Structural characterization of macro domain-containing Thoeris antiphage defense systems.

Thoeris defense systems protect bacteria from infection by phages via abortive infection. In these systems, ThsB proteins serve as sensors of infection and generate signaling nucleotides that activate ThsA effectors. Silent information regulator and SMF/DprA-LOG (SIR2-SLOG) containing ThsA effectors are activated by cyclic ADP-ribose (ADPR) isomers 2'cADPR and 3'cADPR, triggering abortive infection via nicotinamide adenine dinucleotide (NAD+) depletion. Here, we characterize Thoeris systems with transmembrane and macro domain (TM-macro)-containing ThsA effectors. We demonstrate that ThsA macro domains bind ADPR and imidazole adenine dinucleotide (IAD), but not 2'cADPR or 3'cADPR. Combining crystallography, in silico predictions, and site-directed mutagenesis, we show that ThsA macro domains form nucleotide-induced higher-order oligomers, enabling TM domain clustering. We demonstrate that ThsB can produce both ADPR and IAD, and we identify a ThsA TM-macro-specific ThsB subfamily with an active site resembling deoxy-nucleotide and deoxy-nucleoside processing enzymes. Collectively, our study demonstrates that Thoeris systems with SIR2-SLOG and TM-macro ThsA effectors trigger abortive infection via distinct mechanisms.

Public Health Directives in a Pandemic: Paradoxical Messages for Domestic Abuse Victims in Four Countries.

When the COVID-19 pandemic manifested urgent concerns were raised around the globe about the increased risk that public health restrictions could pose for victims of domestic abuse. Governments, NGOs and community services swiftly responded to convey the message that services for victims were operational and restrictions did not apply to those fleeing harm. This paper reports on the various approaches used to communicate this public health messaging during COVID-19, further highlighting strengths and learning which could inform future crises messaging. It utilises data gathered through a rapid review and mapping of policy and practice initiatives across 4 high-middle income countries: UK, Australia, South Africa and Ireland. Four themes were identified: (1) Top-down: National media messaging; (2) Top-down: Political leadership; (3) Traditional media vs. social media and (4) Bottom-up messaging: Localised, community-based messaging. It was found that a strong, clear top-down stance on domestic abuse was perceived as beneficial during COVID-19. However, a stronger focus on evaluation, reach and impact, particularly for minority groups may be required. Newer forms of media were shown to have potential in conveying messaging to minority groups. Community and grassroots organizations demonstrated their experiential knowledge in reaching target audiences. Harnessing this expertise for future crises messaging may be valuable.

SARM1 is a metabolic sensor activated by an increased NMN/NAD+ ratio to trigger axon degeneration.

Axon degeneration is a central pathological feature of many neurodegenerative diseases. Sterile alpha and Toll/interleukin-1 receptor motif-containing 1 (SARM1) is a nicotinamide adenine dinucleotide (NAD+)-cleaving enzyme whose activation triggers axon destruction. Loss of the biosynthetic enzyme NMNAT2, which converts nicotinamide mononucleotide (NMN) to NAD+, activates SARM1 via an unknown mechanism. Using structural, biochemical, biophysical, and cellular assays, we demonstrate that SARM1 is activated by an increase in the ratio of NMN to NAD+ and show that both metabolites compete for binding to the auto-inhibitory N-terminal armadillo repeat (ARM) domain of SARM1. We report structures of the SARM1 ARM domain bound to NMN and of the homo-octameric SARM1 complex in the absence of ligands. We show that NMN influences the structure of SARM1 and demonstrate via mutagenesis that NMN binding is required for injury-induced SARM1 activation and axon destruction. Hence, SARM1 is a metabolic sensor responding to an increased NMN/NAD+ ratio by cleaving residual NAD+, thereby inducing feedforward metabolic catastrophe and axonal demise.

Evaluation of One Program's Use of the Society for Adolescent Health and Medicine Resident Curriculum.

PURPOSE: The publicly available Society for Adolescent Health and Medicine (SAHM) Resident Curriculum provides resources for blended learning. This report presents a formal evaluation of this blended learning curriculum. METHODS: We adapted the SAHM curriculum for a required four-week rotation for pediatricians in training. We selected webinars, videos, articles, and Web sites from the SAHM curriculum to complement the local clinical context. We evaluated the effectiveness of our curriculum using resident pre- and post-self-assessments, weekly knowledge quizzes, and a standardized patient encounter. RESULTS: Resident self-assessment improved in all domains except managing urologic conditions. Residents scored 85% or higher on knowledge quizzes. Standardized patients rated residents a mean of 90.2 out of 100 on adolescent communication and 89.0 out of 100 on parent communication. CONCLUSIONS: A blended learning curriculum consisting of SAHM online materials and local clinical experiences improved resident self-assessment, knowledge, and communication skills.

Acceptability and Barriers to HIV Pre-Exposure Prophylaxis in Atlanta's Adolescents and Their Parents.

Adolescents aged 13-24 years account for 23% of new HIV infections in Atlanta, indicating need for better HIV prevention strategies in this population. Pre-exposure prophylaxis (PrEP) is now approved for adolescent use. This study aims to understand the acceptability of and barriers to PrEP in adolescents and parents. We administered PrEP acceptability and barrier measures to HIV(-) 13-17 year olds and their parents from January to April 2016 in an adolescent clinic and emergency department in Atlanta, GA, stratifying by adolescent sexual activity. Acceptability scores (AS) and barrier scores (BS) were calculated by averaging survey answers 1-3. For AS, 1 was very unlikely to accept PrEP; concomitantly, BS near 3 indicated fewer barriers. Two-sample hypothesis testing, Pearson correlations, and linear regression were used. Of the 102 adolescent/parent dyads, 67% of adolescents were female, 94% black, with a mean age of 15.7 ± 1.5 years, and 31% were sexually active. Parents were 94% female, 96% black, with a mean age of 42.4 ± 8.9 years. AS averaged between somewhat to very likely to accept PrEP (2.4 ± 0.5 and 2.2 ± 0.6) in adolescents and parents, respectively. BS averaged between unlikely and somewhat likely to perceive barriers to PrEP (2.0 ± 0.4 and 1.9 ± 0.5) in adolescents and parents, respectively. The adolescent/parent dyad is likely to accept PrEP, regardless of sexual activity. Limitations include that nearly 70% of adolescents were not sexually active, and the study was conducted before PrEP approval by the Food and Drug Administration for those who are younger than 18 years. These results support future parent and adolescent education on PrEP.

Enterococcus hirae Bacteremia in an Infant: Case Report and Review of the Literature.

Enterococcus hirae is a gram-positive coccus that is rarely implicated in human disease and has not been reported in pediatric patients. We report a case of catheter-associated bloodstream infection and prolonged bacteremia in a 7-month-old infant dependent on total parenteral nutrition. The species was identified by the VITEK2 system and confirmed by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry. The organisms was susceptible to ampicillin, vancomycin, and high-level gentamicin. The patient was treated with vancomycin and gentamicin with adjunctive vancomycin lock therapy but had persistent bacteremia. Therapy was changed to dual ß-lactam therapy of ampicillin and ceftriaxone with synergistic gentamicin, which led to clearance of the enterococcal bacteremia. E hirae is an unusual species that may be difficult for the microbiology laboratory to identify. This is the first pediatric case and the second case of invasive E hirae in the United States.

Being on the Safe Side: A Qualitative Study of Condom Use Motivations According to Contraceptive Type among Adolescents in Atlanta, Georgia.

STUDY OBJECTIVE: Quantitative data suggest that adolescent users of long-acting reversible contraception (LARC), compared with short-acting methods (pill, patch, ring, depot medroxyprogesterone acetate [DMPA]), might be less likely to use condoms. We qualitatively describe and explain adolescent contraceptive users' motivations for condom use, including variation according to contraceptive type. DESIGN: Individual, in-depth qualitative interviews, analyzed thematically. SETTING: Participants were recruited from public family planning clinics and an adolescent medicine clinic, as well as university and other community settings in Atlanta, Georgia. PARTICIPANTS: Sexually active contraceptive users aged 17-19 years old (n = 30), including LARC (n = 10), DMPA (n = 10), and oral contraceptive (n = 10) users. RESULTS: Of the 30 participants, most (n = 25; 83%) used condoms with their more effective contraceptive method, although 11 of 25 used them inconsistently (44%). Oral contraceptive users were particularly motivated to use condoms for pregnancy prevention, because of concerns about contraceptive method efficacy and a desire to be on "the safe side." In contrast, LARC users were primarily motivated by sexually transmitted infection (STI) prevention. DMPA users' motivations were more mixed. Across contraceptive type, factors influencing condom use motivations included sexual health education, personal awareness and/or experience, and perceived consequences and risk. CONCLUSION: Because all participants were using an effective contraceptive method, it is notable that pregnancy prevention was a prominent motivator for using condoms, although LARC users reported STI prevention to be a more important motivation. Parental and school-based sexual health education that clearly addresses STI prevention in addition to pregnancy prevention has the potential to influence condom use motivations and behavior.

Resident Education Curriculum in Pediatric and Adolescent Gynecology: The Short Curriculum 2.0.

The degree of exposure to pediatric and adolescent gynecology (PAG) varies across residency programs in obstetrics and gynecology and pediatrics. Nevertheless, these programs are responsible for training residents and providing opportunities within their programs to fulfill PAG learning objectives. To that end, the North American Society for Pediatric and Adolescent Gynecology has taken a leadership role in PAG resident education by creating and systematically updating the Short Curriculum. This curriculum outlines specific learning objectives that are central to PAG education and lists essential resources for learners' reference. This updated curriculum replaces the previous 2014 publication with added content, resources, and updated references. Additionally, attention to the needs of learners in pediatrics and adolescent medicine is given greater emphasis in this revised North American Society for Pediatric and Adolescent Gynecology Short Curriculum 2.0.

Cultural aspects of pain: A study of Indian Asian women in the UK.

OBJECTIVES: Culture and ethnicity are acknowledged as important factors in the context of the biopsychosocial model. They may contribute to explaining the experience of pain, therapeutic encounters within healthcare, and the strategies that individuals use to cope with pain. The present study explored these issues in a sample of Indian Asian women in the UK. METHODS: Based on a phenomenological approach, 17 women participated in five semi-structured group interviews. Data were analysed using qualitative content analysis, so as to identify core themes and subthemes inductively from the data. RESULTS: Six themes were identified: meaning of pain; personal experience of pain; causes of pain; coping strategies; family and friends; experience of healthcare. Pain was conceptualized in both physical and mental terms, and its experience was explained largely in terms of functional consequences. The causes of pain offered suggested externalized beliefs, relating to events in participants' lives, rather than being expressed in biomedical terms. Alongside culture-specific therapies, the women spoke of coping strategies based on rest and activity. Although satisfaction with healthcare appeared to be high overall, problems due to communication - sometimes related to a language barrier - were voiced by some participants. CONCLUSIONS: Greater attention to cultural aspects of the pain experience may assist health professionals in communicating with and managing patients with pain from ethnic minority backgrounds.

Responding to the support needs of front-line public health nurses who work with vulnerable families and children: a qualitative study.

BACKGROUND: This paper reports on a research study to inform the development of a specialist role to support front line public health nurses (PHNs) working with vulnerable families and at risk children in Ireland. AIMS: This study aimed to investigate the position of a leading role and explore the implications of such change. METHODS: Focus group and semi-structured individual interviews were conducted with ten purposively selected participants in public health nursing, social work and a non-governmental children's organisation working in disadvantaged areas in Dublin. RESULTS: Assistant directors of public health nursing are in a key position to inform decisions regarding the children's services. CONCLUSION: Access to support and appropriate supervision are fundamental resource requirements for PHNs who work with vulnerable families and at risk children. The introduction of a specialist-leading role to support these PHN's is essential to sustaining best practice.

Burkholderia pseudomallei penetrates the brain via destruction of the olfactory and trigeminal nerves: implications for the pathogenesis of neurological melioidosis.

ABSTRACT Melioidosis is a potentially fatal disease that is endemic to tropical northern Australia and Southeast Asia, with a mortality rate of 14 to 50%. The bacterium Burkholderia pseudomallei is the causative agent which infects numerous parts of the human body, including the brain, which results in the neurological manifestation of melioidosis. The olfactory nerve constitutes a direct conduit from the nasal cavity into the brain, and we have previously reported that B. pseudomallei can colonize this nerve in mice. We have now investigated in detail the mechanism by which the bacteria penetrate the olfactory and trigeminal nerves within the nasal cavity and infect the brain. We found that the olfactory epithelium responded to intranasal B. pseudomallei infection by widespread crenellation followed by disintegration of the neuronal layer to expose the underlying basal layer, which the bacteria then colonized. With the loss of the neuronal cell bodies, olfactory axons also degenerated, and the bacteria then migrated through the now-open conduit of the olfactory nerves. Using immunohistochemistry, we demonstrated that B. pseudomallei migrated through the cribriform plate via the olfactory nerves to enter the outer layer of the olfactory bulb in the brain within 24 h. We also found that the bacteria colonized the thin respiratory epithelium in the nasal cavity and then rapidly migrated along the underlying trigeminal nerve to penetrate the cranial cavity. These results demonstrate that B. pseudomallei invasion of the nerves of the nasal cavity leads to direct infection of the brain and bypasses the blood-brain barrier. IMPORTANCE Melioidosis is a potentially fatal tropical disease that is endemic to northern Australia and Southeast Asia. It is caused by the bacterium Burkholderia pseudomallei, which can infect many organs of the body, including the brain, and results in neurological symptoms. The pathway by which the bacteria can penetrate the brain is unknown, and we have investigated the ability of the bacteria to migrate along nerves that innervate the nasal cavity and enter the frontal region of the brain by using a mouse model of infection. By generating a mutant strain of B. pseudomallei which is unable to survive in the blood, we show that the bacteria rapidly penetrate the cranial cavity using the olfactory (smell) nerve and the trigeminal (sensory) nerve that line the nasal cavity.

Nursing students apply evidence-based research principles in primary burn prevention projects.

The purpose of this project was for registered nursing students in a baccalaureate nursing program to look at different prevention strategies that could be utilized in the community to impact change in a family's burn prevention knowledge. The prevention strategies and their corresponding interventions were written in a narrative form, and then a poster was created to serve as a supplemental visual aid for the information. Firefighters from a local fire department evaluated posters and their abstracts based on criteria developed by the students. Five posters were revised and submitted to a national burn prevention contest. Students gained valuable experience in developing and revising evidence-based research (EBR) projects to promote community education in primary burn prevention with firefighter collaboration.

The clinical performance of Invader technology and SurePath when detecting the presence of high-risk HPV cervical infection.

BACKGROUND: Testing for high-risk genotypes of the human papillomavirus (HR HPV) has been fully integrated into the management algorithms for the prevention of cervical cancer. The literature is limited with regard to the evaluation of the clinical performance of laboratory-developed tests (LDT) utilizing Invader V2.0 assay (ThirdWave/Hologic, Madison, WI, USA) for the detection of HR HPV. OBJECTIVES: To evaluate the clinical performance of Invader V2.0 LDT by determining its sensitivity, negative predictive value (NPV), specificity and positive predictive value (PPV). STUDY DESIGN: This study evaluated Invader V2.0 assay results from 12,490 SurePath Pap specimens and 1,931 cervical biopsies in order to assess the clinical performance of the Invader V2.0 assay. The cervical biopsy results were correlated with Invader V2.0 results to determine clinical sensitivity, NPV, clinical specificity, and PPV. RESULTS: The clinical sensitivity and NPV of Invader V2.0 LDT for cervical intraepithelial neoplasia 3 (CIN 3) or higher were 97.4% and 99.1% respectively. The clinical specificity and PPV for CIN 3 were 10.3% and 3.7% respectively. CONCLUSIONS: The results support the use of the Invader V2.0 in identifying patients who are at low risk for CIN 3 or higher. The power of the assay implies that it could be used as a primary screening tool for prevention of cervical cancer if a paradigm shift in cervical screening ever occurs.

A comparison of two methods to determine the presence of high-risk HPV cervical infections.

Clinical tests for human papillomavirus (HPV) DNA require clinical validation before being offered for use by laboratories. To determine the clinical viability of a laboratory-developed test using the Invader HPV reagents (Third Wave Technologies, Madison, WI), a retrospective study was designed using 213 patient cervical cytologic samples. The results of the Invader assay were directly compared with the results obtained using the Hybrid Capture 2 High-Risk HPV assay (Digene, Gaithersburg, MD). The results of both assays were also compared with cytologic evaluation. In addition, clinical performance was evaluated using a standard-of-care approach in which colposcopically guided biopsies were done in cases where standard of care dictated, and the histologic features of the biopsy specimens were noted. The Invader-based test demonstrated a clinical sensitivity in atypical squamous cells of undetermined significance cases of 98% for cervical intraepithelial neoplasia (CIN) 2 or worse and 100% for CIN 3 or worse and a negative predictive value of 96.9% (confidence interval, 89.3%-99.6%) using data generated mostly from the use of an earlier version of reagents. These findings support the clinical and laboratory benefits of the Invader method.

The impact of exposure to domestic violence on children and young people: a review of the literature.

OBJECTIVE: This article reviews the literature concerning the impact of exposure to domestic violence on the health and developmental well-being of children and young people. Impact is explored across four separate yet inter-related domains (domestic violence exposure and child abuse; impact on parental capacity; impact on child and adolescent development; and exposure to additional adversities), with potential outcomes and key messages concerning best practice responses to children's needs highlighted. METHOD: A comprehensive search of identified databases was conducted within an 11-year framework (1995-2006). This yielded a vast literature which was selectively organized and analyzed according to the four domains identified above. RESULTS: This review finds that children and adolescents living with domestic violence are at increased risk of experiencing emotional, physical and sexual abuse, of developing emotional and behavioral problems and of increased exposure to the presence of other adversities in their lives. It also highlights a range of protective factors that can mitigate against this impact, in particular a strong relationship with and attachment to a caring adult, usually the mother. CONCLUSION: Children and young people may be significantly affected by living with domestic violence, and impact can endure even after measures have been taken to secure their safety. It also concludes that there is rarely a direct causal pathway leading to a particular outcome and that children are active in constructing their own social world. Implications for interventions suggest that timely, appropriate and individually tailored responses need to build on the resilient blocks in the child's life. PRACTICE IMPLICATIONS: This study illustrate the links between exposure to domestic violence, various forms of child abuse and other related adversities, concluding that such exposure may have a differential yet potentially deleterious impact for children and young people. From a resilient perspective this review also highlights range of protective factors that influence the extent of the impact of exposure and the subsequent outcomes for the child. This review advocates for a holistic and child-centered approach to service delivery, derived from an informed assessment, designed to capture a picture of the individual child's experience, and responsive to their individual needs.