Promoting OCD WEllness and resilience (POWER) study: Rationale, design, and methods.

Obsessive-compulsive disorder (OCD) affects 1-2% of children and is associated with functional impairment and diminished quality of life. Several treatments are efficacious: cognitive behavioral therapy (CBT) with exposure and response prevention, serotonin reuptake inhibitor (SRI) monotherapy, and combined treatment (SRI + CBT). Expert clinician-informed practice parameters suggest that youth with mild to moderate OCD should be treated initially with CBT yet SRIs are frequently employed as the first-line intervention or in combination with psychotherapy in applied practice. Empirical data to guide SRI discontinuation in pediatric OCD are very limited. This study, Promoting OCD Wellness and Resiliency (POWER), aims to address this gap through a two phase, double-blinded, placebo-controlled, randomized controlled non-inferiority trial with the purpose of evaluating whether youth with OCD on an SRI can discontinue their medication after successful CBT augmentation and maintain wellness for a period of 24 weeks during which they receive maintenance CBT that models standard-of-care. In this paper we describe the rationale and methodological design of the POWER study.

Prevalence of cardiovascular manifestations in patients with hypermobile Ehlers-Danlos syndrome at the University of Miami.

Cardiovascular system involvements have been frequently reported in hypermobile Ehlers-Danlos Syndrome (hEDS). Mitral valve prolapse (MVP) and aortic root dilatation are included in the 2017 international classification criteria for hEDS. Different studies have found conflicting results regarding the significance of cardiac involvement in hEDS patients. We conducted a retrospective review of cardiac involvement in patients diagnosed with hEDS based on the 2017 International diagnostic criteria to provide further evidence toward more defined and reliable diagnostic criteria and recommended cardiac surveillance. A total of 75 hEDS patients with at least one diagnostic cardiac evaluation were included in the study. The most common reported cardiovascular complaints were lightheadedness (80.6%), followed by palpitations (77.6%), fainting (44.8%), and chest pain (32.8%). Of the 62 echocardiogram reports, 57 (91.9%) showed trace/trivial to mild valvular insufficiency, and 13 (21%) had additional abnormalities such as grade I diastolic dysfunction, mild aortic sclerosis, and trivial or small pericardial effusion. Of the 60 electrocardiograms (ECG) reports, 39 (65%) were normal, and 21 (35%) reported minor abnormalities or normal variants. Even though many hEDS patients in our cohort experienced cardiac symptoms, the presence of a significant cardiac abnormality was very low.

Chiari I malformation management in patients with heritable connective tissue disorders.

Background: Chiari malformation type I (CMI) is relatively common neurosurgical condition typically treated with posterior fossa decompression. However, the management of CMI in patients with heritable connective tissue disorders (CTDs), such as Ehlers-Danlos Syndrome, Marfan Syndrome, or Osteogenesis Imperfecta, involves a unique set of perioperative challenges. Objective: This study aims to define the demographic information, comorbidities, and perioperative course of patients with concomitant CMI and CTD. Methods: Patients with CMI admitted for surgical decompression from 2008 to 2015 were captured using the National Inpatient Sample (NIS). Information was collected based on ICD-9 codes. Descriptive and regression analyses were performed in SPSS (version 26). Results: 38,169 CMI patients, 353 of whom had CTD (0.92%), were identified. CMI patients with CTD were more likely to be female (p < 0.001) and present during teenage (p = 0.033) or young adult years (p < 0.001). They had more chronic issues (p < 0.001): systemic comorbidities include postural orthostatic tachycardia syndrome, cardiac dysrhythmias, and gastroparesis (all p < 0.001). CNS comorbidities include migraine, tethered spinal cord, and epilepsy (all p < 0.001). They have increased joint instability (both p < 0.001), as well as craniocervical instability (CCI). More posterior cervical fusion surgeries and application of cervical halo devices were seen during the same inpatient stay (both p < 0.001). Conclusions: Patients with concurrent CTD and CMI were more likely to present with complex Chiari and associated CCI. They were also younger, more often female, and had more systemic, CNS, and joint abnormalities. As such, preoperative recognition of an underlying CTD is imperative to achieve optimal outcomes in this patient population.

Intracranial aneurysms in the infant population: an institutional case series and individual participant data meta-analysis.

OBJECTIVE: Infantile intracranial aneurysms are exceedingly rare. The goal of this study was to evaluate an institutional case series of infantile intracranial aneurysms, as well as those reported in the contemporary literature, to determine their demographics, presentation, management, and long-term outcome. METHODS: A comprehensive literature review from 1980 to 2020 was performed to identify individual cases of intracranial aneurysms in the infantile population ≤ 2 years of age. Additional cases from the authors' institution were identified during the same time period. An individual participant data meta-analysis (IPDMA) was performed, abiding by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Patient demographic, radiographic, and clinical information was obtained. Descriptive statistical data were recorded, and multivariate logistic regression analyses were performed. RESULTS: Patient data were obtained for 133 patients from 87 articles in the literature. Ten additional patients at the authors' institution were also identified, for a total of 143 patients included in the IPDMA. The majority (72.7%) of this cohort consisted of idiopathic aneurysms, while 13.3% were posttraumatic pseudoaneurysms, 9.8% were infectious mycotic aneurysms, and 4.2% were aneurysms associated with a systemic connective tissue disorder or vasculitis. The mean age at presentation was 6.6 months. The majority of infants (97.9%) harbored only 1 aneurysm, and hemorrhage was the most common presenting feature (78.3%). The mean aneurysm size was 14.4 mm, and giant aneurysms ≥ 25 mm comprised 12.9% of the cohort. Most aneurysms occurred in the anterior circulation (80.9%), with the middle cerebral artery (MCA) being the most commonly affected vessel (51.8%). Management strategies included open surgical aneurysm ligation (54.0%), endovascular treatment (35.0%), surgical decompression without aneurysm treatment (4.4%), and medical supportive management only (13.9%). Surgical aneurysm ligation was more commonly performed for MCA and anterior cerebral artery aneurysms (p = 0.004 and p = 0.015, respectively), while endovascular techniques were favored for basilar artery aneurysms (p = 0.042). The mean follow-up period was 29.9 months; 12.4% of the cohort died, and 67.0% had a favorable outcome (Glasgow Outcome Scale score of 5). CONCLUSIONS: This study is, to the authors' knowledge, the largest analysis of infantile intracranial aneurysms to date. The majority were idiopathic aneurysms involving the anterior circulation. Surgical and endovascular techniques yielded equally favorable outcomes in this cohort. Long-term outcomes in the infantile population compared favorably to outcomes in adults.

The utility of congenital cardiac status to predict endoscopic third ventriculostomy and ventriculoperitoneal shunt failure in hydrocephalic infants.

OBJECTIVE: The effect of congenital cardiac status on endoscopic third ventriculostomy (ETV) and ventriculoperitoneal shunt (VPS) failure in hydrocephalic infants is unknown. Because cardiac status in infants can impact central venous pressure (CVP), it is possible that congenital heart disease (CHD) and congenital cardiac anomalies may render these cerebrospinal fluid diversion interventions more susceptible to failure. Correspondingly, the aim of this study was to determine how CHD and congenital cardiac anomalies may impact the failure of these initial interventions. METHODS: A retrospective review of the Nationwide Inpatient Sample (NIS) database was conducted. Infants (aged < 1 year) with known congenital cardiac status managed with either ETV or VPS were included. Quantitative data were compared using either parametric or nonparametric methods, and failure rates were modeled using univariable and multivariable regression analyses. RESULTS: A total of 18,763 infants treated with ETV or VPS for hydrocephalus were identified in our search, with ETV used to treat 7657 (41%) patients and VPS used to treat 11,106 (59%). There were 6722 (36%) patients who presented with CHD at admission, and a total of 25 unique congenital cardiac anomalies were detected across the cohort. Overall, the most common anomaly was patent ductus arteriosus (PDA) in 4990 (27%) patients, followed by atrial septal defect (ASD) in 2437 (13%) patients and pulmonary hypertension in 810 (4%) patients. With respect to initial intervention failure, 3869 (21%) patients required repeat surgical intervention during admission. This was significantly more common in the ETV group than the VPS group (36% vs 10%, p < 0.01). In both the ETV and VPS groups, CHD (p < 0.01), including all congenital cardiac anomalies, was an independent and significant predictor of failure. ASD (p < 0.01) and PDA (p < 0.01) both significantly predicted ETV failure, and PDA (p < 0.01) and pulmonary hypertension (p = 0.02) both significantly predicted VPS failure. CONCLUSIONS: These results indicate that congenital cardiac status predicts ETV and VPS failure in patients with infantile hydrocephalus. The authors hypothesized that this finding was primarily due to changes in CVP; however, this may not be completely universal across both interventions and all congenital cardiac anomalies. Future studies about optimization of congenital cardiac status with ETV and VPS are required to understand the practical significance of these findings.

Pediatric intracranial neurenteric cyst of the oculomotor nerve: a case-based review.

BACKGROUND: Neurenteric cysts (NECs) of the central nervous system (CNS) are uncommon congenital entities arising from embryonal elements. Intracranial NECs in the pediatric population are rare. METHODS: The authors describe the presentation, radiographic imaging, and pathologic findings of an 11-year-old boy with a right oculomotor nerve NEC. A literature review was performed to identify additional cases of pediatric intracranial NECs published in the English language, over the past 30 years (1990-2020). The authors discuss the presentation, investigations, management, and prognosis of this interesting entity. RESULTS: We describe an 11-year-old boy who presented to neurosurgical attention with disconjugate gaze, anisocoria, and ptosis. Magnetic resonance imaging (MRI) demonstrated a lobulated, cystic, and peripherally enhancing mass involving the right oculomotor nerve. The patient underwent pterional craniotomy for drainage of the cyst and subtotal resection of the cyst wall. The tan-colored mass was displacing the basilar artery, compressing the cerebral peduncle, and adherent to the inferior surface of the tentorium. The lesion was within the oculomotor nerve and splitting the fibers, and the cystic contents were thick and mucinous. Histopathological examination of the specimen demonstrated a thin fibrous cyst wall with scattered inflammatory cells and lined by simple columnar epithelium containing mucin. The lining cells were immunoreactive with epithelial membrane antigen (EMA) and pan-keratin AE1/AE3. The diagnosis of a NEC was rendered. A comprehensive literature review of pediatric intracranial NECs yielded 46 additional lesions published in the literature, involving the skull base, posterior fossa, cerebral convexity, and cranial nerves. NECs present with local mass effect and less commonly, with aseptic meningitis or intracystic hemorrhage. Maximal safe GTR remains the mainstay management, although cyst drainage and marsupialization, cyst shunting, and fenestration of cystic contents into the ventricle or basal cisterns have been reported with variable success. CONCLUSION: CNS NECs are rare congenital entities; although they occur less frequently in the intracranial components compared to the spine, their diagnosis and management should be considered for intracranial cystic lesions. Maximal safe GTR is the mainstay treatment and frequently yields favorable outcomes.

Application of the ACMG/NSGC genetic referral guidelines for hereditary renal cell carcinoma at the University of Miami, from 2014 to 2017.

Identifying hereditary syndromes among patients with renal cell carcinoma (RCC) is essential for surveillance of affected individuals and their at-risk family members and for treatment optimization. We conducted a chart review to determine the percentage of patients with RCC who were seen at the University of Miami Health System (UHealth), and met the American College of Medical Genetics (ACMG) and the National Society of Genetic Counselors (NSGC) genetic referral criteria at the University of Miami. Subsequently, we determined the percentage of those who went on to receive genetic evaluation. Patients selected by International Classification of Diseases (ICD) 9/10 codes corresponding to kidney cancer who were at least 18 years of age at the time of diagnosis were included in the study. We included a total of 1443 patients in the final analysis, and after exclusion of charts with incorrect ICD codes, insufficient clinical data, unknown pathology, and patients who were not seen. We used chi-square analysis, ANOVA, and t-test. Of 1443 charts reviewed, 65.7% were male and 34.3% were female. 47.7% self-identified as White, 39.2% as Hispanic, 9.1% as Black, and 4.0% as "other." The mean age of RCC diagnosis was 60.0 ± 12.4 years old. In total, 47.0% of patients met ACMG/NSGC referral criteria for genetic evaluation. Of those, only 4.2% had documented genetic assessment. This study showed a low adherence to ACMG/NSGC genetic referral guidelines at our institution and a need for increasing patients' and practitioners' awareness about the significance of genetic assessment for RCC patients and their family members.

On the coupling between the dynamics of protein and water.

Interactions between water and biomolecules can significantly change the former's structural, dynamic, and thermodynamic properties relative to the bulk. Experimental, theoretical, and computational studies show that changes in water properties can be observed at distances of more than 10 Å from a biomolecule. The effects of biopolymers on hydration water molecules can be attributed to several factors: the chemical nature of the amino acid residues involved, the spatial arrangement of the biomolecule, and its conformational flexibility. In the current study, we concentrate on the effect of protein chain flexibility on the properties of hydration water, using short peptides as a model. We constructed 18 linear peptides with the sequence (XXGG) × 5, where X represents one of the common amino acids, other than glycine and proline. Using molecular dynamics (MD) simulations, we studied how restricting the chain flexibility can affect the structural, dynamic, and thermodynamic properties of hydration water. We found that restricting the peptide dynamics can slow down the translational motions of water molecules to a distance of at least 12-13 Å. Analysis of the 'slow' water molecules (residence time ≥ 100 ps) together with a thermodynamic analysis of water within 4.5 Å of the peptide revealed significant differences between the hydration properties of the peptides. The balance between the entropic and enthalpic solvation effects defines the final contribution to the hydration free energy of the restricted system. Our study implies that different regions of the proteins that have different configurational entropies may also have different solvation entropies and therefore different contributions to the overall thermodynamic stability. Therefore, mutations of a solvent exposed residue may modify the thermodynamic stability depending solely on the flexibility of the mutated sites due to their different solvation characteristics.

MD Simulations of tRNA and Aminoacyl-tRNA Synthetases: Dynamics, Folding, Binding, and Allostery.

While tRNA and aminoacyl-tRNA synthetases are classes of biomolecules that have been extensively studied for decades, the finer details of how they carry out their fundamental biological functions in protein synthesis remain a challenge. Recent molecular dynamics (MD) simulations are verifying experimental observations and providing new insight that cannot be addressed from experiments alone. Throughout the review, we briefly discuss important historical events to provide a context for how far the field has progressed over the past few decades. We then review the background of tRNA molecules, aminoacyl-tRNA synthetases, and current state of the art MD simulation techniques for those who may be unfamiliar with any of those fields. Recent MD simulations of tRNA dynamics and folding and of aminoacyl-tRNA synthetase dynamics and mechanistic characterizations are discussed. We highlight the recent successes and discuss how important questions can be addressed using current MD simulations techniques. We also outline several natural next steps for computational studies of AARS:tRNA complexes.