A Systematic Review of Characteristics Associated with COVID-19 in Children with Typical Presentation and with Multisystem Inflammatory Syndrome.

Setting off a global pandemic, coronavirus disease 2019 (COVID-19) has been marked by a heterogeneous clinical presentation that runs the gamut from asymptomatic to severe and fatal. Although less lethal in children than adults, COVID-19 has nonetheless afflicted the pediatric population. This systematic review used clinical information from published literature to assess the spectrum of COVID-19 presentation in children, with special emphasis on characteristics associated with multisystem inflammatory syndrome (MIS-C). An electronic literature search for English and Chinese language articles in COVIDSeer, MEDLINE, and PubMed from 1 January 2020 through 1 March 2021 returned 579 records, of which 54 were included for full evaluation. Out of the total 4811 patients, 543 (11.29%) exhibited MIS-C. The most common symptoms across all children were fever and sore throat. Children presenting with MIS-C were less likely to exhibit sore throat and respiratory symptoms (i.e., cough, shortness of breath) compared to children without MIS-C. Inflammatory (e.g., rash, fever, and weakness) and gastrointestinal (e.g., nausea/vomiting and diarrhea) symptoms were present to a greater extent in children with both COVID-19 and MIS-C, suggesting that children testing positive for COVID-19 and exhibiting such symptoms should be evaluated for MIS-C.

Quality of Life Changes during the COVID-19 Pandemic for Caregivers of Children with ADHD and/or ASD.

The COVID-19 pandemic has presented many challenges to caregivers of children. Families with children with attention-deficit/hyperactivity disorder (ADHD) and/or autism spectrum disorder (ASD) are an understudied but potentially vulnerable population to changes during the outbreak. As such, the aim of this study was to contrast quality of life for caregivers of children with ADHD and/or ASD, before and during the pandemic, compared to caregivers of neurotypical (NT) children. Total, Parent Health-Related Quality of Life, and Family Functioning Summary Scores from the Family Impact Module of the Pediatric Quality of Life InventoryTM were contrasted among caregivers of children with ADHD, ASD, comorbid ADHD and ASD, and NT development. For all scores, caregivers of ADHD and/or ASD children reported lower quality of life, both before and during the pandemic, in comparison to caregivers of NT children. For all diagnoses, quality of life decreased during the pandemic, but caregivers of children with ADHD and/or ASD reported a greater decrease in quality of life than caregivers for NT children. There are limitations to this study in terms of the composition of the sample and the survey methodology, but we are able to conclude that caregivers of children with ADHD and/or ASD have been disproportionately affected by the pandemic, and it is imperative that these families receive additional resources and support to improve their quality of life.

Key Positions of HIV-1 Env and Signatures of Vaccine Efficacy Show Gradual Reduction of Population Founder Effects at the Clade and Regional Levels.

HIV-1 group M was transmitted to humans nearly one century ago. The virus has since evolved to form distinct clades, which spread to different regions of the world. The envelope glycoproteins (Envs) of HIV-1 have rapidly diversified in all infected populations. We examined whether key antigenic sites of Env and signatures of vaccine efficacy are evolving toward similar or distinct structural forms in different populations worldwide. Patterns of amino acid variants that emerged at each position of Env were compared between diverse HIV-1 clades and isolates from different geographic regions. Interestingly, at each Env position, the amino acid in the clade ancestral or regional-founder virus was replaced by a unique frequency distribution (FD) of amino acids. FDs are highly conserved in populations from different regions worldwide and in paraphyletic and monophyletic subclade groups. Remarkably, founder effects of Env mutations at the clade and regional levels have gradually decreased during the pandemic by evolution of each site toward the unique combination of variants. Therefore, HIV-1 Env is evolving at a population level toward well-defined "target" states; these states are not specific amino acids but rather specific distributions of amino acid frequencies. Our findings reveal the powerful nature of the forces that guide evolution of Env and their conservation across different populations. Such forces have caused a gradual decrease in the interpopulation diversity of Env despite an increasing intrapopulation diversity.IMPORTANCE The Env protein of HIV-1 is the primary target in AIDS vaccine design. Frequent mutations in the virus increase the number of Env forms in each population, limiting the efficacy of AIDS vaccines. Comparison of newly emerging forms in different populations showed that each position of Env is evolving toward a specific combination of amino acids. Similar changes are occurring in different HIV-1 subtypes and geographic regions toward the same position-specific combinations of amino acids, often from distinct ancestral sequences. The predictable nature of HIV-1 Env evolution, as shown here, provides a new framework for designing vaccines that are tailored to the unique combination of variants expected to emerge in each virus subtype and geographic region.

The High Content of Fructose in Human Semen Competitively Inhibits Broad and Potent Antivirals That Target High-Mannose Glycans.

Semen is the primary transmission vehicle for various pathogenic viruses. Initial steps of transmission, including cell attachment and entry, likely occur in the presence of semen. However, the unstable nature of human seminal plasma and its toxic effects on cells in culture limit the ability to study in vitro virus infection and inhibition in this medium. We found that whole semen significantly reduces the potency of antibodies and microbicides that target glycans on the envelope glycoproteins (Envs) of HIV-1. The extraordinarily high concentration of the monosaccharide fructose in semen contributes significantly to the effect by competitively inhibiting the binding of ligands to α1,2-linked mannose residues on Env. Infection and inhibition in whole human seminal plasma are accurately mimicked by a stable synthetic simulant of seminal fluid that we formulated. Our findings indicate that, in addition to the protein content of biological secretions, their small-solute composition impacts the potency of antiviral microbicides and mucosal antibodies.IMPORTANCE Biological secretions allow viruses to spread between individuals. Each type of secretion has a unique composition of proteins, salts, and sugars, which can affect the infectivity potential of the virus and inhibition of this process. Here, we describe HIV-1 infection and inhibition in whole human seminal plasma and a synthetic simulant that we formulated. We discovered that the sugar fructose in semen decreases the activity of a broad and potent class of antiviral agents that target mannose sugars on the envelope protein of HIV-1. This effect of semen fructose likely reduces the efficacy of such inhibitors to prevent the sexual transmission of HIV-1. Our findings suggest that the preclinical evaluation of microbicides and vaccine-elicited antibodies will be improved by their in vitro assessment in synthetic formulations that simulate the effects of semen on HIV-1 infection and inhibition.

The lipid membrane of HIV-1 stabilizes the viral envelope glycoproteins and modulates their sensitivity to antibody neutralization.

The envelope glycoproteins (Envs) of HIV-1 are embedded in the cholesterol-rich lipid membrane of the virus. Chemical depletion of cholesterol from HIV-1 particles inactivates their infectivity. We observed that diverse HIV-1 strains exhibit a range of sensitivities to such treatment. Differences in sensitivity to cholesterol depletion could not be explained by variation in Env components known to interact with cholesterol, including the cholesterol-recognition motif and cytoplasmic tail of gp41. Using antibody-binding assays, measurements of virus infectivity, and analyses of lipid membrane order, we found that depletion of cholesterol from HIV-1 particles decreases the conformational stability of Env. It enhances exposure of partially cryptic epitopes on the trimer and increases sensitivity to structure-perturbing treatments such as antibodies and cold denaturation. Substitutions in the cholesterol-interacting motif of gp41 induced similar effects as depletion of cholesterol. Surface-acting agents, which are incorporated into the virus lipid membrane, caused similar effects as disruption of the Env-cholesterol interaction. Furthermore, substitutions in gp120 that increased structural stability of Env (i.e. induced a "closed" conformation of the trimer) increased virus resistance to cholesterol depletion and to the surface-acting agents. Collectively, these results indicate a critical contribution of the viral membrane to the stability of the Env trimer and to neutralization resistance against antibodies. Our findings suggest that the potency of poorly neutralizing antibodies, which are commonly elicited in vaccinated individuals, may be markedly enhanced by altering the lipid composition of the viral membrane.

Treatment of vagus nerve stimulator-induced sleep-disordered breathing: A case series.

OBJECTIVE: Vagus nerve stimulation (VNS) is a treatment option for patients with drug-resistant seizures, but it is also associated with sleep-disordered breathing (SDB). We present four patients with VNS who underwent polysomnography (PSG) concurrently with VNS stimulation monitoring and adjustment, and positive airway pressure (PAP) treatment. We demonstrate the importance of sleep apnea screening prior to VNS placement and the dilemma of optimizing VNS settings. BACKGROUND: VNS is a common adjunct therapy for refractory epilepsy. Despite its low side effect profile, complications of VNS include delayed arrhythmias, laryngopharyngeal dysfunction, obstructive sleep apnea, and tonsillar pain mimicking glossopharyngeal neuralgia. Risk of developing or exacerbating existing obstructive sleep apnea (OSA) limits the VNS settings, as there appears to be a dose dependent effect. OSA can further cause sleep fragmentation and cause hypoxia, potentially worsening seizures. METHODS: Four patients with drug-resistant epilepsy with VNS underwent PSG with concurrent VNS leads to monitor correlation of SDB and VNS. AHI was calculated to quantify SDB, and it was scored as non-VNS related when the VNS was off, and VNS-induced when the onset of SDB corresponded to VNS activation. Subsequent PAP and VNS adjustment was performed to treat the SDB episodes. RESULTS: Three out of four patients had non-VNS associated SDB, which improved with PAP treatment. All four patients had VNS-induced SDB episodes but none improved with PAP. The VNS-induced SDB events decreased in a dose dependent manner, when VNS was adjusted down and disappeared when turned off completely. CONCLUSION: Our case series provides further evidence of VNS-induced SDB secondary to VNS. PAP treatment alone is ineffective for VNS-induced SDB. Screening for OSA before VNS implant is crucial; further research is needed to establish optimal VNS parameters for prevention andminimization of VNS-induced SDB along with other possible treatments.

Induction of a Tier-1-Like Phenotype in Diverse Tier-2 Isolates by Agents That Guide HIV-1 Env to Perturbation-Sensitive, Nonnative States.

The envelope glycoproteins (Envs) on the surfaces of HIV-1 particles are targeted by host antibodies. Primary HIV-1 isolates demonstrate different global sensitivities to antibody neutralization; tier-1 isolates are sensitive, whereas tier-2 isolates are more resistant. Single-site mutations in Env can convert tier-2 into tier-1-like viruses. We hypothesized that such global change in neutralization sensitivity results from weakening of intramolecular interactions that maintain Env integrity. Three strategies commonly applied to perturb protein structure were tested for their effects on global neutralization sensitivity: exposure to low temperature, Env-activating ligands, and a chaotropic agent. A large panel of diverse tier-2 isolates from clades B and C was analyzed. Incubation at 0°C, which globally weakens hydrophobic interactions, causes gradual and reversible exposure of the coreceptor-binding site. In the cold-induced state, Envs progress at isolate-specific rates to unstable forms that are sensitive to antibody neutralization and then gradually lose function. Agents that mimic the effects of CD4 (CD4Ms) also induce reversible structural changes to states that exhibit isolate-specific stabilities. The chaotropic agent urea (at low concentrations) does not affect the structure or function of native Env. However, urea efficiently perturbs metastable states induced by cold and CD4Ms and increases their sensitivity to antibody neutralization and their inactivation rates Therefore, chemical and physical agents can guide Env from the stable native state to perturbation-sensitive forms and modulate their stability to bestow tier-1-like properties on primary tier-2 strains. These concepts can be applied to enhance the potency of vaccine-elicited antibodies and microbicides at mucosal sites of HIV-1 transmission.IMPORTANCE An effective vaccine to prevent transmission of HIV-1 is a primary goal of the scientific and health care communities. Vaccine-elicited antibodies target the viral envelope glycoproteins (Envs) and can potentially inhibit infection. However, the potency of such antibodies is generally low. Single-site mutations in Env can enhance the global sensitivity of HIV-1 to neutralization by antibodies. We found that such a hypersensitivity phenotype can also be induced by agents that destabilize protein structure. Exposure to 0°C or low concentrations of Env-activating ligands gradually guides Env to metastable forms that expose cryptic epitopes and that are highly sensitive to neutralization. Low concentrations of the chaotropic agent urea do not affect native Env but destabilize perturbed states induced by cold or CD4Ms and increase their neutralization. The concept of enhancing antibody sensitivity by chemical agents that affect the structural stability of proteins can be applied to increase the potency of topical microbicides and vaccine-elicited antibodies.

Accurate predictions of population-level changes in sequence and structural properties of HIV-1 Env using a volatility-controlled diffusion model.

The envelope glycoproteins (Envs) of HIV-1 continuously evolve in the host by random mutations and recombination events. The resulting diversity of Env variants circulating in the population and their continuing diversification process limit the efficacy of AIDS vaccines. We examined the historic changes in Env sequence and structural features (measured by integrity of epitopes on the Env trimer) in a geographically defined population in the United States. As expected, many Env features were relatively conserved during the 1980s. From this state, some features diversified whereas others remained conserved across the years. We sought to identify "clues" to predict the observed historic diversification patterns. Comparison of viruses that cocirculate in patients at any given time revealed that each feature of Env (sequence or structural) exists at a defined level of variance. The in-host variance of each feature is highly conserved among individuals but can vary between different HIV-1 clades. We designate this property "volatility" and apply it to model evolution of features as a linear diffusion process that progresses with increasing genetic distance. Volatilities of different features are highly correlated with their divergence in longitudinally monitored patients. Volatilities of features also correlate highly with their population-level diversification. Using volatility indices measured from a small number of patient samples, we accurately predict the population diversity that developed for each feature over the course of 30 years. Amino acid variants that evolved at key antigenic sites are also predicted well. Therefore, small "fluctuations" in feature values measured in isolated patient samples accurately describe their potential for population-level diversification. These tools will likely contribute to the design of population-targeted AIDS vaccines by effectively capturing the diversity of currently circulating strains and addressing properties of variants expected to appear in the future.

Review of available studies of the neurobiology and pharmacotherapeutic management of trichotillomania.

Trichotillomania (TTM) is a psychiatric disorder characterized by an irresistible urge to pull out one's hair. Currently there are no FDA approved treatments for TTM, which makes it difficult for clinicians to select an appropriate therapeutic plan. The clinical studies that have been performed do not provide sufficient or consistent evidence regarding which drug classes should be administered. Unfortunately, most of the available data consist of case reports and clinical trials with limited sample size. This review provides an overview of currently available clinical literature that targets TTM. A summary of clinical trials as well as case reports is provided. The most common rating scales used for clinical assessment are also reviewed. The etiology of TTM remains unclear. Studies that examine various neuroanatomical, neurobiologic, as well as genetic factors associated with TTM are thoroughly discussed in this review. It is evident that clear understanding of TTM is crucial to provide better recognition, assessment, and treatment to patients of this disorder. Finally, despite research efforts for establishing pharmacological options for treatment, it is clear that new targets are warranted in order to ensure a clinically supported effective pharmacological approach to treat TTM.