Vineland Adaptive Behavior Scale in a Cohort of Four ADNP Syndrome Patients Implicates Age-Dependent Developmental Delays with Increased Impact of Activities of Daily Living.

Activity-dependent neuroprotective protein (ADNP) is one of the lead genes in autism spectrum disorder/intellectual disability. Heterozygous, de novo ADNP mutations cause the ADNP syndrome. Here, to evaluate natural history of the syndrome, mothers of two ADNP syndrome boys aged 6 and a half and two adults aged 27 years (man and woman) were subjected to Vineland III questionnaire assessing adaptive behavior. The boys were assessed again about 2 years after the first measurements. The skill measures, presented as standard scores (SS) included domains of communication, daily living, socialization, motor skills and a sum of adaptive behavior composite. The age equivalent (AE) and growth scale values (GSV) encompassing 11 subdomains assess the age level at which the subject's raw score is found at a norm sample median and the individual temporal progression, respectively. The norm referenced standard scores age-matched, mean 100 ± 15 of the two children showed the lowest outcome in communication (SS: 20-30). Daily living skills presented SS of 50-60, with a possible potential loss of some activities as the child ages, especially in interpersonal relationships with people outside of the immediate family (boy A). In contrast, in socialization, both children were at the SS of 38, with some positive increase to SS of ~ 45 (interpersonal relations with family members and coping skills, depending on the particular individual), 2 years later. Interestingly, there was an apparent large difference in motor skills (gross and fine) at the young age, with subject B showing a relatively higher level of skills (SS: 70), decreasing to subject A level (SS: 40) 2 years later. Together, the adaptive behavior composite suggested a level of SS: 39-48 with B showing a potential increase (SS: 41-44) and A, a substantial decrease (SS: 48-39), suggesting a strong impact of daily living skills. Adults were at SS: 20, which is the lowest possible score. AE showed minor improvements for subject A and B, with all AE values being below 3 years. GSVs for subject A showed some improvement with age, especially in interpersonal, play and leisure, and gross motor subdomains. GSV for subject B showed minor improvements in the various subdomains. Notably, all subjects showed a percentile rank < 1 compared with age-matched norms except for subject B as to motor domain (2nd percentile) at the age of 6 years. In summary, the results, especially comparing SS and AEs between childhood and adulthood, implied a continuous deterioration of activities compared to the general population, encompassing a slower developmental process coupled to possible neurodegeneration, strongly supporting a great need for disease modifying medicinal procedures.

GammaTile® brachytherapy in the treatment of recurrent glioblastomas.

BACKGROUND: GammaTile® (GT) is a recent U.S. Food and Drug Administration (FDA) cleared brachytherapy platform. Here, we report clinical outcomes for recurrent glioblastoma patients after GT treatment following maximal safe resection. METHODS: We prospectively followed twenty-two consecutive Isocitrate Dehydrogenase (IDH) wild-type glioblastoma patients (6 O6-Methylguanine-DNA methyltransferase methylated (MGMTm); sixteen MGMT unmethylated (MGMTu)) who underwent maximal safe resection of recurrent tumor followed by GT placement. RESULTS: The cohort consisted of 14 second and eight third recurrences. In terms of procedural safety, there was one 30-day re-admission (4.5%) for an incisional cerebrospinal fluid leak, which resolved with lumbar drainage. No other wound complications were observed. Six patients (27.2%) declined in Karnofsky Performance Score (KPS) after surgery due to worsening existing deficits. One patient suffered a new-onset seizure postsurgery (4.5%). There was one (4.5%) 30-day mortality from intracranial hemorrhage secondary to heparinization for an ischemic limb. The mean follow-up was 733 days (range 279-1775) from the time of initial diagnosis. Six-month local control (LC6) and twelve-month local control (LC12) were 86 and 81%, respectively. Median progression-free survival (PFS) was comparable for MGMTu and MGMTm patients (~8.0 months). Median overall survival (OS) was 20.0 months for the MGMTu patients and 37.4 months for MGMTm patients. These outcomes compared favorably to data in the published literature and an independent glioblastoma cohort of comparable patients without GT treatment. CONCLUSIONS: This clinical experience supports GT brachytherapy as a treatment option in a multi-modality treatment strategy for recurrent glioblastomas.

Electrocardiographic manifestations of COVID-19: Effect on cardiac activation and repolarization.

BACKGROUND: Prolonged QT intervals are reported in patients with COVID-19. Additionally, virus particles in heart tissue and abnormal troponin levels have been reported. Consequently, we hypothesize that cardiac electrophysiologic abnormalities may be associated with COVID-19. METHODS: This is a retrospective study between March 15th, 2020 and May 30th, 2020 of 828 patients with COVID-19 and baseline ECG. Corrected QT (QTc) and QRS intervals were measured from ECGs performed prior to intervention or administration of QT prolonging drugs. QTc and QRS intervals were evaluated as a function of disease severity (patients admitted versus discharged; inpatients admitted to medical unit vs ICU) and cardiac involvement (troponin elevation >0.03 ng/ml, elevated B-natriuretic peptide (BNP) or NT pro-BNP >500 pg/ml). Multivariable analysis was used to test for significance. Odds ratios for predictors of disease severity and mortality were generated. FINDINGS: Baseline QTc of inpatients was prolonged compared to patients discharged (450.1±30.2 versus 423.4±21.7  msec, p<0.0001) and relative to a control group of patients with influenza (p=0.006). Inpatients with abnormal cardiac biomarkers had prolonged QTc and QRS compared to those with normal levels (troponin - QTc: 460.9±34.6 versus 445.3±26.6  msec, p<0.0001, QRS: 98.7±24.6 vs 90.5±16.9  msec, p<0.0001; BNP - QTc: 465.9±33.0 versus 446.0±26.2  msec, p<0.0001, QRS: 103.6±25.3 versus 90.6±17.6 msec, p<0.0001). Findings were confirmed with multivariable analysis (all p<0.05). QTc prolongation independently predicted mortality (8.3% increase in mortality for every 10  msec increase in QTc; OR 1.083, CI [1.002, 1.171], p=0.04). INTERPRETATION: QRS and QTc intervals are early markers for COVID-19 disease progression and mortality. ECG, a readily accessible tool, identifies cardiac involvement and may be used to predict disease course. FUNDING: St. Francis Foundation.

Reduced cardiac function is associated with cardiac injury and mortality risk in hospitalized COVID-19 Patients.

BACKGROUND: Cardiac injury is common in COVID-19 patients and is associated with increased mortality. However, it remains unclear if reduced cardiac function is associated with cardiac injury, and additionally if mortality risk is increased among those with reduced cardiac function in COVID-19 patients. HYPOTHESIS: The aim of this study was to assess cardiac function among COVID-19 patients with and without biomarkers of cardiac injury and to determine the mortality risk associated with reduced cardiac function. METHODS/RESULTS: This retrospective cohort study analyzed 143 consecutive COVID-19 patients who had an echocardiogram during hospitalization between March 1, 2020 and May 5, 2020. The mean age was 67 ± 16 years. Cardiac troponin-I was available in 131 patients and an increased value (>0.03 ng/dL) was found in 59 patients (45%). Reduced cardiac function, which included reduced left or right ventricular systolic function, was found in 40 patients (28%). Reduced cardiac function was found in 18% of patients without troponin-I elevation, 42% with mild troponin increase (0.04-5.00 ng/dL) and 67% with significant troponin increase (>5 ng/dL). Reduced cardiac function was also present in more than half of the patients on mechanical ventilation or those deceased. The in-hospital mortality of this cohort was 28% (N = 40). Using logistic regression analysis, we found that reduced cardiac function was associated with increased mortality with adjusted odds ratio (95% confidence interval) of 2.65 (1.18 to 5.96). CONCLUSIONS: Reduced cardiac function is highly prevalent among hospitalized COVID-19 patients with biomarkers of myocardial injury and is independently associated with mortality.

Mitochondrial function parameters as a tool for tailored drug treatment of an individual with psychosis: a proof of concept study.

Pharmacological treatment of mental disorders is currently decided based on "trial and error" strategy. Mitochondrial multifaceted dysfunction is assumed to be a major factor in the pathophysiology and treatment of schizophrenia (SZ) and bipolar disorder (BD). This study aimed to explore the feasibility of using a profile of mitochondrial function parameters as a tool to predict the optimal drug for an individual patient (personalized medicine). Healthy controls (n = 40), SZ (n = 48) and BD (n = 27) patients were recruited. Mental and global state of the subjects, six mitochondrial respiration parameters and 14 mitochondrial function-related proteins were assessed in fresh lymphocytes following in-vitro or in-vivo treatment with five antipsychotic drugs and two mood-stabilizers. In healthy controls, hierarchal clustering shows a drug-specific effect profile on the different mitochondrial parameters following in-vitro exposure. Similar changes were observed in untreated SZ and BD patients with psychosis. Following a month of treatment of the latter patients, only responders showed a significant correlation between drug-induced in-vitro effect (prior to in-vivo treatment) and short-term in-vivo treatment effect for 45% of the parameters. Long- but not short-term psychotropic treatment normalized mitochondria-related parameters in patients with psychosis. Taken together, these data substantiate mitochondria as a target for psychotropic drugs and provide a proof of concept for selective mitochondrial function-related parameters as a predictive tool for an optimized psychotropic treatment in a given patient. This, however, needs to be repeated with an expanded sample size and additional mitochondria related parameters.

Prevalence of Coronary Artery Calcium in Patients With Atrial Fibrillation With and Without Cardiovascular Risk Factors.

The burden of coronary artery atherosclerosis in patients with atrial fibrillation (AF) is unknown. We aimed to assess the coronary artery calcium (CAC) in AF patients. We retrospectively analyzed 324 consecutive patients with AF who had CT angiogram before AF ablation and their cardiovascular risk were prospectively collected. Mean age of the cohort was 66 years and 71% were male. The previous history of coronary artery disease (CAD) was present in 19% (n = 63) and CAC was positive in all. In patients without known CAD (n = 261), CAC was present in 70% (n = 182) with a comparable prevalence between men and women, which raised the prevalence of coronary atherosclerosis to 76% (n = 245) for the entire cohort. The median CAC score was 170 (range 1 to 6,157) and largely in multivessel distribution in patients without known CAD. Presence of CAC increased with an increasing number of cardiovascular risk factors. Nevertheless, CAC was present in 58% (n = 40) of patients without conventional cardiovascular risk factors. If CAC score >100 was considered as CAD equivalent as 10-year risk of incident atherosclerotic cardiovascular diseases is >7.5% it would have resulted in higher CAD prevalence of 52% and significant reclassification of CHA2DS2-VASc score in 41% of patients without known CAD. In conclusion, coronary calcium is highly prevalent in AF patients, including those without cardiovascular risk factors. Advanced CAC can potentially shift CHA2DS2-VASc score in many AF patients. Our findings suggest that characterizing CAC in AF may be clinically valuable in thromboembolic risk stratification and management of preventive cardiac therapies.

Rationale and design for AMPLATZER Amulet Left Atrial Appendage Occluder IDE randomized controlled trial (Amulet IDE Trial).

The Amulet IDE Trial is an ongoing, prospective, randomized, multi-national trial, designed to evaluate the safety and effectiveness of the AMPLATZER Amulet Left Atrial Appendage Occluder for stroke prevention in comparison to the WATCHMAN Left Atrial Appendage Closure Device in patients with non-valvular atrial fibrillation. METHODS: Non-valvular atrial fibrillation patients at high risk of stroke (CHADS2 score ≥2 or a CHA2DS2-VASc score of ≥3) who are suitable candidates for left atrial appendage occlusion (LAAO) will be fully informed and requested to participate in the trial. A total of 1878 patients at up to 150 sites worldwide will be randomized in a 1:1 ratio between the AMPLATZER Amulet device (investigational) and the Boston Scientific WATCHMAN device (control). Each patient will be followed for 5 years, with follow-up assessments at discharge, 45 days, 3, 6, 9, 12, 18, and 24 months and then annually. The trial has three primary endpoints: A composite of procedure-related complications, or all-cause death, or major bleeding through 12 months (safety); a composite of ischemic stroke or systemic embolism through 18 months (effectiveness); and effective device LAAO, defined as residual jet around the device ≤5 mm at the 45-day visit (mechanism of action). SUMMARY: The Amulet IDE Trial is the first randomized head-to-head LAAO device trial and will provide data for the AMPLATZER Amulet occluder in a population with a high risk of stroke and bleeding.

Immediate Effects of Transcranial Direct Current Stimulation on Obsession-Induced Anxiety in Refractory Obsessive-Compulsive Disorder: A Pilot Study.

OBJECTIVE: Studies have shown that transcranial direct current stimulation (tDCS) has immediate effects on brain activity. The aim of this study was to investigate the potential use of tDCS to regulate obsession-induced anxiety immediately after symptom provocation in patients with refractory obsessive-compulsive disorder (OCD). METHODS: Twelve patients with refractory OCD received cathode, anode, and sham transcranial direct current stimulation over the medial prefrontal cortex conjugant to pharmacological treatment in a crossover design. Before and after the DC stimulation, patients graded the intensity of their anxiety after a short exposure to a provoking stimulus using the visual analogue scale. Clinical questionnaires assessing symptoms severity were also applied before each stimulation mode. RESULTS: We found a statistically significant decrease in the severity of the obsession-induced anxiety (decreased visual analogue scale) as a result of cathode tDCS in comparison with the anode and sham stimulation. Reduction in obsession-induced anxiety was consistent, yet short lasting, and was independent of symptom severity. CONCLUSIONS: Cathode tDCS could be potentially used to regulate obsession-induced anxiety in refractory OCD patients. Further studies are warranted to confirm our results as well as to determine whether tDCS can achieve prolonged benefits in OCD and be of aid in behavioral treatments based on exposure.

Dissecting disease entities out of the broad spectrum of bipolar-disorders.

The etiopathology of bipolar disorders is yet unraveled and new avenues should be pursued. One such avenue may be based on the assumption that the bipolar broad spectrum includes, among others, an array of rare medical disease entities. Towards this aim we propose a dissecting approach based on a search for rare medical diseases with known etiopathology which also exhibit bipolar disorders symptomatology. We further suggest that the etiopathologic mechanisms underlying such rare medical diseases may also underlie a rare variant of bipolar disorder. Such an assumption may be further reinforced if both the rare medical disease and its bipolar clinical phenotype demonstrate a] a similar mode of inheritance (i.e, autosomal dominant); b] brain involvement; and c] data implicating that the etiopathological mechanisms underlying the rare diseases affect biological processes reported to be associated with bipolar disorders and their treatment. We exemplify our suggested approach by a rare case of autosomal dominant leucodystrophy, a disease entity exhibiting nuclear lamin B1 pathology also presenting bipolar symptomatology.

CTA Detection of Left Atrial Stasis and Thrombus in Patients with Atrial Fibrillation.

BACKGROUND: We investigated computed tomography (CT) angiography (CTA) in assessment of left atrial appendage (LAA) stasis and thrombus in preprocedural evaluation for atrial fibrillation (AF) ablation in a large community cohort. METHODS AND RESULTS: We reviewed CTA and transesophageal echocardiographic images obtained in 861 consecutive patients with a history of AF undergoing same-day CTA and transesophageal echocardiogram (TEE) before AF ablation at a single hospital (2006-2013). CTA findings of LAA filling defects from acquisitions without electrocardiogram gating were compared to TEE features of LAA stasis (grade 0-4) and thrombus. Stasis grade 0 or 1 by TEE in the absence of thrombus was defined as a negative result. In addition, LAA peak flow velocity was assessed by TEE. Average age was 61 ± 10 years and 75% were male. On CTA, 161 patients (19%) had LAA filling defects on CTA and 21 had ≥grade 2 stasis on TEE, including two with thrombus, resulting in a positive predictive value of only 13%. However, among 670 CTA-negative patients, 669 (99%) were negative for thrombus or stasis by TEE with one false-negative CTA in a patient with grade 2 stasis by TEE but no thrombus, yielding a negative predictive value of 99.9%. Slow LAA Doppler flow velocity was the most important determinant of false-positive CTA results in multivariate analysis (P < 0.0001) CONCLUSION: LAA filling defects on CT are associated with slow LAA flow velocity. AF patients without LAA filing defects on CT are free of significant stasis and thrombus on TEE. It may be possible to eliminate TEE in up to 80% of AF ablation patients based on negative CTA findings.

Rapid Identification and Characterization of Formulated Protein Products by Raman Spectroscopy Coupled with Discriminant Analysis.

UNLABELLED: The rapid identification of protein drug products for packaging and receiving can significantly reduce disposition cycle time, and thereby improve the efficiency and productivity of the supply chain to better meet the needs of patients. In this feasibility study, we demonstrate a novel methodology that combines Raman spectroscopy with discriminant analysis that can be used for rapid identification or verification of finished products. With this methodology, Raman spectra of formulated therapeutic proteins were collected non-invasively with the samples either in a quartz cuvette or in the original glass vials, and analyzed without subtraction of buffer or placebo solutions. The algorithm used for the discriminant analysis was Mahalanobis distance by principal component analysis with residuals. In addition to product identification, the methodology has the potential to be used for characterizing formulated proteins when exposed to external stresses based on the changes of Mahalanobis distances. LAY ABSTRACT: The rapid identification of protein drug products for packaging and receiving can significantly reduce disposition cycle time, and thereby improve the efficiency and productivity of the supply chain. In this study, we demonstrate a novel methodology that combines Raman spectroscopy with discriminant analysis to rapidly identify formulated proteins non-invasively.

A pilot open study of long term high dose creatine augmentation in patients with treatment resistant negative symptoms schizophrenia.

BACKGROUND: The effects of creatine on brain metabolism and the potential cognitive enhancing properties of this compound raise the possibility of developing a new augmentation therapeutic strategy in schizophrenia especially in patients demonstrating negative and cognitive symptomatology. METHODS: Seven inpatients with chronic schizophrenia presenting with treatment resistant negative symptoms were enrolled into exploratory treatment study with creatine monohydrate augmentation at a daily high-dose of 10 grams, administered for 6 months. Several clinical rating scales and a computerized cognitive assessment battery were applied. RESULTS: Creatine treatment mildly improved the schizophrenia symptomatology but there were no significant changes in cognitive functions. Several ward behaviors were also improved. Tardive parkinsonism improved numerically by above 40% in 4 out of 6 patients. CONCLUSION: This small, open design study of high dose creatine add-on for 6 months in chronic inpatients with schizophrenia demonstrated only mild positive effects on the patients' symptomatology and behavior and might have beneficial effect on tardive parkinsonism.

[Between neurology and psychiatry].

In this review we will discuss the broad spectrum of possible relationships between the fields of neurology and psychiatry alongside weighing the pros and cons of each alternative relationship. This is in the hope that such discussions will allow an informed decision regarding the construction of future relations between these two areas. The possible connections between the areas are discussed in light of possible relationships that exist between the two groups in the mathematical world with reference to the proposed solutions to the psychophysical mind-body problem.

Elevated homocysteine level in siblings of patients with schizophrenia.

Increased homocysteine plasma levels were reported in patients with schizophrenia and Levine et al. (2002) suggested that such increase characterizes mainly males. In the following study we examined whether such increased levels also characterize male siblings of schizophrenia patients. Forty-four pairs of schizophrenia patients and their corresponding healthy male siblings were recruited and sampled for homocysteine. We also had age-matched controls for each of the sibling. The median homocysteine plasma level for patients was 13.0 µMol/L and 11.7 µMol/L for their male siblings compared with a median of 10.9 µMol/L for the siblings' controls. There was no significant difference between homocysteine plasma level in patients and their siblings. Significant difference was found for homocysteine plasma level between the siblings' group and their matched controls. A partial correlation of Ln plasma homocysteine level between patients and their siblings was found to be close to a zero correlation of -0.089, p=0.57 for the whole study group and -0.15, p=0.38 in the male-male patient-sibling pairs. Our results show that elevated homocysteine plasma level may characterize schizophrenia patients' male siblings, a finding that seems to agree with previous studies suggesting elevated homocysteine level as a risk factor for developing schizophrenia.

A pilot dose-finding clinical trial of creatine monohydrate augmentation to SSRIs/SNRIs/NASA antidepressant treatment in major depression.

Creatine's effects on brain energy metabolism raise the possibility of developing a new therapeutic strategy in depression focusing on the treatment of metabolic hypoactive brain areas. Previous creatine augmentation studies in patients with major depression showed a beneficial effect. Eighteen patients (14 women) with major depression not responding to previous 3 weeks of antidepressant treatment were enrolled into a pilot, dose finding, 4-week double-blind parallel augmentation study where creatine monohydrate 5 or 10 g daily or placebo was added to ongoing SSRIs/SNRIs/NASA treatment. Rating scales included the Hamilton Depression Rating Scale and the Clinical Global Impression Severity scale. Overall, there was no difference between creatine administered at 5 or 10 g daily and its corresponding placebos. Two female patients on creatine augmentation, but none on the placebo, showed early improvement of more than 50% reduction in Hamilton Depression Rating Scale after 2 weeks of creatine treatment. No clinically relevant side effects were reported. This preliminary study seems to suggest that the strategy using creatine augmentation in major depressive women showing no 'real-life response' to 3 weeks of treatment with SSRIs/SNRIs/NASA treatment is of no advantage compared with placebo. However, such creatine augmentation may still induce a more rapid response in a small subgroup of these female patients.

Significance of follow-up left ventricular ejection fraction measurements in the Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation trial (DEFINITE).

BACKGROUND: As left ventricular ejection fraction (LVEF) may improve, worsen, or remain the same over time, patients' prognosis may also be expected to change because of the change in LVEF, among other factors. OBJECTIVE: To evaluate the effect of LVEF change on outcome in the Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation (DEFINITE) trial. METHODS: Patients with nonischemic cardiomyopathy with LVEF<36%, history of symptomatic heart failure, and the presence of significant ventricular ectopic activity were enrolled in the DEFINITE trial. Follow-up LVEF measurements were obtained annually in only a minority (17%) of trial participants. This study therefore evaluated survival and arrhythmic end points in patients whose LVEF was reassessed between 90 and 730 days after enrollment. RESULTS: During the 90-730-day postrandomization period, 187 of 449 (42%) enrolled patients who survived at least 90 days had at least 1 follow-up LVEF measurement; these patients were younger and white; had diabetes, better 6-minute walk test results, and higher BMI; were more likely to have appropriate shocks; and had fewer deaths compared to those without follow-up LVEF measurements. Patients whose LVEF improved had reduced mortality compared to patients whose LVEF decreased (hazard ratio 0.09; 95% confidence interval 0.02-0.39; P = .001). Survival free of appropriate shocks was not significantly related to LVEF improvement during follow-up. CONCLUSIONS: LVEF improvement was associated with improved survival, but not with a significant decrease in appropriate shocks. These data highlight that appropriate caution should be exercised not to extrapolate the positive effect of improved LVEF to the elimination of arrhythmic events.