Title: Male Fertility Supplements Fail to Deliver
Category: Health News
Created: 1/7/2020 12:00:00 AM
Last Editorial Review: 1/8/2020 12:00:00 AM

Title: Could ED Drugs Threaten Men's Vision?
Category: Health News
Created: 2/7/2020 12:00:00 AM
Last Editorial Review: 2/7/2020 12:00:00 AM

Title: High Testosterone Levels Have Different Health Impact for Men and Women
Category: Health News
Created: 2/10/2020 12:00:00 AM
Last Editorial Review: 2/11/2020 12:00:00 AM

Title: Can Men Dine Their Way to Higher Sperm Counts?
Category: Health News
Created: 2/21/2020 12:00:00 AM
Last Editorial Review: 2/24/2020 12:00:00 AM

Title: Sinus Headache Pain, Symptoms, Treatments, Remedies, and Cures
Category: Diseases and Conditions
Created: 1/11/2010 12:00:00 AM
Last Editorial Review: 1/13/2020 12:00:00 AM

Title: First Treatment for Peanut Allergy Approved by FDA
Category: Health News
Created: 2/3/2020 12:00:00 AM
Last Editorial Review: 2/3/2020 12:00:00 AM

Title: First Drug Approved for Treatment of Peanut Allergy in Children
Category: Health News
Created: 2/3/2020 12:00:00 AM
Last Editorial Review: 2/4/2020 12:00:00 AM

Title: Perimenopause
Category: Diseases and Conditions
Created: 7/5/2005 12:00:00 AM
Last Editorial Review: 9/17/2019 12:00:00 AM

Title: Study Links Menopausal Night Sweats to Impaired Thinking
Category: Health News
Created: 9/25/2019 12:00:00 AM
Last Editorial Review: 9/25/2019 12:00:00 AM

Title: How Does Early Menopause Affect a Woman's Heart?
Category: Health News
Created: 10/10/2019 12:00:00 AM
Last Editorial Review: 10/11/2019 12:00:00 AM

Title: HIV Could Speed Menopause Onset
Category: Health News
Created: 11/6/2019 12:00:00 AM
Last Editorial Review: 11/7/2019 12:00:00 AM

Title: Health Tip: Understanding the Menopausal Transition
Category: Health News
Created: 12/2/2019 12:00:00 AM
Last Editorial Review: 12/2/2019 12:00:00 AM

Title: New Study Shakes Up Thinking on Hormone Replacement Therapy
Category: Health News
Created: 12/13/2019 12:00:00 AM
Last Editorial Review: 12/13/2019 12:00:00 AM

Title: Less Sex Could Mean Earlier Menopause
Category: Health News
Created: 1/15/2020 12:00:00 AM
Last Editorial Review: 1/16/2020 12:00:00 AM

Title: AHA News: Estrogen Therapy in Early Menopause May Help Keep Arteries Clear
Category: Health News
Created: 3/3/2020 12:00:00 AM
Last Editorial Review: 3/4/2020 12:00:00 AM

Title: Menopause May Someday Disappear as Women Postpone Pregnancy: Study
Category: Health News
Created: 4/24/2020 12:00:00 AM
Last Editorial Review: 4/27/2020 12:00:00 AM

Title: Women Are Much Safer Drivers Than Men, British Study Finds
Category: Health News
Created: 4/7/2020 12:00:00 AM
Last Editorial Review: 4/7/2020 12:00:00 AM

Title: Is the 'Gratitude Movement' Overrated? Study Finds It Has Limits
Category: Health News
Created: 3/16/2020 12:00:00 AM
Last Editorial Review: 3/17/2020 12:00:00 AM

Title: Could AI Help Doctors Map Out Treatments for Brain Cancers?
Category: Health News
Created: 4/24/2020 12:00:00 AM
Last Editorial Review: 4/27/2020 12:00:00 AM

Overexpression of transcription factor 3 in alveolar soft part sarcoma(ASPS) results in upregulation of cell proliferation pathways. No standard treatment algorithm exists for ASPS; multikinase inhibitors[tyrosine kinase inhibitor (TKI)] and immune checkpoint inhibitors (ICI) have shown clinical benefit. To date, no studies have reported on management strategies or sequencing of therapy. We evaluated ASPS treatment patterns and responses in an experimental therapeutics clinic. Genomic and morphoproteomic analysis was performed to further elucidate novel targets. We retrospectively reviewed patients with ASPS treated on clinical trials. Demographic and clinical next-generation sequencing (NGS) profiles were collected. AACR GENIE database was queried to further evaluate aberrations in ASPS. Morphoproteomic analysis was carried out to better define the biology of ASPS with integration of genomic and proteomic findings. Eleven patients with ASPS were identified; 7 received NGS testing and mutations in CDKN2A (n = 1) and hepatocyte growth factor (n = 1) were present. Ten patients were treated with TKIs with stable disease as best response and 4 patients with ICI (three partial responses). Within GENIE, 20 patients were identified harboring 3 called pathogenic mutations. Tumor mutation burden was low in all samples. Morphoproteomic analysis confirmed the expression of phosphorylated c-Met. In addition, fatty acid synthase and phosphorylated-STAT3 were detected in tumor cell cytoplasm and nuclei. Patients with ASPS have a quiescent genome and derive clinical benefit from VEGF-targeting TKIs. Morphoproteomic analysis has provided both additional correlative pathways and angiogenic mechanisms that are targetable for patients with ASPS. Our study suggests that sequential therapy with TKIs and immune checkpoint inhibitors is a reasonable management strategy.

TNF-related apoptosis-inducing ligand (TRAIL) and an agonistic antibody against the death-inducing TRAIL receptor 5, DR5, are thought to selectively induce tumor cell death and therefore, have gained attention as potential therapeutics currently under investigation in several clinical trials. However, some tumor cells are resistant to TRAIL/DR5–induced cell death, even though they express DR5. Previously, we reported that DR5 is transported into the nucleus by importin β1, and knockdown of importin β1 upregulates cell surface expression of DR5 resulting in increased TRAIL sensitivity in vitro. Here, we examined the impact of importin β1 knockdown on agonistic anti-human DR5 (hDR5) antibody therapy. Drug-inducible importin β1 knockdown sensitizes HeLa cells to TRAIL-induced cell death in vitro, and exerts an antitumor effect when combined with agonistic anti-hDR5 antibody administration in vivo. Therapeutic importin β1 knockdown, administered via the atelocollagen delivery system, as well as treatment with the importin β inhibitor, importazole, induced regression and/or eradication of two human TRAIL-resistant tumor cells when combined with agonistic anti-hDR5 antibody treatment. Thus, these findings suggest that the inhibition of importin β1 would be useful to improve the therapeutic effects of agonistic anti-hDR5 antibody against TRAIL-resistant cancers.

Oil residues occur as solid bitumen in mineralized zones within the Devonian Weardale Granite of the northern Pennines, northern England. Comparable residues are present in the overlying Mississippian rocks and were probably derived from a Carboniferous source, i.e. during later mineralization of the granite. The bitumen was already solidified during fluorite mineralization, which does not contain oil inclusions. The residues do not show the high thermal maturity of organic matter in the region altered by the earliest Permian Whin Sill. Like the sulphide-fluorite mineralization, oil emplacement post-dated intrusion of the sill. Pyrite associated with the oil residues is enriched in trace elements including lead, silver, gold, selenium and tellurium, which suggests that mineralizing fluids at least shared pathways with migrating hydrocarbons and possibly also suggests undiscovered valuable metal resources.

Changes in U.S. health care delivery systems and Commission on Dental Accreditation standards provide impetus for interprofessional education (IPE) and collaborative practice, but roadmaps for engaging dental and dental hygiene faculty to incorporate IPE in a systematic manner are limited. The purpose of this report is to describe the process for creating a strategy and gathering a variety of baseline data to use for determining objectives and metrics and the subsequent development of an IPE strategic plan at the University of North Carolina (UNC) at Chapel Hill Adams School of Dentistry (SOD). SOD IPE committee members included representation from the UNC Schools of Dentistry, Medicine, Pharmacy, and Business. A three-phase framework was developed. Phase 1 (IPE assessment) was an internal environmental scan including a 2017 faculty survey, departmental mapping of IPE activities, comparison of UNC with national results on the IPE component of the American Dental Education Association (ADEA) survey of dental school seniors (2016 graduating class), identification of faculty joint/adjunct appointments at other UNC schools, and a strengths, weaknesses, opportunities, threats (SWOT) analysis. Phase 2 (visioning) consisted of development of IPE mission, vision, and priorities. In Phase 3 (implementation), priorities were developed. Data-gathering led to a strategic plan with three objectives: 1) increase faculty engagement and recognition, 2) develop predoctoral dentistry and dental hygiene IPE curricula, and 3) develop an infrastructure that supports IPE. Specific initiatives and activities, supporting metrics, and estimated costs were developed for each objective. The framework guided a systematic, transparent, and organized process for collecting and monitoring the evidence and directing activities. A three-year strategic plan for IPE was developed in 2017, and implementation is ongoing.

The aim of this cross-sectional study was to examine the faculty mentoring practices in seven dental schools in the U.S. A 34-item survey was administered electronically to dental faculty members of all ranks, tracks, and job categories in seven dental schools using faculty listservs. Survey questions addressed current mentoring practices in which the faculty members were involved; their perceptions of those mentoring practices; their perceived characteristics of an ideal mentoring program, mentor, and mentee; perceived best practices; and respondents’ demographics. The survey was conducted from October 2017 to February 2018. A total of 154 surveys were completed (response rate 22%). Over 58% (90/154) of the respondents reported receiving no mentoring; 31.9% (49/154) said they received informal mentoring; and 9.7% (15/154) received formal mentoring. Of the 64 respondents who received mentoring, both formal and informal, 92.2% (59/64) were full-time faculty, and 7.8% (5/64) were part-time faculty (p=0.001). Approximately 39% of the respondents indicated that their mentoring program was not overseen by anyone and that participation was voluntary. The top three perceived benefits of mentoring were increased overall professional development, development of a career plan, and increased professional networks. The three most important characteristics of an ideal mentoring program for the respondents were a program based on the needs of the mentee, a mentor who has the desire to help the mentee, and a mentee who is eager to learn. The results of this study showed a very low level of formal or informal faculty mentoring programs in the dental schools surveyed. Future studies are needed to determine best practices and strategies to expand and enhance mentoring of faculty members.

Purpose: The purpose of this study was to identify current requirements for initial licensure and entry into the dental hygiene profession across state dental and dental hygiene licensing boards in the United States.Methods: A non-experimental study design was used to study dental and dental hygiene board licensing requirements in the United States, Puerto Rico and the Virgin Islands. Each regulatory board website was searched for requirements for entry-level dental hygiene licensure. Requirements were recorded on an Excel spreadsheet. State dental practice acts were reviewed to gather further information and 20 regulatory bodies were contacted to verify accuracy. Descriptive statistics were used to analyze data.Results: Information from a total of 52 dental boards (n=52) was examined for this study. Nearly all boards (n=51, 98.1%), with the exception of Alabama, required completion of entry-level education from a CODA accredited dental hygiene program and successful completion of the National Board Dental Hygiene Examination. Most states (n=51, 98.1%), except Delaware, also required a live-patient, a clinical board examination. Application fees ranged from $47.70 to $600. States varied considerably in terms of requirements for background checks, age, military status, and infection control training.Conclusion: Although the majority of regulatory bodies require completion of entry-level dental hygiene education from a CODA accredited program and successful completion of national board and a live-patient, clinical examination, there is considerable variation in other additional requirements for initial dental hygiene licensure.

Purpose: Untreated and poorly controlled diabetes causes increased levels of blood glucose associated with poor periodontal disease outcomes. Dental hygienists can play a significant role in screening patients for diabetes mellitus, leading to referral and early diagnosis. The purpose of this study was to determine the knowledge, attitudes, practices, and barriers faced by clinical dental hygienists regarding diabetes risk assessment and screenings.Methods: A mixed method design was used with a convenience sample of dental hygienists in clinical practice (n=316). A 32 item, electronic survey was validated at item-level, and participants were recruited through multiple dental hygiene Facebook groups. Descriptive statistics were used to analyze the data. The survey also included two open-ended attitude questions that were interpreted using thematic analysis to pinpoint common patterns within the data.Results: Dental hygienists had high knowledge scores regarding diabetes and oral health, although many were unaware of their states' specific statutes and regulations for screening practices. Nearly all (95.9%), were likely to educate and refer patients (82%), although fewer than half (40.9%), were likely to perform chairside screening for diabetes. Emergent themes for barriers to screening were time, money, patient acceptance/willingness, lack of education, not having the proper tools, and states' rules and regulations.Conclusion: Despite high knowledge scores regarding diabetes and oral health, there is a gap in regards to dental hygienists' willingness to perform diabetes screenings in a clinical setting. Dental hygienists should be capable of integrating chairside diabetes screening practices into the process of care with proper training.

Purpose: Oral and craniofacial conditions or diseases can impact an individual's health and quality of life. The purpose of this study was to assess the perceived oral health related quality of life (OHRQoL) of children, and evaluate the reported level of agreement between caregivers and their children.Methods: Purposive sampling was used to recruit children ages 8-15, and their caregivers from a dental clinic in a pediatric hospital for this descriptive, cross-sectional study. A modified version of a validated measure, Child Oral Health Impact Profile-Short Form (COHIP-SF), was used for a 22-item questionnaire encompassing three subscales: oral health, functional well-being, and social emotional well-being. Two additional items were included to assess child/caregiver's level of agreement. A dental chart review was also conducted to assess the child's overbite, overjet, and decayed surfaces. Data were analyzed through descriptive statistics and examined for assumptions of normality and linearity.Results: Sixty child/caregiver pairs (n=120) participated in this study. Overbite, overjet and decayed surfaces were not found to be related to any OHRQoL variable, including child/caregiver ratings and overall agreement (p>.05). Average OHRQoL scores for caregivers found to be more positive those of their children (p=.02). Agreement between caregivers and the child's gender was shown to be significant (p=.01). Female child scores differed significantly from males with respect to their caregiver responses (p=.02). Caregivers rated a higher OHRQoL for female children, thus overestimating their female child's reported OHRQoL.Conclusions: The moderate level of agreement found between children and caregivers reinforces the importance of including the child, as well as the caregiver, when assessing OHRQoL.

ABSTRACT

Obesity is associated with increased disease severity, elevated viral titers in exhaled breath, and significantly prolonged viral shed during influenza A virus infection. Due to the mutable nature of RNA viruses, we questioned whether obesity could also influence influenza virus population diversity. Here, we show that minor variants rapidly emerge in obese mice. The variants exhibit increased viral replication, resulting in enhanced virulence in wild-type mice. The increased diversity of the viral population correlated with decreased type I interferon responses, and treatment of obese mice with recombinant interferon reduced viral diversity, suggesting that the delayed antiviral response exhibited in obesity permits the emergence of a more virulent influenza virus population. This is not unique to obese mice. Obesity-derived normal human bronchial epithelial (NHBE) cells also showed decreased interferon responses and increased viral replication, suggesting that viral diversity also was impacted in this increasing population.

IMPORTANCE Currently, 50% of the adult population worldwide is overweight or obese. In these studies, we demonstrate that obesity not only enhances the severity of influenza infection but also impacts viral diversity. The altered microenvironment associated with obesity supports a more diverse viral quasispecies and affords the emergence of potentially pathogenic variants capable of inducing greater disease severity in lean hosts. This is likely due to the impaired interferon response, which is seen in both obese mice and obesity-derived human bronchial epithelial cells, suggesting that obesity, aside from its impact on influenza virus pathogenesis, permits the stochastic accumulation of potentially pathogenic viral variants, raising concerns about its public health impact as the prevalence of obesity continues to rise.

ABSTRACT

In the absence of a vaccine, multidrug-resistant Neisseria gonorrhoeae has emerged as a major human health threat, and new approaches to treat gonorrhea are urgently needed. N. gonorrhoeae pili are posttranslationally modified by a glycan that terminates in a galactose. The terminal galactose is critical for initial contact with the human cervical mucosa via an interaction with the I-domain of complement receptor 3 (CR3). We have now identified the I-domain galactose-binding epitope and characterized its galactose-specific lectin activity. Using surface plasmon resonance and cellular infection assays, we found that a peptide mimic of this galactose-binding region competitively inhibited the N. gonorrhoeae-CR3 interaction. A compound library was screened for potential drugs that could similarly prohibit the N. gonorrhoeae-CR3 interaction and be repurposed as novel host-targeted therapeutics for multidrug-resistant gonococcal infections in women. Two drugs, methyldopa and carbamazepine, prevented and cured cervical cell infection by multidrug-resistant gonococci by blocking the gonococcal-CR3 I-domain interaction.

IMPORTANCE Novel therapies that avert the problem of Neisseria gonorrhoeae with acquired antibiotic resistance are urgently needed. Gonococcal infection of the human cervix is initiated by an interaction between a galactose modification made to its surface appendages, pili, and the I-domain region of (host) complement receptor 3 (CR3). By targeting this crucial gonococcal–I-domain interaction, it may be possible to prevent cervical infection in females. To this end, we identified the I-domain galactose-binding epitope of CR3 and characterized its galactose lectin activity. Moreover, we identified two drugs, carbamazepine and methyldopa, as effective host-targeted therapies for gonorrhea treatment. At doses below those currently used for their respective existing indications, both carbamazepine and methyldopa were more effective than ceftriaxone in curing cervical infection ex vivo. This host-targeted approach would not be subject to N. gonorrhoeae drug resistance mechanisms. Thus, our data suggest a long-term solution to the growing problem of multidrug-resistant N. gonorrhoeae infections.

ABSTRACT

Horizontal gene transfer (HGT) promotes the spread of genes within bacterial communities. Among the HGT mechanisms, natural transformation stands out as being encoded by the bacterial core genome. Natural transformation is often viewed as a way to acquire new genes and to generate genetic mixing within bacterial populations. Another recently proposed function is the curing of bacterial genomes of their infectious parasitic mobile genetic elements (MGEs). Here, we propose that these seemingly opposing theoretical points of view can be unified. Although costly for bacterial cells, MGEs can carry functions that are at points in time beneficial to bacteria under stressful conditions (e.g., antibiotic resistance genes). Using computational modeling, we show that, in stochastic environments, an intermediate transformation rate maximizes bacterial fitness by allowing the reversible integration of MGEs carrying resistance genes, although these MGEs are costly for host cell replication. Based on this dual function (MGE acquisition and removal), transformation would be a key mechanism for stabilizing the bacterial genome in the long term, and this would explain its striking conservation.

IMPORTANCE Natural transformation is the acquisition, controlled by bacteria, of extracellular DNA and is one of the most common mechanisms of horizontal gene transfer, promoting the spread of resistance genes. However, its evolutionary function remains elusive, and two main roles have been proposed: (i) the new gene acquisition and genetic mixing within bacterial populations and (ii) the removal of infectious parasitic mobile genetic elements (MGEs). While the first one promotes genetic diversification, the other one promotes the removal of foreign DNA and thus genome stability, making these two functions apparently antagonistic. Using a computational model, we show that intermediate transformation rates, commonly observed in bacteria, allow the acquisition then removal of MGEs. The transient acquisition of costly MGEs with resistance genes maximizes bacterial fitness in environments with stochastic stress exposure. Thus, transformation would ensure both a strong dynamic of the bacterial genome in the short term and its long-term stabilization.

ABSTRACT

The nonsense-mediated decay (NMD) pathway presents a challenge for RNA viruses with termination codons that precede extended 3' untranslated regions (UTRs). The umbravirus Pea enation mosaic virus 2 (PEMV2) is a nonsegmented, positive-sense RNA virus with an unusually long 3' UTR that is susceptible to NMD. To establish a systemic infection, the PEMV2 long-distance movement protein p26 was previously shown to both stabilize viral RNAs and bind them for transport through the plant’s vascular system. The current study demonstrated that p26 protects both viral and nonviral messenger RNAs from NMD. Although p26 localizes to both the cytoplasm and nucleolus, p26 exerts its anti-NMD effects exclusively in the cytoplasm independently of long-distance movement. Using a transcriptome-wide approach in the model plant Nicotiana benthamiana, p26 protected a subset of cellular NMD target transcripts, particularly those containing long, structured, GC-rich 3' UTRs. Furthermore, transcriptome sequencing (RNA-seq) revealed that the NMD pathway is highly dysfunctional during PEMV2 infection, with 1,820 (48%) of NMD targets increasing in abundance. Widespread changes in the host transcriptome are common during plant RNA virus infections, and these results suggest that, in at least some instances, virus-mediated NMD inhibition may be a major contributing factor.

IMPORTANCE Nonsense-mediated decay (NMD) represents an RNA regulatory pathway that degrades both natural and faulty messenger RNAs with long 3' untranslated regions. NMD targets diverse families of RNA viruses, requiring that viruses counteract the NMD pathway for successful amplification in host cells. A protein required for long-distance movement of Pea enation mosaic virus 2 (PEMV2) is shown to also protect both viral and host mRNAs from NMD. RNA-seq analyses of the Nicotiana benthamiana transcriptome revealed that PEMV2 infection significantly impairs the host NMD pathway. RNA viruses routinely induce large-scale changes in host gene expression, and, like PEMV2, may use NMD inhibition to alter the host transcriptome in an effort to increase virus amplification.

ABSTRACT

Frequent and excessive use of antibiotics primes patients to Clostridioides difficile infection (CDI), which leads to fatal pseudomembranous colitis, with limited treatment options. In earlier reports, we used a drug repurposing strategy and identified amoxapine (an antidepressant), doxapram (a breathing stimulant), and trifluoperazine (an antipsychotic), which provided significant protection to mice against lethal infections with several pathogens, including C. difficile. However, the mechanisms of action of these drugs were not known. Here, we provide evidence that all three drugs offered protection against experimental CDI by reducing bacterial burden and toxin levels, although the drugs were neither bacteriostatic nor bactericidal in nature and had minimal impact on the composition of the microbiota. Drug-mediated protection was dependent on the presence of the microbiota, implicating its role in evoking host defenses that promoted protective immunity. By utilizing transcriptome sequencing (RNA-seq), we identified that each drug increased expression of several innate immune response-related genes, including those involved in the recruitment of neutrophils, the production of interleukin 33 (IL-33), and the IL-22 signaling pathway. The RNA-seq data on selected genes were confirmed by quantitative real-time PCR (qRT-PCR) and protein assays. Focusing on amoxapine, which had the best anti-CDI outcome, we demonstrated that neutralization of IL-33 or depletion of neutrophils resulted in loss of drug efficacy. Overall, our lead drugs promote disease alleviation and survival in the murine model through activation of IL-33 and by clearing the pathogen through host defense mechanisms that critically include an early influx of neutrophils.

IMPORTANCE Clostridioides difficile is a spore-forming anaerobic bacterium and the leading cause of antibiotic-associated colitis. With few therapeutic options and high rates of disease recurrence, the need to develop new treatment options is urgent. Prior studies utilizing a repurposing approach identified three nonantibiotic Food and Drug Administration-approved drugs, amoxapine, doxapram, and trifluoperazine, with efficacy against a broad range of human pathogens; however, the protective mechanisms remained unknown. Here, we identified mechanisms leading to drug efficacy in a murine model of lethal C. difficile infection (CDI), advancing our understanding of the role of these drugs in infectious disease pathogenesis that center on host immune responses to C. difficile. Overall, these studies highlight the crucial involvement of innate immune responses, as well as the importance of immunomodulation as a potential therapeutic option to combat CDI.

ABSTRACT

The recent discovery of complete ammonia oxidizers (comammox) contradicts the paradigm that chemolithoautotrophic nitrification is always catalyzed by two different microorganisms. However, our knowledge of the survival strategies of comammox in complex ecosystems, such as full-scale wastewater treatment plants (WWTPs), remains limited. Analyses of genomes and in situ transcriptomes of four comammox organisms from two full-scale WWTPs revealed that comammox were active and showed a surprisingly high metabolic versatility. A gene cluster for the utilization of urea and a gene encoding cyanase suggest that comammox may use diverse organic nitrogen compounds in addition to free ammonia as the substrates. The comammox organisms also encoded the genomic potential for multiple alternative energy metabolisms, including respiration with hydrogen, formate, and sulfite as electron donors. Pathways for the biosynthesis and degradation of polyphosphate, glycogen, and polyhydroxyalkanoates as intracellular storage compounds likely help comammox survive unfavorable conditions and facilitate switches between lifestyles in fluctuating environments. One of the comammox strains acquired from the anaerobic tank encoded and transcribed genes involved in homoacetate fermentation or in the utilization of exogenous acetate, both pathways being unexpected in a nitrifying bacterium. Surprisingly, this strain also encoded a respiratory nitrate reductase which has not yet been found in any other Nitrospira genome and might confer a selective advantage to this strain over other Nitrospira strains in anoxic conditions.

IMPORTANCE The discovery of comammox in the genus Nitrospira changes our perception of nitrification. However, genomes of comammox organisms have not been acquired from full-scale WWTPs, and very little is known about their survival strategies and potential metabolisms in complex wastewater treatment systems. Here, four comammox metagenome-assembled genomes and metatranscriptomic data sets were retrieved from two full-scale WWTPs. Their impressive and—among nitrifiers—unsurpassed ecophysiological versatility could make comammox Nitrospira an interesting target for optimizing nitrification in current and future bioreactor configurations.

ABSTRACT

Lassa virus (LASV) poses a significant public health problem within the regions of Lassa fever endemicity in Western Africa. LASV infects several hundred thousand individuals yearly, and a considerable number of Lassa fever cases are associated with high morbidity and lethality. No approved LASV vaccine is available, and current therapy is limited to an off-label usage of ribavirin that is only partially effective and associated with significant side effects. The impact of Lassa fever on human health, together with the limited existing countermeasures, highlights the importance of developing effective vaccines against LASV. Here, we present the development and characterization of a recombinant LASV (rLASV) vaccine candidate [rLASV(IGR/S-S)], which is based on the presence of the noncoding intergenic region (IGR) of the small (S) genome segment (S-IGR) in both large (L) and S LASV segments. In cultured cells, rLASV(IGR/S-S) was modestly less fit than wild-type rLASV (rLASV-WT). rLASV(IGR/S-S) was highly attenuated in guinea pigs, and a single subcutaneous low dose of the virus completely protected against otherwise lethal infection with LASV-WT. Moreover, rLASV(IGR/S-S) was genetically stable during serial passages in cultured cells. These findings indicate that rLASV(IGR/S-S) can be developed into a LASV live-attenuated vaccine (LAV) that has the same antigenic composition as LASV-WT and a well-defined mechanism of attenuation that overcomes concerns about increased virulence that could be caused by genetic changes in the LAV during multiple rounds of multiplication.

IMPORTANCE Lassa virus (LASV), the causative agent of Lassa fever, infects several hundred thousand people in Western Africa, resulting in many lethal Lassa fever cases. No U.S. Food and Drug Administration-licensed countermeasures are available to prevent or treat LASV infection. We describe the generation of a novel LASV live-attenuated vaccine candidate rLASV(IGR/S-S), which is based on the replacement of the large genomic segment noncoding intergenic region (IGR) with that of the small genome segment. rLASV(IGR/S-S) is less fit in cell culture than wild-type virus and does not cause clinical signs in inoculated guinea pigs. Importantly, rLASV(IGR/S-S) protects immunized guinea pigs against an otherwise lethal exposure to LASV.

ABSTRACT

Host persistence of bacteria is facilitated by mutational and recombinatorial processes that counteract loss of genetic variation during transmission and selection from evolving host responses. Genetic variation was investigated during persistent asymptomatic carriage of Neisseria meningitidis. Interrogation of whole-genome sequences for paired isolates from 25 carriers showed that de novo mutations were infrequent, while horizontal gene transfer occurred in 16% of carriers. Examination of multiple isolates per time point enabled separation of sporadic and transient allelic variation from directional variation. A comprehensive comparative analysis of directional allelic variation with hypermutation of simple sequence repeats and hyperrecombination of class 1 type IV pilus genes detected an average of seven events per carrier and 2:1 bias for changes due to localized hypermutation. Directional genetic variation was focused on the outer membrane with 69% of events occurring in genes encoding enzymatic modifiers of surface structures or outer membrane proteins. Multiple carriers exhibited directional and opposed switching of allelic variants of the surface-located Opa proteins that enables continuous expression of these adhesins alongside antigenic variation. A trend for switching from PilC1 to PilC2 expression was detected, indicating selection for specific alterations in the activities of the type IV pilus, whereas phase variation of restriction modification (RM) systems, as well as associated phasevarions, was infrequent. We conclude that asymptomatic meningococcal carriage on mucosal surfaces is facilitated by frequent localized hypermutation and horizontal gene transfer affecting genes encoding surface modifiers such that optimization of adhesive functions occurs alongside escape of immune responses by antigenic variation.

IMPORTANCE Many bacterial pathogens coexist with host organisms, rarely causing disease while adapting to host responses. Neisseria meningitidis, a major cause of meningitis and septicemia, is a frequent persistent colonizer of asymptomatic teenagers/young adults. To assess how genetic variation contributes to host persistence, whole-genome sequencing and hypermutable sequence analyses were performed on multiple isolates obtained from students naturally colonized with meningococci. High frequencies of gene transfer were observed, occurring in 16% of carriers and affecting 51% of all nonhypermutable variable genes. Comparative analyses showed that hypermutable sequences were the major mechanism of variation, causing 2-fold more changes in gene function than other mechanisms. Genetic variation was focused on genes affecting the outer membrane, with directional changes in proteins responsible for bacterial adhesion to host surfaces. This comprehensive examination of genetic plasticity in individual hosts provides a significant new platform for rationale design of approaches to prevent the spread of this pathogen.

ABSTRACT

Urinary tract infections (UTI) affect half of all women at least once during their lifetime. The rise in the numbers of extended-spectrum beta-lactamase-producing strains and the potential for carbapenem resistance within uropathogenic Escherichia coli (UPEC), the most common causative agent of UTI, create an urgent need for vaccine development. Intranasal immunization of mice with UPEC outer membrane iron receptors FyuA, Hma, IreA, and IutA, conjugated to cholera toxin, provides protection in the bladder or kidneys under conditions of challenge with UPEC strain CFT073 or strain 536. On the basis of these data, we sought to optimize the vaccination route (intramuscular, intranasal, or subcutaneous) in combination with adjuvants suitable for human use, including aluminum hydroxide gel (alum), monophosphoryl lipid A (MPLA), unmethylated CpG synthetic oligodeoxynucleotides (CpG), polyinosinic:polycytidylic acid (polyIC), and mutated heat-labile E. coli enterotoxin (dmLT). Mice intranasally vaccinated with dmLT-IutA and dmLT-Hma displayed significant reductions in bladder colonization (86-fold and 32-fold, respectively), with 40% to 42% of mice having no detectable CFU. Intranasal vaccination of mice with CpG-IutA and polyIC-IutA significantly reduced kidney colonization (131-fold) and urine CFU (22-fold), respectively. dmLT generated the most consistently robust antibody response in intranasally immunized mice, while MPLA and alum produced greater concentrations of antigen-specific serum IgG with intramuscular immunization. On the basis of these results, we conclude that intranasal administration of Hma or IutA formulated with dmLT adjuvant provides the greatest protection from UPEC UTI. This report advances our progress toward a vaccine against uncomplicated UTI, which will significantly improve the quality of life for women burdened by recurrent UTI and enable better antibiotic stewardship.

IMPORTANCE Urinary tract infections (UTI) are among the most common bacterial infection in humans, affecting half of all women at least once during their lifetimes. The rise in antibiotic resistance and health care costs emphasizes the need to develop a vaccine against the most common UTI pathogen, Escherichia coli. Vaccinating mice intranasally with a detoxified heat-labile enterotoxin and two surface-exposed receptors, Hma or IutA, significantly reduced bacterial burden in the bladder. This work highlights progress in the development of a UTI vaccine formulated with adjuvants suitable for human use and antigens that encode outer membrane iron receptors required for infection in the iron-limited urinary tract.

Finding common ground and building trust between local stakeholders could help prevent violent encounters between police and young black men, new research finds.

Phosphatidylcholine and phosphatidylethanolamine are two major phospholipid classes in eukaryotes. Each biosynthesis pathway starts with the phosphorylation of choline (Cho) or ethanolamine (Etn) catalyzed by either choline or ethanolamine kinase (CEK). Arabidopsis contains four CEK isoforms, but their isozyme-specific roles in metabolism and development are poorly described. Here, we showed that these four CEKs have distinct substrate specificities in vitro. While CEK1 and CEK2 showed substrate preference for Cho over Etn, CEK3 and CEK4 had clear substrate specificity for Cho and Etn, respectively. In vivo, CEK1, CEK2, and CEK3 exhibited kinase activity for Cho but not Etn, although the latter two isoforms showed rather minor contributions to total Cho kinase activity in both shoots and roots. The knockout mutants of CEK2 and CEK3 both affected root growth, and these isoforms had nonoverlapping cell-type-specific expression patterns in the root meristematic zone. In-depth phenotype analysis, as well as chemical and genetic complementation, revealed that CEK3, a Cho-specific kinase, is involved in cell elongation during root development. Phylogenetic analysis of CEK orthologs in Brassicaceae species showed evolutionary divergence between Etn kinases and Cho kinases. Collectively, our results demonstrate the distinct roles of the four CEK isoforms in Cho/Etn metabolism and plant development.

The past 20 years have seen major advances in the understanding and treatment of pulmonary arterial hypertension (PAH; group 1 of the pulmonary hypertension (PH) clinical classification) [1]. A strong basis of knowledge has been acquired in: 1) large randomised clinical trials for drug development; 2) national registries for epidemiology and outcome; and 3) smaller studies on the pathophysiological mechanisms of the disease. This knowledge has been reviewed at World Symposia on Pulmonary Hypertension (the most recent in 2018 [2]) and summarised in European Respiratory Society (ERS)/European Society of Cardiology (ESC) clinical guidelines (the most recent in 2015 [3, 4]). We are, however, much less knowledgeable on specific aspects such as 1) the implementation of guidelines and access to therapies in different European countries; 2) the management of PH crises and progressive (acute on chronic) heart failure; and 3) other groups of PH, such as PH due to lung diseases. Therapeutic strategies also need to be optimised, in particular regarding the combination of drugs, the use of anticoagulants, the place for new medications targeting different pathophysiological pathways, etc.

The treatment for obstructive sleep apnoea (OSA) with continuous positive airway pressure (CPAP) or mandibular advancement devices (MADs) is associated with blood pressure (BP) reduction; however, the overall effect is modest. The aim of this systematic review and meta-analysis of randomised controlled trials (RCTs) comparing the effect of such treatments on BP was to identify subgroups of patients who respond best to treatment.

The article search was performed in three different databases with specific search terms and selection criteria. From 2289 articles, we included 68 RCTs that compared CPAP or MADs with either passive or active treatment. When all the studies were pooled together, CPAP and MADs were associated with a mean BP reduction of –2.09 (95% CI –2.78– –1.40) mmHg for systolic BP and –1.92 (95% CI –2.40– –1.43) mmHg for diastolic BP and –1.27 (95% CI –2.34– –0.20) mmHg for systolic BP and –1.11 (95% CI –1.82– –0.41) mmHg for diastolic BP, respectively. The subgroups of patients who showed a greater response were those aged <60 years (systolic BP –2.93 mmHg), with uncontrolled BP at baseline (systolic BP –4.14 mmHg) and with severe oxygen desaturations (minimum arterial oxygen saturation measured by pulse oximetry <77%) at baseline (24-h systolic BP –7.57 mmHg).

Although this meta-analysis shows that the expected reduction of BP by CPAP/MADs is modest, it identifies specific characteristics that may predict a pronounced benefit from CPAP in terms of BP control. These findings should be interpreted with caution; however, they are particularly important in identifying potential phenotypes associated with BP reduction in patients treated for OSA.

Although elevated blood or sputum eosinophils are present in many patients with COPD, uncertainties remain regarding the anatomical distribution pattern of lung-infiltrating eosinophils. Basophils have remained virtually unexplored in COPD. This study mapped tissue-infiltrating eosinophils, basophils and eosinophil-promoting immune mechanisms in COPD-affected lungs.

Surgical lung tissue and biopsies from major anatomical compartments were obtained from COPD patients with severity grades Global Initiative for Chronic Obstructive Lung Disease stages I–IV; never-smokers/smokers served as controls. Automated immunohistochemistry and in situ hybridisation identified immune cells, the type 2 immunity marker GATA3 and eotaxins (CCL11, CCL24).

Eosinophils and basophils were present in all anatomical compartments of COPD-affected lungs and increased significantly in very severe COPD. The eosinophilia was strikingly patchy, and focal eosinophil-rich microenvironments were spatially linked with GATA3⁺ cells, including type 2 helper T-cell lymphocytes and type 2 innate lymphoid cells. A similarly localised and interleukin-33/ST2-dependent eosinophilia was demonstrated in influenza-infected mice. Both mice and patients displayed spatially confined eotaxin signatures with CCL11⁺ fibroblasts and CCL24⁺ macrophages.

In addition to identifying tissue basophilia as a novel feature of advanced COPD, the identification of spatially confined eosinophil-rich type 2 microenvironments represents a novel type of heterogeneity in the immunopathology of COPD that is likely to have implications for personalised treatment.

Objective

To investigate the frequency of levodopa-induced dyskinesia in dementia with Lewy bodies (DLBs) and Parkinson disease with dementia (PDD) and compare these frequencies with patients with incident Parkinson disease (PD) through a population-based cohort study.

Objective

To use the variations in neurology consultations requested by emergency department (ED) physicians to identify opportunities to implement multidisciplinary interventions in an effort to reduce ED overcrowding.

Objective

To assess the risk of subsequent stroke among older patients discharged from an emergency department (ED) without a diagnosis of TIA or stroke.