes. This individual variation could not be attributed to age in a simple way or to ' cis ' sequences, suggesting the influence of genetic background or other factors. A familial effect is suggested in one family where both the father and son gave highly unusual spectra compared with other individuals matched for age and repeat number. A statistical model based on incomplete processing of Okazaki fragments during DNA replication was found to provide an excellent fit to the data but variation in parameter values among individuals suggests that the molecular mechanism might be more complex.

Length-dependent gametic CAG repeat instability in the Huntington's disease knock-in mouse.

The CAG repeats in the human Huntington's disease (HD) gene exhibit striking length-dependent intergenerational instability, typically small size increases or decreases of one to a few CAGs, but little variation in somatic tissues. In a subset of male transmissions, larger size increases occur to produce extreme HD alleles that display somatic instability and cause juvenile onset of the disorder. Initial efforts to reproduce these features in a mouse model transgenic for HD exon 1 with 48 CAG repeats revealed only mild intergenerational instability ( approximately 2% of meioses). A similar pattern was obtained when this repeat was inserted into exon 1 of the mouse Hdh gene. However, lengthening the repeats in Hdh to 90 and 109 units produced a graded increase in the mutation frequency to >70%, with instability being more evident in female transmissions. No large jumps in CAG length were detected in either male or female transmissions. Instead, size changes were modest increases and decreases, with expansions typically emanating from males and contractions from females. Limited CAG variation in the somatic tissues gave way to marked mosaicism in liver and striatum for the longest repeats in older mice. These results indicate that gametogenesis is the primary source of inherited instability in the Hdh knock-in mouse, as it is in man, but that the underlying repeat length-dependent mechanism, which may or may not be related in the two species, operates at higher CAG numbers. Moreover, the large CAG repeat increases seen in a subset of male HD transmissions are not reproduced in the mouse, suggesting that these arise by a different fundamental mechanism than the small size fluctuations that are frequent during gametogenesis in both species.

Huntingtin interacts with a family of WW domain proteins.

The hallmark neuropathology of Huntington's disease (HD) is due to elongation of a polyglutamine segment in huntingtin, a novel approximately 350 kDa protein of unknown function. We used a yeast two-hybrid interactor screen to identify proteins whose association with huntingtin might be altered in the pathogenic process. Surprisingly, no interactors were found with internal and C-terminal segments of huntingtin. In contrast, huntingtin's N-terminus detected 13 distinct proteins, seven novel and six reported previously. Among these, we identified a major interactor class, comprising three distinct WW domain proteins, HYPA, HYPB and HYPC, that bind normal and mutant huntingtin in extracts of HD lymphoblastoid cells. This interaction is mediated by huntingtin's proline-rich region and is enhanced by lengthening the adjacent glutamine tract. Although HYPB and HYPC are novel, HYPA is human FBP-11, a protein implicated in spliceosome function. The emergence of this class of proteins as huntingtin partners argues that a WW domain-mediated process, such as non-receptor signaling, protein degradation or pre-mRNA splicing, may participate in HD pathogenesis.

Reduced penetrance of the Huntington's disease mutation.

Controversy persists concerning the significance of Huntington disease (HD) alleles in the 36-39 repeat range. Although some clinically affected persons have been documented with repeats in this range, elderly unaffected individuals have also been reported. We examined 10 paternal transmissions of HD alleles of 37-39 repeats in collateral branches of families with de novo HD. All 10 descendants, including many who are elderly, are without symptoms of HD. Forty percent of the transmissions were unstable, although none varied by more than one repeat. The observation that individuals with alleles of 37-39 repeats may survive unaffected beyond common life expectancy supports the presence of reduced penetrance for HD among some persons with repeat sizes which overlap the clinical range. Non-penetrance may be increased in the collateral branches of de novo mutation families when compared to penetrance estimates from patient series. There was no CAA-->CAG mutation for the penultimate glutamine in either a de novo expanded 42 repeat allele or the corresponding non-penetrant 38 repeat allele in a family with fresh mutation to HD.

Differential expression of normal and mutant Huntington's disease gene alleles.

Huntingtin expression was examined by Western blot and immunoprecipitation studies of lymphoblastoid cell lines from Huntington's disease (HD) homozygotes, heterozygotes, and a phenotypically normal individual with a t(4p16.3;12p13.3) breakpoint in the HD gene. The latter produced a reduced level of normal huntingtin without evidence of an altered protein, indicating that simple loss of huntingtin activity does not cause HD. In juvenile onset HD heterozygotes, NH2- and COOH-terminal antisera revealed reduced relative expression from the mutant allele. Pulse-chase studies indicated that huntingtin is a stable protein whose differential allelic expression is not due to destabilization of the mutant isoform. No stable breakdown products specific to mutant huntingtin were detected in either HD homozygotes or heterozygotes. These data are consistent with HD involving either a gain of function or a dominant negative loss of function that operates within severe constraints and suggest that in either case the pathogenic process is usually saturated by the amount of abnormal huntingtin produced from a single mutant allele.

Single sperm analysis of the trinucleotide repeats in the Huntington's disease gene: quantification of the mutation frequency spectrum.

The CAG triplet repeat region of the Huntington's disease gene was amplified in 923 single sperm from three affected and two normal individuals. Average-size alleles (15-18 repeats) showed only three contraction mutations among 475 sperm (0.6%). A 30 repeat normal allele showed an 11% mutation frequency. The mutation frequency of a 36 repeat intermediate allele was 53% with 8% of all gametes having expansions which brought the allele size into the HD disease range (> or = 38 repeats). Disease alleles (38-51 repeats) showed a very high mutation frequency (92-99%). As repeat number increased there was a marked elevation in the frequency of expansions, in the mean number of repeats added per expansion and the size of the largest observed expansion. Contraction frequencies also appeared to increase with allele size but decreased as repeat number exceeded 36. Our sperm typing data are of a discrete nature rather than consisting of smears of PCR product from pooled sperm. This allowed the observed mutation frequency spectra to be compared to the distribution calculated using discrete stochastic models based on current molecular ideas of the expansion process. An excellent fit was found when the model specified that a random number of repeats are added during the progression of the polymerase through the repeated region.