Bioinformatic analysis suggests potential mechanisms underlying parasitoid venom evolution and function.

Hymenopteran parasitoid wasps are a diverse collection of species that infect arthropod hosts and use factors found in their venoms to manipulate host immune responses, physiology, and behaviour. Whole parasitoid venoms have been profiled using proteomic approaches, and here we present a bioinformatic characterization of the venom protein content from Ganaspis sp. 1, a parasitoid that infects flies of the genus Drosophila. We find evidence that diverse evolutionary processes including multifunctionalization, co-option, gene duplication, and horizontal gene transfer may be acting in concert to drive venom gene evolution in Ganaspis sp.1. One major role of parasitoid wasp venom is host immune evasion. We previously demonstrated that Ganaspis sp. 1 venom inhibits immune cell activation in infected Drosophila melanogaster hosts, and our current analysis has uncovered additional predicted virulence functions. Overall, this analysis represents an important step towards understanding the composition and activity of parasitoid wasp venoms.

Efficacy of BrighterSide, a Self-Guided App for Suicidal Ideation: Randomized Controlled Trial.

Background: Self-guided digital interventions can reduce the severity of suicidal ideation, although there remain relatively few rigorously evaluated smartphone apps targeting suicidality. Objective: This trial evaluated whether the BrighterSide smartphone app intervention was superior to a waitlist control group at reducing the severity of suicidal ideation. Methods: A total of 550 adults aged 18 to 65 years with recent suicidal ideation were recruited from the Australian community. In this randomized controlled trial, participants were randomly assigned to receive either the BrighterSide app or to a waitlist control group that received treatment as usual. The app was self-guided, and participants could use the app at their own pace for the duration of the study period. Self-report measures were collected at baseline, 6 weeks, and 12 weeks. The primary outcome was severity and frequency of suicidal ideation, and secondary outcomes included psychological distress and functioning and recovery. Additional data were collected on app engagement and participant feedback. Results: Suicidal ideation reduced over time for all participants, but there was no significant interaction between group and time. Similar improvements were observed for self-harm, functioning and recovery, days out of role, and coping. Psychological distress was significantly lower in the intervention group at the 6-week follow-up, but this was not maintained at 12 weeks. Conclusions: The BrighterSide app did not lead to a significant improvement in suicidal ideation relative to a waitlist control group. Possible reasons for this null finding are discussed.

The Effect of Explicit Suicide Language in Engagement With a Suicide Prevention Search Page Help-Seeking Prompt: Nonrandomized Trial.

BACKGROUND: Given that signage, messaging, and advertisements (ads) are the gateway to many interventions in suicide prevention, it is important that we understand what type of messaging works best for whom. OBJECTIVE: We investigated whether explicitly mentioning suicide increases engagement using internet ads by investigating engagement with campaigns with different categories of keywords searched, which may reflect different cognitive states. METHODS: We ran a 2-arm study Australia-wide, with or without ads featuring explicit suicide wording. We analyzed whether there were differences in engagement for campaigns with explicit and nonexplicit ads for low-risk (distressed but not explicitly suicidal), high-risk (explicitly suicidal), and help-seeking for suicide keywords. RESULTS: Our analyses revealed that having explicit wording has opposite effects, depending on the search terms used: explicit wording reduced the engagement rate for individuals searching for low-risk keywords but increased engagement for those using high-risk keywords. CONCLUSIONS: The findings suggest that individuals who are aware of their suicidality respond better to campaigns that explicitly use the word "suicide." We found that individuals who search for low-risk keywords also respond to explicit ads, suggesting that some individuals who are experiencing suicidality search for low-risk keywords.

Suicide Prevention Using Google Ads: Randomized Controlled Trial Measuring Engagement.

BACKGROUND: Studies have shown that individuals may search for suicide-related terms on the internet prior to an attempt. OBJECTIVE: Thus, across 2 studies, we investigated engagement with an advertisement campaign designed to reach individuals contemplating suicide. METHODS: First, we designed the campaign to focus on crisis, running a campaign for 16 days in which crisis-related keywords would trigger an ad and landing page to help individuals find the national suicide hotline number. Second, we expanded the campaign to also help individuals contemplating suicide, running the campaign for 19 days with a wider range of keywords through a co-designed website with a wider range of offerings (eg, lived experience stories). RESULTS: In the first study, the ad was shown 16,505 times and was clicked 664 times (4.02% click rate). There were 101 calls to the hotline. In the second study, the ad was shown 120,881 times and clicked 6227 times (5.15% click rate); of these 6227 clicks, there were 1419 (22.79%) engagements with the site, a substantially higher rate than the industry average of 3%. The number of clicks on the ad was high despite a suicide hotline banner likely being present. CONCLUSIONS: Search advertisements are a quick, far-reaching, and cost-efficient way of reaching those contemplating suicide and are needed despite suicide hotline banners being present. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12623000084684; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=385209.

An ACE2 decamer viral trap as a durable intervention solution for current and future SARS-CoV.

The capacity of SARS-CoV-2 to evolve poses challenges to conventional prevention and treatment options such as vaccination and monoclonal antibodies, as they rely on viral receptor binding domain (RBD) sequences from previous strains. Additionally, animal CoVs, especially those of the SARS family, are now appreciated as a constant pandemic threat. We present here a new antiviral approach featuring inhalation delivery of a recombinant viral trap composed of ten copies of angiotensin-converting enzyme 2 (ACE2) fused to the IgM Fc. This ACE2 decamer viral trap is designed to inhibit SARS-CoV-2 entry function, regardless of viral RBD sequence variations as shown by its high neutralization potency against all known SARS-CoV-2 variants, including Omicron BQ.1, BQ.1.1, XBB.1 and XBB.1.5. In addition, it demonstrates potency against SARS-CoV-1, human NL63, as well as bat and pangolin CoVs. The multivalent trap is effective in both prophylactic and therapeutic settings since a single intranasal dosing confers protection in human ACE2 transgenic mice against viral challenges. Lastly, this molecule is stable at ambient temperature for more than twelve weeks and can sustain physical stress from aerosolization. These results demonstrate the potential of a decameric ACE2 viral trap as an inhalation solution for ACE2-dependent coronaviruses of current and future pandemic concerns.

Morphological evidence indicates a role for microglia in shaping the PCOS-like brain.

Although polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility worldwide, the aetiology of the disorder remains poorly defined. Animal-based evidence highlights the brain as a prime suspect in both the development and maintenance of PCOS. Prenatally androgenised (PNA) models of PCOS exhibit excessive GABAergic wiring associated with PCOS-like reproductive deficits in adulthood, with aberrant brain wiring detected as early as postnatal day (P) 25, prior to disease onset, in the PNA mouse. The mechanisms underlying this aberrant brain wiring remain unknown. Microglia, the immune cells of the brain, are regulators of neuronal wiring across development, mediating both the formation and removal of neuronal inputs. Here, we tested the hypothesis that microglia play a role in the excessive GABAergic wiring that leads to PCOS-like features in the PNA brain. Using specific immunolabelling, microglia number and morphology associated with activation states were analysed in PNA and vehicle-treated controls across developmental timepoints, including embryonic day 17.5, P0, P25 and P60 (n = 7-14 per group), and in two regions of the hypothalamus implicated in fertility regulation. At P0, fewer amoeboid microglia were observed in the rostral preoptic area (rPOA) of PNA mice. However, the greatest changes were observed at P25, with PNA mice exhibiting fewer total microglia, and specifically fewer "sculpting" microglia, in the rPOA. Based on these findings, we assessed microglia-mediated refinement of GABAergic synaptic terminals at two developmental stages of peak synaptic refinement: P7 and P15 (n = 7 per group). PNA mice showed a reduction in the uptake of GABAergic synaptic material at P15. These findings reveal time-specific changes in the microglia population and refinement of GABAergic inputs in a mouse model of PCOS driven by prenatal androgen excess and suggest a role for microglia in shaping the atypical brain wiring associated with the development of PCOS features.

Inner-nuclear-membrane-associated degradation employs Dfm1-independent retrotranslocation and alleviates misfolded transmembrane-protein toxicity.

Before their delivery to and degradation by the 26S proteasome, misfolded transmembrane proteins of the endoplasmic reticulum (ER) and inner-nuclear membrane (INM) must be extracted from lipid bilayers. This extraction process, known as retrotranslocation, requires both quality-control E3 ubiquitin ligases and dislocation factors that diminish the energetic cost of dislodging the transmembrane segments of a protein. Recently, we showed that retrotranslocation of all ER transmembrane proteins requires the Dfm1 rhomboid pseudoprotease. However, we did not investigate whether Dfm1 also mediated retrotranslocation of transmembrane substrates in the INM, which is contiguous with the ER but functionally separated from it by nucleoporins. Here, we show that canonical retrotranslocation occurs during INM-associated degradation (INMAD) but proceeds independently of Dfm1. Despite this independence, ER-associated degradation (ERAD)-M and INMAD cooperate to mitigate proteotoxicity. We show a novel misfolded-transmembrane-protein toxicity that elicits genetic suppression, demonstrating the cell's ability to tolerate a toxic burden of misfolded transmembrane proteins without functional INMAD or ERAD-M. This strikingly contrasted the suppression of the dfm1Δ null, which leads to the resumption of ERAD-M through HRD-complex remodeling. Thus, we conclude that INM retrotranslocation proceeds through a novel, private channel that can be studied by virtue of its role in alleviating membrane-associated proteotoxicity.

Virginia Health Catalyst: A public health perspective frames strategies to ensure oral health is health.

The Virginia Oral Health Coalition was created to increase the number of Virginians who access dental services. The organization celebrates its tenth birthday with the expanded focus of ensuring everyone in the state has equitable access to comprehensive health care that includes oral health. It also has a new name - Virginia Health Catalyst. Why does removing 'oral health' from its' name honor dental care more than keeping it?

The influence of maternal androgen excess on the male reproductive axis.

Prenatal androgen excess is suspected to contribute to the development of polycystic ovary syndrome (PCOS) in women. Evidence from preclinical female animal models links maternal androgen excess with the development of PCOS-like features and associated alterations in the neuronal network regulating the reproductive axis. There is some evidence suggesting that maternal androgen excess leads to similar reproductive axis disruptions in men, despite the critical role that androgens play in normal sexual differentiation. Here, the specific impact of maternal androgen excess on the male hypothalamic-pituitary-gonadal axis was investigated using a prenatal androgenization protocol in mice shown to model PCOS-like features in females. Reproductive phenotyping of prenatally androgenised male (PNAM) mice revealed no discernible impact of maternal androgen excess at any level of the reproductive axis. Luteinising hormone pulse characteristics, daily sperm production, plasma testosterone and anti-Müllerian hormone levels were not different in the male offspring of dams administered dihydrotestosterone (DHT) during late gestation compared to controls. Androgen receptor expression was quantified through the hypothalamus and identified as unchanged. Confocal imaging of gonadotropin-releasing hormone (GnRH) neurons revealed that in contrast with prenatally androgenised female mice, PNAM mice exhibited no differences in the density of putative GABAergic innervation compared to controls. These data indicate that a maternal androgen environment capable of inducing reproductive dysfunction in female offspring has no evident impact on the reproductive axis of male littermates in adulthood.

Comparison of luteolysis and timed artificial insemination pregnancy rates after administration of PGF2α in the muscle or the ischiorectal fossa in cattle.

Prostaglandin F2α (PGF2α) is commonly injected intramuscularly (IM) in female cattle in synchronization protocols. A novel site for administration of PGF2α that improves beef quality assurance is the ischiorectal fossa (IRF). The objective of this study was to determine whether administration of PGF2α in the IRF results in a similar physiological response to an intramuscular injection. Yearling angus-cross heifers (n = 112) were blocked by weight and randomly assigned within blocks to be injected with 5 mL PGF2α either IM in the neck or in the IRF. Blood samples taken at 0, 8, 16, 24, 36, and 48 h post-injection were analyzed for serum progesterone concentration using a radioimmunoassay. Progesterone concentration curves for each heifer were plotted to determine luteolysis. The median times to luteolysis for neck and IRF injections were 18.1 h and 20.0 h, respectively (p = 0.06). Angus cross commercial beef cows (n = 1471) at least 30 days post-partum were blocked by age and randomly assigned within blocks to be injected with 5 mL PGF2α either IM in the neck muscle or in IRF as part of a 7-Day CO-Synch + CIDR synchronization protocol. Pregnancy diagnosis was performed via ultrasound at 60 days post insemination. Results were analyzed with Proc Glimmix (SAS). Pregnancy rates for neck and IRF injections were 52.6% and 57.2%, respectively (p = 0.06). In summary, injection of PGF2α in the IRF for synchronization of estrus and luteolysis did not differ from IM injection. Utilizing the ischiorectal fossa as an injection site for PGF2α may serve as an alternative that more closely aligns with beef quality assurance.

What We Do: Key Activities of an Outpatient Palliative Care Team at an Academic Cancer Center.

BACKGROUND: Outpatient palliative care (PC) has been shown to positively impact quality of life and decrease healthcare utilization, but there are limited data describing what activities render these benefits. OBJECTIVE: Describe the topics addressed by an outpatient PC team during scheduled visits. DESIGN: Longitudinal cohort study. SETTING: The Symptom Management Service, an ambulatory PC program at an academic comprehensive cancer center. MEASUREMENT: Between March 23, 2015 and June 14, 2016, outpatient PC providers completed a checklist after each clinic visit, documenting topics covered during the visit. RESULTS: During the study period, 1243 visits were conducted for 577 unique patients. Symptom management was the topic most commonly addressed during initial visits (in 92% of visits), followed by an introduction of PC (69%), support for family caregivers (47%), and communication with other clinicians (38%). Providers also supported patients to understand their prognosis (28%), treatment options (36%), and to make care decisions (22%). Formal advance care planning activities occurred infrequently, however, including designation of a Durable Power of Attorney for Healthcare (26%), completion of an advance directive or Provider Orders for Life-Sustaining Treatment form (10%), and discussing hospice (8%). Follow-up visits were dominated by symptom management (93%) and caregiver support (27%). CONCLUSIONS: Symptom management, support for family and caregivers, and care coordination are the most common activities that occurred during scheduled outpatient PC visits. These findings can guide developing PC practices, as well as clinicians who provide primary PC.

When prison is "easier": probationers' perceptions of health and wellbeing.

PURPOSE: There are currently over 300,000 offenders in England and Wales and the majority, around 240,000, are in the community on probation. However, there is a paucity of research on their health and healthcare needs. The purpose of this paper is to explore issues around health and access to health services for those on probation. In particular the paper explores what people on probation consider to be the key health issues currently affecting them, and to identify barriers to accessing healthcare in the community. DESIGN/METHODOLOGY/APPROACH: The authors ran six focus groups with a total of 41 participants; two were with staff and the others with men and women on probation. In each focus group, the researchers used semi-structured guide and the discussions were recorded electronically and then transcribed. The paper adopted a thematic analytical framework and used NVivo 7 to facilitate analysis. FINDINGS: Both probationers and professionals largely agreed about the key issues which included substance use and mental health problems. However, the most important issue for probationers was dealing with the stress of being on probation which was not generally recognised by professionals. All participants recognised the impact of issues such as housing, finances and employment on the wellbeing of probationers and were concerned about the lack of access to health services, in particular mental health and alcohol services. RESEARCH LIMITATIONS/IMPLICATIONS: This was a small study conducted in one part of England and therefore it is not clear that the findings are generalisable. However, it raises important issues about the mental health needs of probationers and the lack of appropriate services for them. Effective services may have positive impact on re-offending and further research is needed to evaluate models of care. PRACTICAL IMPLICATIONS: The challenge remains for local health service commissioners and providers and the probation service to work together to provide appropriate and accessible services for all those on probation. ORIGINALITY/VALUE: Nearly one-quarter of a million people are on probation at any one time in the UK but the existing evidence on their health is patchy and dated. Little is known about effective health interventions or the extent to which their health needs are met. This study shows that probationers see the stress of being on probation as their most important health concern. Both probationers and staff recognise that mental health and substance use are persistent problems and that these important health needs in these areas are not being met by existing services.

Fertility in Angus cross beef cows following 5-day CO-Synch + CIDR or 7-day CO-Synch + CIDR estrus synchronization and timed artificial insemination.

The present study determined whether a 5-day CO-Synch + controlled internal drug release (CIDR) protocol with two doses of PGF2α would improve timed artificial insemination (AI) pregnancy rate compared with 7-day CO-Synch + CIDR protocol in beef cows. Angus cross beef cows (N = 1817) at 12 locations were randomly assigned to 5-day CO-Synch + CIDR or 7-day CO-Synch + CIDR groups. All cows received 100 µg of GnRH and a CIDR insert on Day 0. Cows (n = 911) in the 5-day CO-Synch + CIDR group received two doses of 25 mg PGF, the first dose given on Day 5 at CIDR removal and the second dose 6 hours later, and 100 µg GnRH on Day 8 and were inseminated concurrently, 72 hours after CIDR removal. Cows (n = 906) in 7-day CO-Synch + CIDR group received 25 mg of PGF at CIDR removal on Day 7, and 100 µg GnRH on Day 10 and were inseminated concurrently, 66 to 72 hours after CIDR removal. All cows were fitted with a heat detector aid at CIDR removal and were observed twice daily until insemination for estrus and heat detector aid status. Accounting for estrus expression at or before AI (P < 0.0001) and body condition score (P < 0.01), cows in the 5-day CO-Synch + CIDR group had greater AI pregnancy rate compared with cows in the 7-day CO-Synch + CIDR group (58.1% vs. 55.1%; P = 0.04). More cows that exhibited estrus at or before AI became pregnant compared with cows that did not [65.7% (681/1037) vs. 44.5% (347/780); P < 0.0001]. The AI pregnancy rate was lesser for cows with body condition ≤4 [≤4 - 49.3% (101/219), 5-6 - 57.9%; >6 - 55.8%]. The mean AI pregnancy rate difference between treatment groups and projected economic outcome varied among locations. In conclusion, cows synchronized with the 5-day CO-Synch + CIDR protocol had greater AI pregnancy rate than those that received the 7-day CO-Synch + CIDR protocol.

An exploration of young women's experiences of living with excess weight.

The experiences of eight young women with excess weight were explored using a semi structured interview consisting of open ended questions and also the Child Attachment Interview (CAI). Interpretative Phenomenological Analysis indicated four group themes around participants' experience of having excess weight; emotional regulation, focus on family relationships, lack of control and sense of self. The CAIs indicated that many of the young women had adopted a caring role in their families, which were often characterized by conflict within family relationships. Dismissing their own vulnerability and emotional needs in preference for self reliance was the dominant attachment strategy adopted by participants. It is suggested that obesity is a complex condition and one that requires an understanding of each individual's experiences and relationship with food, in order to offer treatment that is most likely to be effective.

Delayed closure of the hard palate leads to speech problems and deleterious maxillary growth.

BACKGROUND: Hard palate cleft closure has been associated with maxillary hypoplasia. The Schweckendiek procedure offers delayed hard palate closure to avoid early subperiosteal dissection and palatal scarring. This study sought to compare single-stage versus delayed hard palate closure for speech outcome and maxillary growth. METHODS: A retrospective outcome study was performed of unilateral cleft lip and palate patients with either delayed hard palate repair with a pinned-retained speech prosthesis (Schweckendiek repair) (group 1, delayed hard palate repair, 1978 to 1983) or single-stage cleft palate repair (group 2, single-stage repair, 1983 to 1988). Patients with complete records to maturity at the University of Pittsburgh Cleft Palate Craniofacial Center (n = 82, two equal groups of 41 patients) were studied. Comparative data were collected from multidisciplinary evaluations, perceptual speech scores, speech tests, and cephalometric analysis. RESULTS: Single-stage cleft palate repair had a lower fistulization rate (11 percent) compared with delayed hard palate repair (58 percent). It also had better speech outcomes compared with delayed hard palate repair: mean speech score, 3.1 versus 7.8; final speech score, 0.9 versus 2.9; velopharyngeal incompetency, 21 percent versus 66 percent; failed video fluoroscopy or nasoendoscopy, 18 percent versus 52 percent; and need for secondary speech procedure, 20 percent versus 63 percent. Single-stage repair showed less maxillary growth disturbance, with class III malocclusion, 31 percent versus 66 percent; cephalometric SNA, 78.2 versus 74.8; need for Le Fort I advancement, 24 percent versus 42 percent; and amount of maxillary advancement required, 6 mm versus 9 mm. CONCLUSION: The delayed cleft palate repair led to worse speech outcomes; thus, the authors' center abandoned this technique in favor of single-stage repair. In addition, their data showed that the delayed cleft palate repair led to deleterious maxillary growth.

The L brachioplasty: an innovative approach to correct excess tissue of the upper arm, axilla, and lateral chest.

BACKGROUND: Brachioplasty is aesthetic reshaping of the upper arm after removal of excess medial skin and fat. Massive weight loss patients evolve a severe arm deformity that extends through the axilla and onto the chest. Prevalent operations are incomplete and leave conspicuous scars along the bicipital groove that end as Ts or Zs in the axilla. The L brachioplasty starts with a long ellipse centered over the lower half of the inner arm that sweeps up to the deltopectoral groove. A shorter ellipse is connected at right angles through the axilla onto the chest. The V flap formed between the ellipses is advanced across the axilla to raise the posterior axillary fold. An improved arm, axilla, and chest have an L-shaped zigzag crossing the axilla. METHODS: L brachioplasty, along with upper body lifting, was applied to 24 female weight loss patients over the last 2 years. Ultrasound-assisted lipoplasty was also performed in five patients. All patients were interviewed. Follow-up ranged from 6 to 28 months. RESULTS: All 22 patients were improved and pleased. One patient requested and received a limited scar revision. Three patients had delayed healing at the tip of the triangular flap. Four seromas near the elbow responded to multiple aspirations. One hypertrophic scar was improved with intense pulsed light. CONCLUSIONS: The L-shaped brachioplasty is an innovative, effective, reliable, aesthetic, and safe technique. Integrating the brachioplasty into the upper body lift improves the contours of the axilla, breast, and upper lateral chest, contributing to improved harmonious body contour.

AD/HD and the capture of attention by briefly exposed delay-related cues: evidence from a conditioning paradigm.

BACKGROUND: The selective attention of children with attention deficit/hyperactivity disorder (AD/HD) to briefly exposed delay-related cues was examined in two experiments using a dot-probe conditioning paradigm. METHOD: Colour cues were paired with negatively (i.e., imposition of delay) and positively valenced cues (i.e., escape from or avoidance of delay) during a conditioning phase. These cues were presented alongside neutral cues in a subsequent dot-probe detection phase. RESULTS: In experiment 1 teacher-identified children with AD/HD (N = 12), but not controls (N = 12), displayed an attentional bias towards both positively and negatively valenced cues. In experiment 2 children with a diagnosis of hyperkinetic disorder (N = 15), but not controls (N = 15), displayed a bias towards delay-related cues. However, this effect was largely carried by the response to positively valenced cues. CONCLUSIONS: These results confirm the dot-probe conditioning paradigm as a useful test of motivational influence on attention. They provide the first evidence of qualitative differences in the attentional style of children with AD/HD and give further support to those theories that highlight the motivational significance of delay in AD/HD.