Antibody evasion by SARS-CoV-2 Omicron subvariants BA.2.12.1, BA.4 and BA.5.

SARS-CoV-2 Omicron subvariants BA.2.12.1 and BA.4/5 have surged notably to become dominant in the United States and South Africa, respectively1,2. These new subvariants carrying further mutations in their spike proteins raise concerns that they may further evade neutralizing antibodies, thereby further compromising the efficacy of COVID-19 vaccines and therapeutic monoclonals. We now report findings from a systematic antigenic analysis of these surging Omicron subvariants. BA.2.12.1 is only modestly (1.8-fold) more resistant to sera from vaccinated and boosted individuals than BA.2. However, BA.4/5 is substantially (4.2-fold) more resistant and thus more likely to lead to vaccine breakthrough infections. Mutation at spike residue L452 found in both BA.2.12.1 and BA.4/5 facilitates escape from some antibodies directed to the so-called class 2 and 3 regions of the receptor-binding domain3. The F486V mutation found in BA.4/5 facilitates escape from certain class 1 and 2 antibodies but compromises the spike affinity for the viral receptor. The R493Q reversion mutation, however, restores receptor affinity and consequently the fitness of BA.4/5. Among therapeutic antibodies authorized for clinical use, only bebtelovimab retains full potency against both BA.2.12.1 and BA.4/5. The Omicron lineage of SARS-CoV-2 continues to evolve, successively yielding subvariants that are not only more transmissible but also more evasive to antibodies.

Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7.

The COVID-19 pandemic has had widespread effects across the globe, and its causative agent, SARS-CoV-2, continues to spread. Effective interventions need to be developed to end this pandemic. Single and combination therapies with monoclonal antibodies have received emergency use authorization1-3, and more treatments are under development4-7. Furthermore, multiple vaccine constructs have shown promise8, including two that have an approximately 95% protective efficacy against COVID-199,10. However, these interventions were directed against the initial SARS-CoV-2 virus that emerged in 2019. The recent detection of SARS-CoV-2 variants B.1.1.7 in the UK11 and B.1.351 in South Africa12 is of concern because of their purported ease of transmission and extensive mutations in the spike protein. Here we show that B.1.1.7 is refractory to neutralization by most monoclonal antibodies against the N-terminal domain of the spike protein and is relatively resistant to a few monoclonal antibodies against the receptor-binding domain. It is not more resistant to plasma from individuals who have recovered from COVID-19 or sera from individuals who have been vaccinated against SARS-CoV-2. The B.1.351 variant is not only refractory to neutralization by most monoclonal antibodies against the N-terminal domain but also by multiple individual monoclonal antibodies against the receptor-binding motif of the receptor-binding domain, which is mostly due to a mutation causing an E484K substitution. Moreover, compared to wild-type SARS-CoV-2, B.1.351 is markedly more resistant to neutralization by convalescent plasma (9.4-fold) and sera from individuals who have been vaccinated (10.3-12.4-fold). B.1.351 and emergent variants13,14 with similar mutations in the spike protein present new challenges for monoclonal antibody therapies and threaten the protective efficacy of current vaccines.

Prevention of Neisseria gonorrhoeae With Meningococcal B Vaccine: A Matched Cohort Study in Southern California.

BACKGROUND: Neisseria gonorrhoeae is acquiring increasing resistance to available oral antibiotics, and current screening and treatment approaches have not decreased gonorrhea incidence. Although a gonorrhea-specific vaccine does not exist, N. gonorrhoeae shares much of its genome with Neisseria meningitidis, notably critical antigenic determinants including outer membrane vesicles (OMV). Prior observational studies have suggested that OMV-based meningococcal serogroup B vaccines confer protection against gonorrhea. METHODS: We conducted a matched cohort study from 2016 to 2020 to examine the association of OMV-containing recombinant meningococcal serogroup B vaccine (4CMenB) with gonorrhea infection among teens and young adults at Kaiser Permanente Southern California. Recipients of 4CMenB were matched in a ratio of 1:4 to recipients of non-OMV-containing polysaccharide-conjugate vaccine targeting serotypes A, C, W, and Y (MenACWY) who had not received 4CMenB and were followed for incident gonorrhea. We used Cox proportional hazards regression to compare gonorrhea rates among recipients of 4CMenB vs MenACWY, adjusting for potential confounders. We conducted the same analysis with chlamydia as a negative control outcome. RESULTS: The study included 6641 recipients of 4CMenB matched to 26 471 recipients of MenACWY. During follow-up, gonorrhea incidence rates per 1000 person-years (95% confidence intervals [CIs]) were 2.0 (1.3-2.8) for recipients of 4CMenB and 5.2 (4.6-5.8) for recipients of MenACWY. In adjusted analyses, gonorrhea rates were 46% lower among recipients of 4CMenB vs MenACWY (hazard ratio [HR], 0.54; 95% CI, .34-.86), but chlamydia rates were similar between vaccine groups (HR, 0.98; 95% CI, .82-1.17). CONCLUSIONS: These results suggest cross-protection of 4CMenB against gonorrhea, supporting the potential for vaccination strategies to prevent gonorrhea.

Antigenic Distance between North American Swine and Human Seasonal H3N2 Influenza A Viruses as an Indication of Zoonotic Risk to Humans.

Human-to-swine transmission of influenza A virus (IAV) repeatedly occurs, leading to sustained transmission and increased diversity in swine; human seasonal H3N2 introductions occurred in the 1990s and 2010s and were maintained in North American swine. Swine H3N2 strains were subsequently associated with zoonotic infections, highlighting the need to understand the risk of endemic swine IAV to humans. We quantified antigenic distances between swine H3N2 and human seasonal vaccine strains from 1973 to 2014 using a panel of monovalent antisera raised in pigs in hemagglutination inhibition (HI) assays. Swine H3N2 lineages retained the closest antigenic similarity to human vaccine strains from the decade of incursion. Swine lineages from the 1990s were antigenically more similar to human vaccine strains of the mid-1990s but had substantial distance from recent human vaccine strains. In contrast, lineages from the 2010s were closer to human vaccine strains from 2011 and 2014 and the most antigenically distant from human vaccine strains prior to 2007. HI assays using ferret antisera demonstrated that swine lineages from the 1990s and 2010s had significant fold reductions compared to the homologous HI titer of the nearest pandemic preparedness candidate vaccine virus (CVV) or seasonal vaccine strain. The assessment of postinfection and postvaccination human serum cohorts demonstrated limited cross-reactivity to swine H3N2 from the 1990s, especially in older adults born before the 1970s. We identified swine strains to which humans are likely to lack population immunity or are not protected against by a current human seasonal vaccine or CVV to use in prioritizing future human CVV strain selection. IMPORTANCE Human H3N2 influenza A viruses spread to pigs in North America in the 1990s and more recently in the 2010s. These cross-species events led to sustained circulation and increased H3N2 diversity in pig populations. The evolution of H3N2 in swine led to a reduced similarity to human seasonal H3N2 and the vaccine strains used to protect human populations. We quantified the antigenic phenotypes and found that North American swine H3N2 lineages retained more antigenic similarity to historical human vaccine strains from the decade of incursion but had substantial differences compared to recent human vaccine strains. Additionally, pandemic preparedness vaccine strains demonstrated a loss of similarity to contemporary swine strains. Finally, human sera revealed that although these adults had antibodies against human H3N2 strains, many had limited immunity to swine H3N2, especially older adults born before 1970. Antigenic assessment of swine H3N2 provides critical information for pandemic preparedness and candidate vaccine development.

Managing Menopausal Symptoms: Common Questions and Answers.

Menopausal symptoms are widespread and significantly impact quality of life. Common symptoms of menopause are vasomotor (i.e., hot flashes and night sweats) and genitourinary (e.g., vulvovaginal irritation and dryness, dyspareunia, urinary problems), although women may also experience changes in sexual function, mood, and sleep. Estrogen-containing hormone therapy is effective treatment for vasomotor symptoms. Nonhormonal medications for vasomotor symptoms include selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and gabapentin. Selective serotonin reuptake inhibitors should not be administered to women taking tamoxifen. Cognitive behavior therapy and clinical hypnosis are effective for short-term reduction of vasomotor symptoms and associated sleep disturbances, but data are lacking to support the effectiveness of other nonpharmacologic treatments such as herbal or botanicalsupplements, exercise, and acupuncture. Hormone-free vaginal moisturizers are noninferior to estrogen-based therapies for treating genitourinary syndrome of menopause. Other treatment options for vaginal dryness and dyspareunia associated with menopause include ospemifene and intravaginal dehydroepiandrosterone. Management of menopausal symptoms should involve shared decision-making that is informed by the best available evidence and individual risks and preferences.

Quorum Sensing Regulation of a Major Facilitator Superfamily Transporter Affects Multiple Streptococcal Virulence Factors.

Cell-cell signaling mediated by Rgg-family transcription factors and their cognate pheromones is conserved in Firmicutes, including all streptococci. In Streptococcus pyogenes, or group A strep (GAS), one of these systems, the Rgg2/3 quorum sensing (QS) system, has been shown to regulate phenotypes, including cellular aggregation and biofilm formation, lysozyme resistance, and macrophage immunosuppression. Here, we show the abundance of several secreted virulence factors (streptolysin O, SpyCEP, and M protein) decreases upon induction of QS. The main mechanism underlying the changes in protein levels appears to be transcriptional, occurs downstream of the QS circuit, and is dysregulated by the deletion of an Rgg2/3 QS-regulated major facilitator superfamily (MFS) transporter. Additionally, we identify this MFS transporter as the factor responsible for a previously observed increase in aminoglycoside sensitivity in QS-induced cells. IMPORTANCE The production of virulence factors is a tightly regulated process in bacterial pathogens. Efforts to elucidate the mechanisms by which genes are regulated may advance the understanding of factors influencing pathogen behavior or cellular physiology. This work finds expression of a major facilitator superfamily (MFS) transporter, which is governed by a quorum sensing (QS) system, impacts the expression of multiple virulence factors and accounts for QS-dependent antibiotic susceptibility. Although the mechanism underlying this effect is not clear, MFS orthologs with high sequence similarity from S. pneumoniae and S. porcinus were unable to substitute indicating substrate specificity of the GAS MFS gene. These findings demonstrate novel associations between expression of a transmembrane transporter and virulence factor expression and aminoglycoside transport.

SARS-CoV-2 RNA Shedding in Semen and Oligozoospermia of Patient with Severe Coronavirus Disease 11 Weeks after Infection.

We report severe acute respiratory syndrome coronavirus 2 in semen by using quantitative reverse transcription PCR during the late convalescent phase. Virus was associated with adequate humoral and cell-mediated responses, suggesting possible seeding of the immune-privileged testes. We provide longitudinal semen quality data for 6 other men, including 3 who had oligozoospermia.

Evolution and Antigenic Advancement of N2 Neuraminidase of Swine Influenza A Viruses Circulating in the United States following Two Separate Introductions from Human Seasonal Viruses.

Two separate introductions of human seasonal N2 neuraminidase genes were sustained in U.S. swine since 1998 (N2-98) and 2002 (N2-02). Herein, we characterized the antigenic evolution of the N2 of swine influenza A virus (IAV) across 2 decades following each introduction. The N2-98 and N2-02 expanded in genetic diversity, with two statistically supported monophyletic clades within each lineage. To assess antigenic drift in swine N2 following the human-to-swine spillover events, we generated a panel of swine N2 antisera against representative N2 and quantified the antigenic distance between wild-type viruses using enzyme-linked lectin assay and antigenic cartography. The antigenic distance between swine and human N2 was smallest between human N2 circulating at the time of each introduction and the archetypal swine N2. However, sustained circulation and evolution in swine of the two N2 lineages resulted in significant antigenic drift, and the N2-98 and N2-02 swine N2 lineages were antigenically distinct. Although intralineage antigenic diversity was observed, the magnitude of antigenic drift did not consistently correlate with the observed genetic differences. These data represent the first quantification of the antigenic diversity of neuraminidase of IAV in swine and demonstrated significant antigenic drift from contemporary human seasonal strains as well as antigenic variation among N2 detected in swine. These data suggest that antigenic mismatch may occur between circulating swine IAV and vaccine strains. Consequently, consideration of the diversity of N2 in swine IAV for vaccine selection may likely result in more effective control and aid public health initiatives for pandemic preparedness. IMPORTANCE Antibodies inhibiting the neuraminidase (NA) of IAV reduce clinical disease, virus shedding, and transmission, particularly in the absence of neutralizing immunity against hemagglutinin. To understand antibody recognition of the genetically diverse NA in U.S. swine IAV, we characterized the antigenic diversity of N2 from swine and humans. N2 detected in swine IAV were derived from two distinct human-to-swine spillovers that persisted, are antigenically distinct, and underwent antigenic drift. These findings highlight the need for continued surveillance and vaccine development in swine with increased focus on the NA. Additionally, human seasonal N2 isolated after 2005 were poorly inhibited by representative swine N2 antisera, suggesting a lack of cross-reactive NA antibody-mediated immunity between contemporary swine and human N2. Bidirectional transmission between humans and swine represents a One Health challenge, and determining the correlates of immunity to emerging IAV strains is critical to mitigating zoonotic and reverse-zoonotic transmission.

Changes in Testing and Diagnoses of Sexually Transmitted Infections and HIV During the COVID-19 Pandemic.

ABSTRACT: We evaluated changes in rates of testing and diagnoses of sexually transmitted infections during the 2017-2020 period at Kaiser Permanente Southern California. During the COVID-19 pandemic period, we observed profound reductions in testing and fewer diagnoses of chlamydia, gonorrhea, and HIV compared with prepandemic periods, but syphilis diagnoses rates increased by 32%.

Application of deep machine learning for the radiographic diagnosis of periodontitis.

OBJECTIVE: Successful application of deep machine learning could reduce time-consuming and labor-intensive clinical work of calculating the amount of radiographic bone loss (RBL) in diagnosing and treatment planning for periodontitis. This study aimed to test the accuracy of RBL classification by machine learning. MATERIALS AND METHODS: A total of 236 patients with standardized full mouth radiographs were included. Each tooth from the periapical films was evaluated by three calibrated periodontists for categorization of RBL and radiographic defect morphology. Each image was pre-processed and augmented to ensure proper data balancing without data pollution, then a novel multitasking InceptionV3 model was applied. RESULTS: The model demonstrated an average accuracy of 0.87 ± 0.01 in the categorization of mild (< 15%) or severe (≥ 15%) bone loss with fivefold cross-validation. Sensitivity, specificity, positive predictive, and negative predictive values of the model were 0.86 ± 0.03, 0.88 ± 0.03, 0.88 ± 0.03, and 0.86 ± 0.02, respectively. CONCLUSIONS: Application of deep machine learning for the detection of alveolar bone loss yielded promising results in this study. Additional data would be beneficial to enhance model construction and enable better machine learning performance for clinical implementation. CLINICAL RELEVANCE: Higher accuracy of radiographic bone loss classification by machine learning can be achieved with more clinical data and proper model construction for valuable clinical application.

Innovations in Human Immunodeficiency Virus (HIV) Care Delivery During the Coronavirus Disease 2019 (COVID-19) Pandemic: Policies to Strengthen the Ending the Epidemic Initiative-A Policy Paper of the Infectious Diseases Society of America and the HIV Medicine Association.

The goal of the Ending the HIV Epidemic Initiative is to reduce new infections in the United States by 90% by 2030. Success will require fundamentally changing human immunodeficiency virus (HIV) prevention and care delivery to engage more persons with HIV and at risk of HIV in treatment. While the coronavirus disease 2019 (COVID-19) pandemic reduced in-person visits to care facilities and led to concern about interruptions in care, it also accelerated growth of alternative options, bolstered by additional funding support. These included the use of telehealth, medication delivery to the home, and increased flexibility facilitating access to Ryan White HIV/AIDS Program services. While the outcomes of these programs must be studied, many have improved accessibility during the pandemic. As the pandemic wanes, long-term policy changes are needed to preserve these options for those who benefit from them. These new care paradigms may provide a roadmap for progress for those with other chronic health issues as well.

Aerosol Transmission from Infected Swine to Ferrets of an H3N2 Virus Collected from an Agricultural Fair and Associated with Human Variant Infections.

Influenza A viruses (IAV) sporadically transmit from swine to humans, typically associated with agricultural fairs in the United States. A human seasonal H3 virus from the 2010-2011 IAV season was introduced into the U.S. swine population and termed H3.2010.1 to differentiate it from the previous swine H3 virus. This H3N2 lineage became widespread in the U.S. commercial swine population, subsequently spilling over into exhibition swine, and caused a majority of H3N2 variant (H3N2v) cases in humans in 2016 and 2017. A cluster of human H3N2v cases were reported at an agricultural fair in 2017 in Ohio, where 2010.1 H3N2 IAV was concurrently detected in exhibition swine. Genomic analysis showed that the swine and human isolates were nearly identical. In this study, we evaluated the propensity of a 2010.1 H3N2 IAV (A/swine/Ohio/A01354299/2017 [sw/OH/2017]) isolated from a pig in the agricultural fair outbreak to replicate in ferrets and transmit from swine to ferret. sw/OH/2017 displayed robust replication in the ferret respiratory tract, causing slight fever and moderate weight loss. Further, sw/OH/2017 was capable of efficient respiratory droplet transmission from infected pigs to contact ferrets. These findings establish a model for evaluating the propensity of swine IAV to transmit from pig to ferret as a measure of risk to the human population. The identification of higher-risk swine strains can then be targeted for control measures to limit the dissemination at human-swine interfaces to reduce the risk of zoonotic infections and to inform pandemic planning.IMPORTANCE A recently emerged lineage of human-like H3N2 (H3.2010.1) influenza A virus (IAV) from swine has been frequently detected in commercial and exhibition swine in recent years and has been associated with H3N2 variant cases in humans from 2016 and 2017. To demonstrate a model for characterizing the potential for zoonotic transmission associated with swine IAV, we performed an in vivo study of transmission between pigs infected with an H3.2010.1 H3N2 IAV and aerosol contact ferrets. The efficient interspecies transmission demonstrated for the H3.2010.1 IAV in swine emphasizes the need for further characterization of viruses circulating at the swine-human interface for transmission potential prior to human spillover and the development and implementation of more robust vaccines and control strategies to mitigate human exposure to higher-risk swine strains.

Longitudinal Viral Load Monitoring Using Home-Collected Dried Blood Spot Specimens of MSM Living with HIV: Results from a Feasibility Pilot Study.

Novel viral load monitoring strategies are needed to help individuals maintain an undetectable viral load (UVL). In 2018, U.S. MSM living with HIV with a past detectable VL received a dried blood spot (DBS) kit at baseline and 3-month follow-up and returned specimens to a research laboratory. Of 56 consenting participants, 91% returned specimens at baseline and 77% at 3-month follow-up; 74% who returned two specimens had UVL at both time points. At-home DBS collection and longitudinal VL monitoring is feasible among U.S. MSM with fluctuating viral load. This complementary approach to clinical care could improve viral suppression maintenance.

RESUMEN: Se necesitan nuevas estrategias para evaluar los niveles de la carga viral para ayudar a las personas viviendo con VIH a mantener una carga viral indetectable (CVI). En 2018, hombres viviendo con VIH, que reportaron sexo con hombres y una carga viral detectable, recibieron dos paquetes de materiales para colectar muestras de sangre seca después de completar una evaluación basal y después de tres meses de seguimiento. Participantes devolvieron las muestras de sangre seca a un laboratorio. De 56 participantes que dieron su consentimiento a participar en el estudio, el 91% devolvió una muestra de sangre seca al inicio del estudio y el 77% a los 3 meses de seguimiento. Además, el 74% que devolvió dos muestras de sangre seca tenían CVI en ambos puntos de tiempo. La colección de sangre seca en el hogar y el monitoreo longitudinal de la carga viral de VIH es factible entre los hombres viviendo con el VIH y que tienen sexo con hombres. Los resultados de este estudio pueden proporcionar un enfoque complementario a la atención clínica para mejorar la supresión viral del VIH.

The impact of smoking on non-surgical periodontal therapy: A systematic review and meta-analysis.

AIM: Smoking is a risk factor for periodontitis. This study aimed to evaluate the impact of smoking on clinical outcomes of non-surgical periodontal therapy. MATERIALS AND METHODS: Electronic databases were searched to screen studies published before May 2020. The included studies had to have two groups: smokers (S) and non-smokers (NS) with periodontitis. The outcomes evaluated were differences between groups in probing depth (PD) reduction and clinical attachment level (CAL) gain after non-surgical periodontal therapy. Meta-regressions were conducted to evaluate correlations between outcomes and other contributing factors. RESULTS: Seventeen studies were included. The post-treatment PD reduction in the S group was smaller than in the NS group (weighted mean difference in PD reduction: -0.33 mm, 95% confidence interval (CI): [-0.49, -0.17], p < .01). The CAL gain in the S group was also smaller than in the NS group (weighted mean difference in CAL gain: -0.20 mm, CI: [-0.39, -0.02], p < .01). Additionally, baseline PD significantly affected the difference in PD reduction between two groups. CONCLUSIONS: Smoking negatively impacts clinical responses to non-surgical periodontal therapy. Smokers with periodontitis have significantly less PD reduction and CAL gain than non-smokers.

The New Normal: Coronavirus Pandemic Response Utilizing Microsoft SharePoint.

On March 11, 2020, the World Health Organization (WHO) declared the novel coronavirus disease (COVID-19) a pandemic. Hospitals throughout the USA and the residency programs housed therein have drastically altered their standard operations to slow the spread of disease. Maintaining the educational mission of a residency program within the parameters of social distancing mandates is an unprecedented challenge to graduate medical education and will remain so for the near future. We evaluated resident perception of our efforts to transition educational activities within the residency to an online, remote format utilizing Microsoft SharePoint. Educational conferences were transitioned to a videoconferencing platform on March 13, 2020 in conjunction with the deployment of an intradepartmental Microsoft SharePoint site to provide educational resources, disseminate scheduling changes, and provide wellness resources in response to the COVID-19 pandemic. An 11-question survey available from 4 Jan 2020-4 Jun 2020 surveyed resident perceptions of the instituted changes. Twenty-six of 31 residents (83.8%) responded to the resident survey invitation. Twenty-four of 26 residents (92.3%) characterized the SharePoint as useful. Twenty of 26 residents (76.9%) desired attending guidance as to how to utilize the online resources for each resident rotation. A total of 92.3% (24/26) of residents felt that the program's response utilizing SharePoint engendered a greater sense of belonging to their work community. Resident perception of the transition to online learning utilizing Microsoft SharePoint as a distribution platform was generally positive, helping to mitigate untoward educational consequences of the COVID-19 pandemic.

A Call to Action: The Role of Antiretroviral Stewardship in Inpatient Practice, a Joint Policy Paper of the Infectious Diseases Society of America, HIV Medicine Association, and American Academy of HIV Medicine.

Persons living with human immunodeficiency virus (HIV) and others receiving antiretrovirals are at risk for medication errors during hospitalization and at transitions of care. These errors may result in adverse effects or viral resistance, limiting future treatment options. A range of interventions is described in the literature to decrease the occurrence or duration of medication errors, including review of electronic health records, clinical checklists at care transitions, and daily review of medication lists. To reduce the risk of medication-related errors, antiretroviral stewardship programs (ARVSPs) are needed to enhance patient safety. This call to action, endorsed by the Infectious Diseases Society of America, the HIV Medicine Association, and the American Academy of HIV Medicine, is modeled upon the success of antimicrobial stewardship programs now mandated by the Joint Commission. Herein, we propose definitions of ARVSPs, suggest resources for ARVSP leadership, and provide a summary of published, successful strategies for ARVSP that healthcare facilities may use to develop locally appropriate programs.

Region-specific glial homeostatic signature in prion diseases is replaced by a uniform neuroinflammation signature, common for brain regions and prion strains with different cell tropism.

Chronic neuroinflammation is recognized as a major neuropathological hallmark in a broad spectrum of neurodegenerative diseases including Alzheimer's, Parkinson's, Frontal Temporal Dementia, Amyotrophic Lateral Sclerosis, and prion diseases. Both microglia and astrocytes exhibit region-specific homeostatic transcriptional identities, which under chronic neurodegeneration, transform into reactive phenotypes in a region- and disease-specific manner. Little is known about region-specific identity of glia in prion diseases. The current study was designed to determine whether the region-specific homeostatic signature of glia changes with the progression of prion diseases, and whether these changes occur in a region-dependent or universal manner. Also of interest was whether different prion strains give rise to different reactive phenotypes. To answer these questions, we analyzed gene expression in the thalamus, cortex, hypothalamus and hippocampus of mice infected with 22L and ME7 prion strains using a Nanostring Neuroinflammation panel at the subclinical, early clinical and advanced stages of the disease. We found that at the preclinical stage of the disease, the region-specific homeostatic identities were preserved. However, with the appearance of clinical signs, the region-specific signatures were partially lost and replaced with a neuroinflammation signature. While the same sets of genes were activated by both prion strains, the timing of neuroinflammation and the degree of activation in different brain regions was strain-specific. Changes in astrocyte function scored at the top of the activated pathways. Moreover, clustering analysis suggested that the astrocyte function pathway responded to prion infection prior to the Activated Microglia or Neuron and Neurotransmission pathways. The current work established neuroinflammation gene expression signature associated with prion diseases. Our results illustrate that with the disease progression, the region-specific homeostatic transcriptome signatures are replaced by the region-independent neuroinflammation signature, which is common for prion strains with different cell tropism. The prion-associated neuroinflammation signature identified in the current study overlapped only partially with the microglia degenerative phenotype and the disease-associated microglia phenotype reported for animal models of other neurodegenerative diseases.

Effects of White Potatoes Consumed With Eggs on Satiety, Food Intake, and Glycemic Response in Children and Adolescents.

Objective: Short-term studies in adults have shown that white potatoes increase satiety and suppress food intake (FI) compared with several other carbohydrate-containing foods; however, studies are limited in children. The objective was to compare the effects of white potatoes in mixed meals on satiety, FI, and glycemic response in 9-14-year-old children and adolescents.Methods: Using a within-subject, repeated-measures design, 21 children completed five counter-balanced test sessions. After an overnight fast, children consumed one of four isocaloric treatment meals (450 kcal) of French fries, mashed potatoes, or white beans served with a fixed portion of egg omelet (30 g of protein), a control meal with cereal, milk, and bread, or continued to fast (i.e., meal skipping). Subjective appetite was measured using visual analogue scales. FI at an ad libitum pizza meal at 180 min and rest of day diet record were used to measure lunch FI and rest of day energy intake, respectively. Total daily energy intake was calculated by adding the energy intake from the treatment meal, the ad libitum pizza lunch, and rest of day food record. Capillary blood samples were collected to assess glycemic response over 180 min.Results: Change from baseline subjective average appetite scores were lower after mashed potatoes compared with all other treatment conditions (p < 0.001), and higher after French fries compared with white beans (p = 0.04). Lunch FI (kcal) was significantly lower (p < 0.001) after French fries (1010±73) and mashed potatoes (1039±74) compared with the control meal (1257±92) and meal skipping (1235±74). Total daily energy intake (kcal) was lower after French fries compared with the control meal (2228±141 vs. 2624±137; p = 0.04). Change from baseline blood glucose was lower after white beans and French fries compared with mashed potatoes (p < 0.05) and the control meal (p < 0.001).Conclusion: In conclusion, white potatoes with eggs increased satiety, decreased short-term FI, and resulted in similar energy intakes compared with meal skipping.

Actigraphy to Measure Physical Activity in the Intensive Care Unit: A Systematic Review.

OBJECTIVE: In the intensive care unit (ICU), prolonged inactivity is common, increasing patients' risk for adverse outcomes, including ICU-acquired weakness. Hence, interventions to minimize inactivity are gaining popularity, highlighting actigraphy, a measure of activity involving a wristwatch-like accelerometer, as a method to inform these efforts. Therefore, we performed a systematic review of studies that used actigraphy to measure patient activity in the ICU setting. DATA SOURCES: We searched PubMed, EMBASE, CINAHL, Cochrane Library, and ProQuest from inception until December 2016. STUDY SELECTION: Two reviewers independently screened studies for inclusion. A study was eligible for inclusion if it was published in a peer-reviewed journal and used actigraphy to measure activity in ≥5 ICU patients. DATA EXTRACTION: Two reviewers independently performed data abstraction and risk of bias assessment. Abstracted actigraphy-based activity data included total activity time and activity counts. RESULTS: Of 16 studies (607 ICU patients) identified, 14 (88%) were observational, 2 (12%) were randomized control trials, and 5 (31%) were published after 2009. Mean patient activity levels per 15 to 60 second epoch ranged from 25 to 37 daytime and 2 to 19 nighttime movements. Actigraphy was evaluated in the context of ICU and post-ICU outcomes in 11 (69%) and 5 (31%) studies, respectively, and demonstrated potential associations between actigraphy-based activity levels and delirium, sedation, pain, anxiety, time to extubation, and length of stay. CONCLUSION: Actigraphy has demonstrated that patients are profoundly inactive in the ICU with actigraphy-based activity levels potentially associated with important measures, such as delirium, sedation, and length of stay. Larger and more rigorous studies are needed to further evaluate these associations and the overall utility of actigraphy in the ICU setting.

ADHD in Children: Common Questions and Answers.

Attention-deficit/hyperactivity disorder (ADHD) is a multidimensional chronic neurodevelopmental condition that affects 8.4% of U.S. children between two and 17 years of age and may pose long-term morbidity if untreated. The evaluation for ADHD begins when parents or caregivers present to primary care physicians with concerns about behavior problems or poor school or social function. A comprehensive history and physical examination should assess for comorbid or other conditions that can mimic ADHD. The combination of Diagnostic and Statistical Manual of Mental Disorders, 5th ed., criteria and validated screening tools completed by parents, teachers, or other adults can aid in establishing the diagnosis. The goals of treatment include symptom reduction and improved social and cognitive function. Psychosocial interventions are the recommended first-line treatment for preschool children (four to five years) and can improve overall function when used as an adjunct therapy in elementary school children (six to 11 years of age) and adolescents (12 to 17 years of age). Stimulant medications are well-established as an effective treatment for reducing symptoms of ADHD in elementary school children and adolescents. Nonstimulant medications are less effective but reasonable as adjunct or alternative therapy when stimulants are ineffective or not tolerated. Regular follow-up is key in the management of ADHD and should assess symptoms, overall function, presence of comorbidities, adverse effects of treatment, and medication use.