Tracking the genetic diversity of SARS-CoV-2 variants in Nicaragua throughout the COVID-19 Pandemic.

The global circulation of SARS-CoV-2 has been extensively documented, yet the dynamics within Central America, particularly Nicaragua, remain underexplored. This study characterizes the genomic diversity of SARS-CoV-2 in Nicaragua from March 2020 through December 2022, utilizing 1064 genomes obtained via next-generation sequencing. These sequences were selected nationwide and analyzed for variant classification, lineage predominance, and phylogenetic diversity. We employed both Illumina and Oxford Nanopore Technologies for all sequencing procedures. Results indicated a temporal and spatial shift in dominant lineages, initially from B.1 and A.2 in early 2020 to various Omicron subvariants towards the study's end. Significant lineage shifts correlated with changes in COVID-19 positivity rates, underscoring the epidemiological impact of variant dissemination. The comparative analysis with regional data underscored the low diversity of circulating lineages in Nicaragua and their delayed introduction compared to other countries in the Central American region. The study also linked specific viral mutations with hospitalization rates, emphasizing the clinical relevance of genomic surveillance. This research advances the understanding of SARS-CoV-2 evolution in Nicaragua and provide valuable information regarding its genetic diversity for public health officials in Central America. We highlight the critical role of ongoing genomic surveillance in identifying emergent lineages and informing public health strategies.

Simultaneous co-circulation of two genotypes of dengue virus serotype 3 causing a large outbreak in Sri Lanka in year 2023.

As many other countries, Sri Lanka experienced a marked rise in the number of dengue cases in 2023, with an unusual pattern of disease epidemiology. This rise coincided with the emergence of dengue virus (DENV) serotype 3 in Sri Lanka as the predominant serotype after 2009. Interestingly, a discrepancy between NS1 rapid antigen test positivity and quantitative real time PCR positivity was observed, with 50% of NS1 positive samples being negative by molecular diagnostics. Following sequencing of the DENV-3 strains in 2023, we identified two DENV-3 genotypes (I and III) co-circulating. While DENV-3 genotype III was detected by the modified CDC DENV-3 primers, genotype I evaded detection due to key mutations at forward and reverse primer binding sites. The co-circulation of multiple genotypes associated with an increase in cases highlights the importance of continuous surveillance of DENVs to identify mutations resulting in non-detection by diagnostics and differences in virulence.

Introduction of New Dengue Virus Lineages of Multiple Serotypes after COVID-19 Pandemic, Nicaragua, 2022.

Major dengue epidemics throughout Nicaragua's history have been dominated by 1 of 4 dengue virus serotypes (DENV-1-4). To examine serotypes during the dengue epidemic in Nicaragua in 2022, we performed real-time genomic surveillance in-country and documented cocirculation of all 4 serotypes. We observed a shift toward co-dominance of DENV-1 and DENV-4 over previously dominant DENV-2. By analyzing 135 new full-length DENV sequences, we found that introductions underlay the resurgence: DENV-1 clustered with viruses from Ecuador in 2014 rather than those previously seen in Nicaragua; DENV-3, which last circulated locally in 2014, grouped instead with Southeast Asia strains expanding into Florida and Cuba in 2022; and new DENV-4 strains clustered within a South America lineage spreading to Florida in 2022. In contrast, DENV-2 persisted from the formerly dominant Nicaragua clade. We posit that the resurgence emerged from travel after the COVID-19 pandemic and that the resultant intensifying hyperendemicity could affect future dengue immunity and severity.

Perceived Negative Effects of Tic Management Strategies in Adults With Tic Disorders.

Behavior therapy is a well-established and empirically supported treatment for tic disorders (TDs). However, concerns have been expressed about the negative effects of behavioral interventions, such as tic worsening, tic substitution, and excessive effort. This study explored perceived negative effects of tic management strategies in adults with TDs and predictors of these experiences. Participants (N = 72) completed semi-structured interviews 11 years after receiving behavior therapy or supportive therapy in a randomized clinical trial. We examined responses to interview questions about managing tics and predictors of reported negative effects. Most participants did not experience tic worsening (84%) or tic substitution (75%) from tic management strategies. The majority felt they could manage tics while participating in their environment (87%) and did not report life interference from tic management (77%). About half (45%) felt less present when managing tics. Treatment non-responders in the original trial were more likely to report negative effects of tic management strategies. No differences in reported negative consequences were found between those who received behavior therapy versus supportive therapy, suggesting that behavior therapy specifically does not lead to such adverse effects. These findings could reduce misconceptions about behavior therapy for TDs and enhance its acceptability and utilization.

Early-life stress alters chromatin modifications in VTA to prime stress sensitivity.

Early-life stress increases sensitivity to subsequent stress, which has been observed among humans, other animals, at the level of cellular activity, and at the level of gene expression. However, the molecular mechanisms underlying such long-lasting sensitivity are poorly understood. We tested the hypothesis that persistent changes in transcription and transcriptional potential were maintained at the level of the epigenome, through changes in chromatin. We used a combination of bottom-up mass spectrometry, viral-mediated epigenome-editing, behavioral quantification, and RNA-sequencing in a mouse model of early-life stress, focusing on the ventral tegmental area (VTA), a brain region critically implicated in motivation, reward learning, stress response, and mood and drug disorders. We find that early-life stress in mice alters histone dynamics in VTA and that a majority of these modifications are associated with an open chromatin state that would predict active, primed, or poised gene expression, including enriched histone-3 lysine-4 methylation and the H3K4 monomethylase Setd7. Mimicking ELS through over-expression of Setd7 and enrichment of H3K4me1 in VTA recapitulates ELS-induced behavioral and transcriptional hypersensitivity to future stress. These findings enrich our understanding of the epigenetic mechanisms linking early-life environmental experiences to long-term alterations in stress reactivity within the brain's reward circuitry, with implications for understanding and potentially treating mood and anxiety disorders in humans.

Sleep Disorders, Sleep Medication Use, and Predictors of Sleep Disturbance in Children with Persistent Tic Disorders.

The present study examined rates of sleep disorders and sleep medication use, and predictors of sleep disturbance in children with persistent tic disorders (PTD). Sixty-three parents of children aged 10 to 17 years with PTDs completed an internet survey evaluating sleep patterns and clinical symptoms. Insomnia (19.4%), nightmares (16.1%), and bruxism (13.1%) were the most commonly reported lifetime sleep disorders. Fifty-two percent endorsed current sleep medication use. Higher ADHD severity, overall life impairment, and female sex predicted greater sleep disturbance. Findings suggest the utility of clinical management of co-occurring ADHD and impairment to mitigate sleep disturbance in children with PTDs.

Treating Tourette Together: An Agenda for Patient-Centered Research Focused on Comprehensive Behavioral Intervention for Tics.

To establish a patient-centered agenda for research that will lead to effective, widespread availability, adoption, and utilization of evidence-based behavioral treatment of Tourette syndrome and other tic disorders (TDs), we planned and executed a multistage, collaborative "Treating Tourette Together" research planning project with researchers, clinicians, patients, families, and other interested parties. Priorities for future behavioral treatment research were solicited from these parties via anonymous community surveys, a 2-day research planning summit with 46 individuals representing key stakeholder groups, and community response to summit reports. Four high-priority research domains were identified: (a) expanding treatment access, (b) improving treatment outcomes, (c) optimizing treatment within a broader care model, and (d) evaluating outcomes beyond tic severity. Community-engaged participatory research models can efficiently delineate clear and actionable priorities for clinical research. This approach holds promise for improving the impact of clinical research in TDs and other neuropsychiatric disorders.

Thyroid hormones mediate the impact of early-life stress on ventral tegmental area gene expression and behavior.

Proper thyroid function is essential to the developing brain, including dopamine neuron differentiation, growth, and maintenance. Stress across the lifespan impacts thyroid hormone signaling and anxiety disorders and depression have been associated with thyroid dysfunction (both hypo- and hyper-active). However, less is known about how stress during postnatal development impacts thyroid function and related brain development. Our previous work in mice demonstrated that early-life stress (ELS) transiently impinged on expression of a transcription factor in dopamine neurons, Otx2, shown to be regulated by thyroid hormones. We hypothesized that thyroid hormone signaling may link experience of ELS with transcriptional dysregulation within the dopaminergic midbrain, and ultimately behavior. Here, we find that ELS transiently increases thyroid-stimulating hormone levels (inversely related to thyroid signaling) in both male and female mice at P21, an effect which recovers by adolescence. We next tested whether transient treatment of ELS mice with synthetic thyroid hormone (levothyroxine, LT4) could ameliorate the impact of ELS on sensitivity to future stress, and on expression of genes related to dopamine neuron development and maintenance, thyroid signaling, and plasticity within the ventral tegmental area. Among male mice, but not females, juvenile LT4 treatment prevented hypersensitivity to adult stress. We also found that rescuing developmental deficits in thyroid hormone signaling after ELS restored levels of some genes altered directly by ELS, and prevented alterations in expression of other genes sensitive to the second hit of adult stress. These findings suggest that thyroid signaling mediates the deleterious impact of ELS on VTA development, and that temporary treatment of hypothyroidism after ELS may be sufficient to prevent future stress hypersensitivity.

Transcriptional signatures of early-life stress and antidepressant treatment efficacy.

Individuals with a history of early-life stress (ELS) tend to have an altered course of depression and lower treatment response rates. Research suggests that ELS alters brain development, but the molecular changes in the brain following ELS that may mediate altered antidepressant response have not been systematically studied. Sex and gender also impact the risk of depression and treatment response. Here, we leveraged existing RNA sequencing datasets from 1) blood samples from depressed female- and male-identifying patients treated with escitalopram or desvenlafaxine and assessed for treatment response or failure; 2) the nucleus accumbens (NAc) of female and male mice exposed to ELS and/or adult stress; and 3) the NAc of mice after adult stress, antidepressant treatment with imipramine or ketamine, and assessed for treatment response or failure. We find that transcriptomic signatures of adult stress after a history of ELS correspond with transcriptomic signatures of treatment nonresponse, across species and multiple classes of antidepressants. Transcriptomic correspondence with treatment outcome was stronger among females and weaker among males. We next pharmacologically tested these predictions in our mouse model of early-life and adult social defeat stress and treatment with either chronic escitalopram or acute ketamine. Among female mice, the strongest predictor of behavior was an interaction between ELS and ketamine treatment. Among males, however, early experience and treatment were poor predictors of behavior, mirroring our bioinformatic predictions. These studies provide neurobiological evidence for molecular adaptations in the brain related to sex and ELS that contribute to antidepressant treatment response.

Thyroid hormones mediate the impact of early-life stress on ventral tegmental area gene expression and behavior.

Proper thyroid function is essential to the developing brain, including dopamine neuron differentiation, growth, and maintenance. Stress across the lifespan impacts thyroid hormone signaling and anxiety disorders and depression have been associated with thyroid dysfunction (both hypo- and hyper-active). However, less is known about how stress during postnatal development impacts thyroid function and related brain development. Our previous work in mice demonstrated that early-life stress (ELS) transiently impinged on expression of a transcription factor in dopamine neurons shown to be regulated by thyroid hormones. We hypothesized that thyroid hormone signaling may link experience of ELS with transcriptional dysregulation within the dopaminergic midbrain, and ultimately behavior. Here, we find that ELS transiently increases thyroid-stimulating hormone levels (inversely related to thyroid signaling) in both male and female mice at P21, an effect which recovers by adolescence. We next tested whether transient treatment of ELS mice with synthetic thyroid hormone (levothyroxine, LT4) could ameliorate the impact of ELS on sensitivity to future stress, and on expression of genes related to dopamine neuron development and maintenance, thyroid signaling, and plasticity within the ventral tegmental area. Among male mice, but not females, juvenile LT4 treatment prevented hypersensitivity to adult stress. We also found that rescuing developmental deficits in thyroid hormone signaling after ELS restored levels of some genes altered directly by ELS, and prevented alterations in expression of other genes sensitive to the second hit of adult stress. These findings suggest that thyroid signaling mediates the deleterious impact of ELS on VTA development, and that temporary treatment of hypothyroidism after ELS may be sufficient to prevent future stress hypersensitivity.

Phylodynamics of dengue virus 2 in Nicaragua leading up to the 2019 epidemic reveals a role for lineage turnover.

BACKGROUND: Dengue is a mosquito-borne viral disease posing a significant threat to public health. Dengue virus (DENV) evolution is often characterized by lineage turnover, which, along with ecological and immunological factors, has been linked to changes in dengue phenotype affecting epidemic dynamics. Utilizing epidemiologic and virologic data from long-term population-based studies (the Nicaraguan Pediatric Dengue Cohort Study and Nicaraguan Dengue Hospital-based Study), we describe a lineage turnover of DENV serotype 2 (DENV-2) prior to a large dengue epidemic in 2019. Prior to this epidemic, Nicaragua had experienced relatively low levels of DENV transmission from 2014 to 2019, a period dominated by chikungunya in 2014/15 and Zika in 2016. RESULTS: Our phylogenetic analyses confirmed that all Nicaraguan DENV-2 isolates from 2018 to 2019 formed their own clade within the Nicaraguan lineage of the Asian/American genotype. The emergence of the new DENV-2 lineage reflects a replacement of the formerly dominant clade presiding from 2005 to 2009, a lineage turnover marked by several shared derived amino acid substitutions throughout the genome. To elucidate evolutionary drivers of lineage turnover, we performed selection pressure analysis and reconstructed the demographic history of DENV-2. We found evidence of adaptive evolution by natural selection at the codon level as well as in branch formation. CONCLUSIONS: The timing of its emergence, along with a statistical signal of adaptive evolution and distinctive amino acid substitutions, the latest in the NS5 gene, suggest that this lineage may have increased fitness relative to the prior dominant DENV-2 strains. This may have contributed to the intensity of the 2019 DENV-2 epidemic, in addition to previously identified immunological factors associated with pre-existing Zika virus immunity.

Reactivation of Early-Life Stress-Sensitive Neuronal Ensembles Contributes to Lifelong Stress Hypersensitivity.

Early-life stress (ELS) is one of the strongest lifetime risk factors for depression, anxiety, suicide, and other psychiatric disorders, particularly after facing additional stressful events later in life. Human and animal studies demonstrate that ELS sensitizes individuals to subsequent stress. However, the neurobiological basis of such stress sensitization remains largely unexplored. We hypothesized that ELS-induced stress sensitization would be detectable at the level of neuronal ensembles, such that cells activated by ELS would be more reactive to adult stress. To test this, we leveraged transgenic mice to genetically tag, track, and manipulate experience-activated neurons. We found that in both male and female mice, ELS-activated neurons within the nucleus accumbens (NAc), and to a lesser extent the medial prefrontal cortex, were preferentially reactivated by adult stress. To test whether reactivation of ELS-activated ensembles in the NAc contributes to stress hypersensitivity, we expressed hM4Dis receptor in control or ELS-activated neurons of pups and chemogenetically inhibited their activity during experience of adult stress. Inhibition of ELS-activated NAc neurons, but not control-tagged neurons, ameliorated social avoidance behavior following chronic social defeat stress in males. These data provide evidence that ELS-induced stress hypersensitivity is encoded at the level of corticolimbic neuronal ensembles.SIGNIFICANCE STATEMENT Early-life stress enhances sensitivity to stress later in life, yet the mechanisms of such stress sensitization are largely unknown. Here, we show that neuronal ensembles in corticolimbic brain regions remain hypersensitive to stress across the life span, and quieting these ensembles during experience of adult stress rescues stress hypersensitivity.

Current regulatory landscape for viral point-of-care testing in the United States.

Historically, the diagnosis of viral infections has been accomplished using a combination of laboratory-based methods, including culture, serology, antigen-based tests, and molecular (e.g., real-time PCR) assays. Although these methods provide an accurate way to detect viral pathogens, testing in a centralized laboratory may delay results, which could impact patient diagnosis and management. Point-of-care tests, including antigen- and molecular-based assays, have been developed to assist with the timely diagnosis of several viral infections, such as influenza, respiratory syncytial virus, and COVID-19. Despite the ability of point-of-care tests to provide rapid results (i.e., <30 min), there are issues to consider prior to their routine use, including test performance and specific regulatory requirements. This review will provide a summary of the regulatory landscape of point-of-care tests for viral infections in the United States, and address important considerations such as site certification, training and inspection readiness.

Phylogenetic Analysis of Transmission Dynamics of Dengue in Large and Small Population Centers, Northern Ecuador.

Although dengue is typically considered an urban disease, rural communities are also at high risk. To clarify dynamics of dengue virus (DENV) transmission in settings with characteristics generally considered rural (e.g., lower population density, remoteness), we conducted a phylogenetic analysis in 6 communities in northwestern Ecuador. DENV RNA was detected by PCR in 121/488 serum samples collected from febrile case-patients during 2019-2021. Phylogenetic analysis of 27 samples from Ecuador and other countries in South America confirmed that DENV-1 circulated during May 2019-March 2020 and DENV-2 circulated during December 2020-July 2021. Combining locality and isolation dates, we found strong evidence that DENV entered Ecuador through the northern province of Esmeraldas. Phylogenetic patterns suggest that, within this province, communities with larger populations and commercial centers were more often the source of DENV but that smaller, remote communities also play a role in regional transmission dynamics.

The Effect of the Secret Agent Society Group Program on Parent-Teacher Agreement Regarding Children's Social Emotional Functioning.

Differences in social-emotional processing and functioning characterize children with Attention Deficit Hyperactivity Disorder (ADHD), Autism Spectrum Disorder (ASD), and Anxiety Disorders. These can contribute to difficulties forming friendships and secondary challenges such as academic underachievement, depression, and substance use in adolescence. To be optimally successful, interventions typically require parents and teachers to have a shared understanding of a child's social-emotional needs and use consistent support strategies across home and school environments. However, research is yet to examine the effect that clinic-based programs have on parent-teacher agreement regarding children's social-emotional functioning. To the authors' knowledge, this is the first published study to explore this. A sample of eighty-nine youth (aged 8 to 12 years) with ASD, ADHD, and/or an Anxiety Disorder participated in the Secret Agent Society Program. The Social Skills Questionnaire and Emotion Regulation and Social Skills Questionnaire were administered to parents and teachers at pre-program, post-program, and six-month follow-up. Parent-teacher agreement was assessed at each time point. Pearson Product Moment correlations and intraclass correlations indicated that parent-teacher agreement on the measures of children's social-emotional functioning improved over time. These findings suggest that clinic-based programs can contribute to key stakeholders developing a shared understanding of children's social-emotional needs. The implications of these findings and directions for future research are discussed.

Diagnostic quality model (DQM): an integrated framework for the assessment of diagnostic quality when using AI/ML.

BACKGROUND: Laboratory medicine has reached the era where promises of artificial intelligence and machine learning (AI/ML) seem palpable. Currently, the primary responsibility for risk-benefit assessment in clinical practice resides with the medical director. Unfortunately, there is no tool or concept that enables diagnostic quality assessment for the various potential AI/ML applications. Specifically, we noted that an operational definition of laboratory diagnostic quality - for the specific purpose of assessing AI/ML improvements - is currently missing. METHODS: A session at the 3rd Strategic Conference of the European Federation of Laboratory Medicine in 2022 on "AI in the Laboratory of the Future" prompted an expert roundtable discussion. Here we present a conceptual diagnostic quality framework for the specific purpose of assessing AI/ML implementations. RESULTS: The presented framework is termed diagnostic quality model (DQM) and distinguishes AI/ML improvements at the test, procedure, laboratory, or healthcare ecosystem level. The operational definition illustrates the nested relationship among these levels. The model can help to define relevant objectives for implementation and how levels come together to form coherent diagnostics. The affected levels are referred to as scope and we provide a rubric to quantify AI/ML improvements while complying with existing, mandated regulatory standards. We present 4 relevant clinical scenarios including multi-modal diagnostics and compare the model to existing quality management systems. CONCLUSIONS: A diagnostic quality model is essential to navigate the complexities of clinical AI/ML implementations. The presented diagnostic quality framework can help to specify and communicate the key implications of AI/ML solutions in laboratory diagnostics.

High Rates of Anxiety Among Adolescents in a Partial Hospitalization Program.

Background: Anxiety disorders are garnering increasing attention for their contribution to high-risk issues and functional impairment. Adolescents are typically admitted to partial hospitalization programs (PHPs) due to high-risk presentations. However, the frequency of anxiety disorders in PHPs is not well-established, in part because anxiety can be overlooked in acute settings due to limited lengths of stay and focus on stabilization. Objective: This study aims to evaluate the frequency and severity of anxiety disorders among a sample of adolescent PHP patients to assess the need for anxiety-specific assessment and interventions in higher acuity settings. Methods: Participants were 158 youths ages 13 to 19 years old (M = 15.49 years, SD = 1.50) who were admitted to an adolescent PHP and their caregivers. Clinician-reported diagnostic information was collected from the youth's electronic medical record, and self- and caregiver-rated severity of anxiety was collected using the Screen for Child Anxiety Related Emotions Disorders (SCARED-C/P). Frequency of anxiety and related disorder diagnoses and self- and caregiver-reported severity were assessed using descriptive statistical methods. Results: 75% of participants were diagnosed with an anxiety disorder (n = 118). On average, participants with anxiety disorders had elevated SCARED-C scores. Youths with depressive disorders had elevated SCARED-C scores even when they did not carry anxiety disorder diagnoses. Caregiver ratings of the youth's anxiety symptoms on the SCARED-P were elevated when youths had anxiety disorders. Conclusions: These findings suggest that anxiety is common in an adolescent PHP setting and support investing in evidence-based assessment and treatment of anxiety in high-acuity settings.

Diagnosis and Management of Functional Tic-Like Phenomena.

Over the past 3 years, a global phenomenon has emerged characterized by the sudden onset and frequently rapid escalation of tics and tic-like movements and phonations. These symptoms have occurred not only in youth known to have tics or Tourette syndrome (TS), but also, and more notably, in youth with no prior history of tics. The Tourette Association of America (TAA) convened an international, multidisciplinary working group to better understand this apparent presentation of functional neurological disorder (FND) and its relationship to TS. Here, we review and summarize the literature relevant to distinguish the two, with recommendations to clinicians for diagnosis and management. Finally, we highlight areas for future emphasis and research.

Childhood Predictors of Long-Term Tic Severity and Tic Impairment in Tourette's Disorder.

Tics peak in late childhood and decline during adolescence. Yet, for some with Tourette's disorder, tics persist into adulthood. We evaluated childhood predictors of adult tic severity and tic impairment, and change over time. Eighty adolescents/adults were evaluated 11 years following a randomized-controlled trial of behavior therapy. An independent evaluator rated tic severity and tic impairment at baseline, posttreatment, and long-term follow-up. At baseline, parents completed demographics/medical history, and youth tic, internalizing, and externalizing symptom ratings. Youth rated premonitory urge severity and family functioning. After controlling for prior tic treatment effects, female sex and higher tic severity predicted higher tic severity in adulthood; and female sex, no stimulant medication use, higher tic severity, and poorer family functioning predicted higher tic impairment. Higher tic severity and premonitory urge severity predicted smaller reductions in tic severity, whereas higher externalizing symptoms predicted greater reduction in tic severity. Female sex predicted smaller reduction in tic impairment, and externalizing symptoms predicted greater reduction in tic impairment. Female sex and childhood tic severity are important predictors of tic severity and tic impairment in adulthood. Family functioning, premonitory urge severity, and tic severity are important modifiable targets for early or targeted intervention to improve long-term outcomes.

Youth Top Problems in an Acute Psychiatric Sample: Describing Consumer-Nominated Treatment Needs in an Adolescent Partial Hospital Setting.

Given the wide range of diagnostic presentations treated in partial hospital programs, finding efficient ways to identify and measure progress on the chief concerns of consumers in these settings is important. The current study uses a self-administered version of the Top Problems Assessment to describe treatment targets identified by youth and their caregivers presenting for care at an adolescent partial hospital setting. Caregiver-youth agreement on these chief concerns upon admission and predictors of agreement were explored. About one-third (34.65%) of caregiver-youth pairs did not match on any target problems. Although anxiety and depression were the most commonly cited top problems in this sample, caregivers and youth exhibited disagreement on these domains. Treatment teams in acute care settings such as a partial hospital program can benefit from careful assessment surrounding the initial goals of treatment as youth and their caregivers may not agree on the referral problems upon entering a program.