Post-discharge outcomes of hospitalized children diagnosed with acute SARS-CoV-2 or MIS-C.

Introduction: Hospitalized children diagnosed with SARS-CoV-2-related conditions are at risk for new or persistent symptoms and functional impairments. Our objective was to analyze post-hospital symptoms, healthcare utilization, and outcomes of children previously hospitalized and diagnosed with acute SARS-CoV-2 infection or Multisystem Inflammatory Syndrome in Children (MIS-C). Methods: Prospective, multicenter electronic survey of parents of children <18 years of age surviving hospitalization from 12 U.S. centers between January 2020 and July 2021. The primary outcome was a parent report of child recovery status at the time of the survey (recovered vs. not recovered). Secondary outcomes included new or persistent symptoms, readmissions, and health-related quality of life. Multivariable backward stepwise logistic regression was performed for the association of patient, disease, laboratory, and treatment variables with recovered status. Results: The children [n = 79; 30 (38.0%) female] with acute SARS-CoV-2 (75.7%) or MIS-C (24.3%) had a median age of 6.5 years (interquartile range 2.0-13.0) and 51 (64.6%) had a preexisting condition. Fifty children (63.3%) required critical care. One-third [23/79 (29.1%)] were not recovered at follow-up [43 (31, 54) months post-discharge]. Admission C-reactive protein levels were higher in children not recovered vs. recovered [5.7 (1.3, 25.1) vs. 1.3 (0.4, 6.3) mg/dl, p = 0.02]. At follow-up, 67% overall had new or persistent symptoms. The most common symptoms were fatigue (37%), weakness (25%), and headache (24%), all with frequencies higher in children not recovered. Forty percent had at least one return emergency visit and 24% had a hospital readmission. Recovered status was associated with better total HRQOL [87 (77, 95) vs. 77 (51, 83), p = 0.01]. In multivariable analysis, lower admission C-reactive protein [odds ratio 0.90 (95% confidence interval 0.82, 0.99)] and higher admission lymphocyte count [1.001 (1.0002, 1.002)] were associated with recovered status. Conclusions: Children considered recovered by their parents following hospitalization with SARS-CoV-2-related conditions had less symptom frequency and better HRQOL than those reported as not recovered. Increased inflammation and lower lymphocyte count on hospital admission may help to identify children needing longitudinal, multidisciplinary care. Clinical Trial Registration: ClinicalTrials.gov (NCT04379089).

Severe Pediatric Neurological Manifestations With SARS-CoV-2 or MIS-C Hospitalization and New Morbidity.

Importance: Neurological manifestations during acute SARS-CoV-2-related multisystem inflammatory syndrome in children (MIS-C) are common in hospitalized patients younger than 18 years and may increase risk of new neurocognitive or functional morbidity. Objective: To assess the association of severe neurological manifestations during a SARS-CoV-2-related hospital admission with new neurocognitive or functional morbidities at discharge. Design, Setting, and Participants: This prospective cohort study from 46 centers in 10 countries included patients younger than 18 years who were hospitalized for acute SARS-CoV-2 or MIS-C between January 2, 2020, and July 31, 2021. Exposure: Severe neurological manifestations, which included acute encephalopathy, seizures or status epilepticus, meningitis or encephalitis, sympathetic storming or dysautonomia, cardiac arrest, coma, delirium, and stroke. Main Outcomes and Measures: The primary outcome was new neurocognitive (based on the Pediatric Cerebral Performance Category scale) and/or functional (based on the Functional Status Scale) morbidity at hospital discharge. Multivariable logistic regression analyses were performed to examine the association of severe neurological manifestations with new morbidity in each SARS-CoV-2-related condition. Results: Overall, 3568 patients younger than 18 years (median age, 8 years [IQR, 1-14 years]; 54.3% male) were included in this study. Most (2980 [83.5%]) had acute SARS-CoV-2; the remainder (588 [16.5%]) had MIS-C. Among the patients with acute SARS-CoV-2, 536 (18.0%) had a severe neurological manifestation during hospitalization, as did 146 patients with MIS-C (24.8%). Among survivors with acute SARS-CoV-2, those with severe neurological manifestations were more likely to have new neurocognitive or functional morbidity at hospital discharge compared with those without severe neurological manifestations (27.7% [n = 142] vs 14.6% [n = 356]; P < .001). For survivors with MIS-C, 28.0% (n = 39) with severe neurological manifestations had new neurocognitive and/or functional morbidity at hospital discharge compared with 15.5% (n = 68) of those without severe neurological manifestations (P = .002). When adjusting for risk factors in those with severe neurological manifestations, both patients with acute SARS-CoV-2 (odds ratio, 1.85 [95% CI, 1.27-2.70]; P = .001) and those with MIS-C (odds ratio, 2.18 [95% CI, 1.22-3.89]; P = .009) had higher odds of having new neurocognitive and/or functional morbidity at hospital discharge. Conclusions and Relevance: The results of this study suggest that children and adolescents with acute SARS-CoV-2 or MIS-C and severe neurological manifestations may be at high risk for long-term impairment and may benefit from screening and early intervention to assist recovery.

Infantile ischemic stroke secondary to profound arteriopathy.

Pediatric arterial ischemic stroke (AIS) is an uncommon emergency department (ED) presentation. We share the case of a 4-month-old female with a chief complaint of irritability and difficulty feeding. During ED evaluation, she developed lateral gaze deviation, tongue deviation, and rhythmic leg movements. Computed tomography of the head revealed a right-sided hypodensity concerning for ischemic infarct without hemorrhagic conversion. Subsequent brain magnetic resonance imaging and arteriography confirmed a large right-sided cerebral infarct and demonstrated narrowing and tortuosity of almost all extra- and intracranial vessels. Comprehensive pediatric AIS workup, including echocardiogram and laboratory tests for anemia, hypercoagulability, inflammatory, and genetic panels, were non-diagnostic. This case highlights the difficulty in diagnosis of pediatric AIS due to low clinical suspicion, limited neurologic examination, and non-specific presentations that may suggest stroke mimics. Maintenance of clinical suspicion and early recognition of pediatric AIS can result in earlier initiation of neuroprotective measures and optimization of imaging strategies for better outcomes.

Pediatric Functional Neurological Disorder: Demographic and Clinical Factors Impacting Care.

This is a multicenter retrospective EMR-based chart review of 88 patients aged 3-21 years admitted for evaluation of functional neurologic disorder (FND). We sought to establish characteristics associated with FND, calculate incidence of abnormal neurodiagnostic findings, and determine features associated with variability in workup and treatment. FND patients were 65% female, 40% White, 33% Hispanic, and 88% primarily English speaking with median 13.9 years. We detected variability in management by age, ethnicity, psychiatric comorbidity, and hospital site. Our findings suggest limited utility to CTs in this setting (100% normal) and that workup can be safely informed by physical exam, which predicted abnormal MRI and LP results. We favor screening for adverse childhood experiences in FND patients. Hospitalization may be a rare opportunity for psychiatry contact.

Words Matter: An Antibias Workshop for Health Care Professionals to Reduce Stigmatizing Language.

Introduction: Biased language influences health care providers' perceptions of patients, impacts their clinical care, and prevents vulnerable populations from seeking treatment. Training clinicians to systematically replace biased verbal and written language is an essential step to providing equitable care. Methods: We designed and implemented an interactive workshop to teach health care professionals a framework to identify and replace stigmatizing language in clinical practice. The workshop included a reflective exercise, role-play, brief didactic session, and case-based discussion. We developed the program for a broad target audience of providers and initially delivered it at three academic conferences. We used descriptive statistics to analyze Likert-style items on course evaluations and identified themes in open-text responses. Results: A total of 66 participants completed course evaluations; most believed the workshop met its objectives (4.8 out of 5.0) and strongly agreed that they would apply skills learned (4.8). Participants planned to incorporate reflection into their verbal and written language. Potential barriers to applying course content included perceived difficulty in changing entrenched practice habits, burnout, and fatigue. Suggestions for improvement included more time for group discussions and strategies to teach skills to colleagues. Discussion: Participants found the course material highly engaging and relevant to their clinical practice. Learners left the workshop feeling motivated to engage in more mindful word choice and to share key concepts with their colleagues.

Cervical puncture to deliver nusinersen in patients with spinal muscular atrophy.

OBJECTIVE: To report our experience delivering intrathecal nusinersen through cervical puncture in patients with spinal muscular atrophy (SMA) with no lumbar access. BACKGROUND: SMA is a neuromuscular disorder characterized by profound muscle weakness, atrophy, and paralysis due to degeneration of the anterior horn cells. Nusinersen, the first Food and Drug Administration-approved treatment for SMA, is administered intrathecally via lumbar puncture; however, many patients with SMA have scoliosis or solid spinal fusion with hardware that makes lumbar access impossible. Studies in primates have demonstrated better spinal cord tissue concentration with intrathecal injections than with intracerebral ventricular injections. Therefore we have used C1/C2 puncture as an alternative to administer nusinersen. METHOD: Retrospective chart review. RESULTS: Intrathecal nusinersen via cervical puncture was given to 3 patients who had thoracic and lumbosacral spinal fusion: a 12-year-old girl with type 1 SMA and 2 17-year-old girls with type 2 SMA. Cervical puncture was performed without deep sedation under fluoroscopic guidance using a 25-G or a 24-G Whitacre needle in the posterior aspect of C1-C2 interspace and full dose of nusinersen (12 mg/5 mL) was injected after visualizing free CSF flow. Patients completed their 4 loading doses and first maintenance dose of nusinersen, and 15 procedures were successful and well-tolerated. CONCLUSION: Cervical puncture is a feasible alternative delivery route to administer intrathecal nusinersen in patients with longstanding SMA and spine anatomy precluding lumbar access when done by providers with expertise in this procedure.

Beyond the Classic VTA: Extended Amygdala Projections to DA-Striatal Paths in the Primate.

The central extended amygdala (CEA) has been conceptualized as a 'macrosystem' that regulates various stress-induced behaviors. Consistent with this, the CEA highly expresses corticotropin-releasing factor (CRF), an important modulator of stress responses. Stress alters goal-directed responses associated with striatal paths, including maladaptive responses such as drug seeking, social withdrawal, and compulsive behavior. CEA inputs to the midbrain dopamine (DA) system are positioned to influence striatal functions through mesolimbic DA-striatal pathways. However, the structure of this amygdala-CEA-DA neuron path to the striatum has been poorly characterized in primates. In primates, we combined neuronal tracer injections into various arms of the circuit through specific DA subpopulations to assess: (1) whether the circuit connecting amygdala, CEA, and DA cells follows CEA intrinsic organization, or a more direct topography involving bed nucleus vs central nucleus divisions; (2) CRF content of the CEA-DA path; and (3) striatal subregions specifically involved in CEA-DA-striatal loops. We found that the amygdala-CEA-DA path follows macrostructural subdivisions, with the majority of input/outputs converging in the medial central nucleus, the sublenticular extended amygdala, and the posterior lateral bed nucleus of the stria terminalis. The proportion of CRF+ outputs is >50%, and mainly targets the A10 parabrachial pigmented nucleus (PBP) and A8 (retrorubal field, RRF) neuronal subpopulations, with additional inputs to the dorsal A9 neurons. CRF-enriched CEA-DA projections are positioned to influence outputs to the 'limbic-associative' striatum, which is distinct from striatal regions targeted by DA cells lacking CEA input. We conclude that the concept of the CEA is supported on connectional grounds, and that CEA termination over the PBP and RRF neuronal populations can influence striatal circuits involved in associative learning.

Molecular modeling on structure-function analysis of human progesterone receptor modulators.

Considering the significance of progesterone receptor (PR) modulators, the present study is explored to envisage the biophoric signals for binding to selective PR subtype-A using ligand-based quantitative structure activity relationship (QSAR) and pharmacophore space modeling studies on nonsteroidal substituted quinoline and cyclocymopol monomethyl ether derivatives. Consensus QSAR models (Training set (Tr): n(Tr)=100, R(2) (pred)=0.702; test set (Ts): n(Ts)=30, R(2) (pred)=0.705, R(2) (m)=0.635; validation set (Vs): n(Vs)=40, R(2) (pred)=0.715, R(2) (m)=0.680) suggest that molecular topology, atomic polarizability and electronegativity, atomic mass and van der Waals volume of the ligands have influence on the presence of functional atoms (F, Cl, N and O) and consequently contribute significant relations on ligand binding affinity. Receptor independent space modeling study (Tr: n(Tr)=26, Q(2)=0.927; Ts: n(Ts)=60, R(2) (pred)=0.613, R(2) (m)=0.545; Vs: n(Vs)=84, R(2) (pred)=0.611, R(2) (m)=0.507) indicates the importance of aromatic ring, hydrogen bond donor, molecular hydrophobicity and steric influence for receptor binding. The structure-function characterization is adjudged with the receptor-based docking study, explaining the significance of the mapped molecular attributes for ligand-receptor interaction in the catalytic cleft of PR-A.

Pharmacophore search for anti-fertility and estrogenic potencies of estrogen analogs.

Estrogen mediates its action following binding to the estrogen receptor to form an estrogen-receptor complex. The complex initiates gene transcription and produces estrogen-induced cell and/or tissue responses, i.e., estrogenic actions. High doses of estrogen can be used effectively as a contraceptive but are associated with side effects. Considering the long-term benefit-to-risk ratio of estrogen analogs as oral contraceptives, the present study was performed to deduce the active pharmacophore features required to differentiate the anti-fertility potency from the estrogenic activity of the steroidal motif. Implementing classical quantitative structure-activity relationship (QSAR) studies, substitution by an electron-donating group at the C17 position and the presence of a hydrogen bond acceptor at C11, along with the orientation and conformational rigidity of the molecule, were found to be critically important features for estrogenic potency, including anti-fertility activity. However, low electron density at C2 and high electronegativity at C16, which may be due to substitution on those and/or neighboring atoms, favor contraceptive potency, whereas high electron density at C5 and substitution by an electron-withdrawing group at C7, which may confer hydrophobicity on the steroidal scaffold and an overall increment of electron affinity of the molecule, are favorable for estrogenicity. Further CATALYST-based 3D space modeling demonstrates that the presence of the aromatic ring (ring A), hydrophobic zone (ring B), and hydrogen bond acceptor at C17 in ring D, along with steric influence due to conformational rigidity of the compound, impart estrogenic contraceptive activity, but the presence of a second acceptor in ring A, and the critical distances between these features, selectively differentiate the anti-fertility potency from the estrogenic activity.