Blunted startle reactivity in everyday sadism and psychopathy.

Two studies examined the amplitude of the startle response as a function of the Dark Tetrad of personality (narcissism, Machiavellianism, psychopathy, and sadism). We measured electromyographic activity of the orbicularis oculi muscle evoked by a startle stimulus while participants viewed images on a computer screen. Both studies revealed a negative correlation between general startle reactivity (averaged across positive, negative, and neutral images) and sadistic tendencies. In Study 2, all four dark traits were negative correlates of general startle reactivity. Study 2 also examined the personality correlates of aversive startle potentiation (ASP; indexed by greater reactivity while viewing negatively-valenced images than positive or neutral images). ASP correlated negatively with a variety of personality measures of psychopathy and sadism, their facets, and related personality tendencies (callousness, risk-taking, and restricted affect). These findings suggest that ordinary people with high levels of callousness and antagonism display physiological evidence of non-reactivity (i.e., blunted acoustic startle in general), whereas psychopathy and sadism are preferentially associated with reduced ASP.

Mental health and unemployment: A systematic review and meta-analysis of interventions to improve depression and anxiety outcomes.

BACKGROUND: Unemployment is associated with substantially greater depression and anxiety, constituting a considerable public health concern. The current review provides the most comprehensive synthesis to date, and first meta-analysis, of controlled intervention trials aimed at improving depression and anxiety outcomes during unemployment. METHODS: Searches were conducted within PsycInfo, Cochrane Central, PubMed and Embase from their inception to September 2022. Included studies conducted controlled trials of interventions focused on improving mental health within unemployed samples, and reported on validated measures of depression, anxiety, or distress (mixed depression and anxiety). Narrative syntheses and random effects meta-analyses were conducted among prevention- and treatment-level interventions for each outcome. RESULTS: A total of 39 articles reporting on 33 studies were included for review (sample sizes ranging from 21 to 1801). Both prevention and treatment interventions tended to be effective overall, with treatment interventions producing larger effect sizes than prevention interventions. The clearest evidence for particular intervention approaches emerged for prevention-level Cognitive Therapy/CBT, followed by prevention-level work-related interventions, although neither produced entirely consistent effects. LIMITATIONS: Risk of bias was generally high across studies. Low numbers of studies within subgroups precluded any comparisons between long-term and short-term unemployment, limited comparisons among treatment studies, and reduced the power of meta-analyses. CONCLUSIONS: Both prevention- and treatment-level mental health-focused interventions have merit for reducing symptoms of anxiety and depression among those experiencing unemployment. Cognitive Therapy/CBT and work-related interventions hold the most robust evidence base, which can inform both prevention and treatment strategies implemented by clinicians, employment services providers, and governments.

A report on the International Society for Cell & Gene Therapy 2022 Scientific Signature Series, "Therapeutic advances with native and engineered human extracellular vesicles".

The International Society for Cell & Gene Therapy Scientific Signature Series event "Therapeutic Advances With Native and Engineered Human EVs" took place as part of the International Society for Cell & Gene Therapy 2022 Annual Meeting, held from May 4 to 7, 2022, in San Francisco, California, USA. This was the first signature series event on extracellular vesicles (EVs) and a timely reflection of the growing interest in EVs, including both native and engineered human EVs, for therapeutic applications. The event successfully gathered academic and industrial key opinion leaders to discuss the current state of the art in developing and understanding native and engineered EVs and applying our knowledge toward advancing EV therapeutics. Latest advancements in understanding the mechanisms by which native and engineered EVs exert their therapeutic effects against different diseases in animal models were presented, with some diseases such as psoriasis and osteoarthritis already reaching clinical testing of EVs. The discussion also covered various aspects relevant to advancing the clinical translation of EV therapies, including EV preparation, manufacturing, consistency, site(s) of action, route(s) of administration, and luminal cargo delivery of RNA and other compounds.

Attention to risk information in direct-to-consumer prescription drug print ads: An eye-tracking study.

PURPOSE: FDA regulations state print ads for prescription drugs must provide a true statement of information "in brief summary" describing "side effects, contraindications and effectiveness." To fulfill these requirements, these ads typically display risk information both as important safety information (ISI) on the "main" ad page with the product claims and on a separate "brief summary" page. The ISI can be lengthy and may repeat brief summary content. METHODS: The authors tested two versions of the ISI (short versus long) and the presence or absence of a brief summary in direct-to-consumer prescription drug print ads for two medical conditions: overactive bladder (N = 181) and rheumatoid arthritis (N = 179). Attention was measured with eye-tracking and self-report methods. Risk retention and perceptions were self-reported. RESULTS: Participants spent more time viewing ads with a long ISI or a brief summary and in some instances, recalled more risks. The combination of a long ISI and a brief summary did not increase or decrease attention to or retention of risk information. CONCLUSION: A long ISI and a brief summary may perform similar functions.

Is the Window of Learning Only Cracked Open? Parents' Perspectives on Virtual Learning for Deaf and Hard of Hearing Students.

During the COVID-19 pandemic, parents quickly assumed the role of teachers to support their children's learning at home. Deaf and hard of hearing (DHH) students often rely on additional accommodations to access their education. The authors investigated the perspectives of 40 parents of K-12 DHH students on the use of virtual learning during the pandemic. An electronic survey was distributed through Qualtrics to gain an understanding of the new learning environment of remote instruction. The participants' responses revealed that they felt that challenges occurred in the areas of time management, language access, technology, motivation, and children's ability to function independently. The respondents were almost evenly split between satisfaction and dissatisfaction with their child's overall educational experience during the pandemic. The results indicated that degree of access significantly influenced the children's experiences of education in virtual learning settings.

Comparability of in-person and web screening: Does mode affect what households report?

Household screening is common when information about characteristics of household members is needed for selection of survey respondents. When key characteristics have a low prevalence, or are oversampled, this can result in a large number of sampled households screened, many of which have no persons selected. For in-person surveys this can be inefficient and costly, especially in an environment of declining response. A multimode design using a mail, push-to-web approach is an attractive alternative due to lower cost and high internet penetration. However, little is known about the comparable data quality properties between in-person and web modes. While in-person screening is considered a gold standard approach, respondents may fail to report household members and interviewers may unintentionally screen out reluctant respondents. Similarly, those self-responding sometimes fail to report unrelated household members or young children. In this study we compared in-person and web screening in the National Health and Nutrition Examination Survey. Households were randomly selected to complete a self-administered web screener and subsequently be screened by an interviewer during an in-person visit. We report on the comparability of household characteristics between modes to determine if web screening provides data equivalent to in-person screening. We examine time between the web and in-person screening to see if true change can account for differences. In the presence of conflicting data, we examine selection criteria based on the screening responses to see how inaccuracies affect selection status, or if inaccuracies or person omissions are systematically related to a specific mode. Approximately 93% (80/86) of households agreed on selection status between the web and in-person modes. Household composition matched fully for 84% (72/86) of households. These results indicate that web screening is a viable option enumerating households in population surveys.

In vivo tracking of [89Zr]Zr-labeled engineered extracellular vesicles by PET reveals organ-specific biodistribution based upon the route of administration.

Extracellular vesicles (EVs) have garnered increasing interest as delivery vehicles for multiple classes of therapeutics based on their role as mediators in an important, natural intercellular communication system. We recently described a platform to allow the design, production and in vivo study of human EVs with specific properties (drug or tropism modifiers). This article seeks to compare and expand upon historical biodistribution and kinetic data by comparing systemically and compartmentally administered labeled engineered EVs using in vivo and ex vivo techniques. METHODS: EVs were surface-labeled to high radiochemical purity and specific activity with 89Zirconium deferoxamine ([89Zr]Zr-DFO) and/or cy7-scrambled antisense oligonucleotide (Cy7-ExoASOscr), or luminally loaded with GFP for in vivo tracking in rodents and non-human primates (NHPs). Positron Emission Tomography (PET) and subsequent immunohistochemistry (IHC) and autoradiography (ARG) cross-validation enabled assessment of the anatomical and cellular distribution of labeled EVs both spatially and temporally. RESULTS: Over time, systemic administration of engineered EVs distributed preferentially to the liver and spleen (Intravenous, IV), gastrointestinal tract and lymph nodes (Intraperitoneal, IP) and local/regional lymph nodes (Subcutaneous, SC). Immunostaining of dissected organs displaying PET signal revealed co-localization of an EV marker (PTGFRN) with a subset of macrophage markers (CD206, F4/80, IBA1). Compartmental dosing into NHP cerebrospinal fluid (CSF) resulted in a heterogenous distribution of labeled EVs depending upon whether the route was intrathecal (ITH), intracisterna magna (ICM) or intracerebroventricular (ICV), compared to the homogeneous distribution observed in rodents. Thus anatomically, ITH administration in NHP revealed meningeal distribution along the neuraxis to the base of the skull. In contrast ICM and ICV dosing resulted in meningeal distribution around the skull and to the cervical and thoracic spinal column. Further characterization using IHC shows uptake in a subset of meningeal macrophages. CONCLUSIONS: The present studies provide a comprehensive assessment of the fate of robustly and reproducibly labeled engineered EVs across several mammalian species. The in vivo distribution was observed to be both spatially and temporally dependent upon the route of administration providing insight into potential targeting opportunities for engineered EVs carrying a therapeutic payload.

Deep Learning and its Application for Healthcare Delivery in Low and Middle Income Countries.

As anyone who has witnessed firsthand knows, healthcare delivery in low-resource settings is fundamentally different from more affluent settings. Artificial Intelligence, including Machine Learning and more specifically Deep Learning, has made amazing advances over the past decade. Significant resources are now dedicated to problems in the field of medicine, but with the potential to further the digital divide by neglecting underserved areas and their specific context. In the general case, Deep Learning remains a complex technology requiring deep technical expertise. This paper explores advances within the narrower field of deep learning image analysis that reduces barriers to adoption and allows individuals with less specialized software skills to effectively employ these techniques. This enables a next wave of innovation, driven largely by problem domain expertise and the creative application of this technology to unaddressed concerns in LMIC settings. The paper also explores the central role of NGOs in problem identification, data acquisition and curation, and integration of new technologies into healthcare systems.

ExoSTING, an extracellular vesicle loaded with STING agonists, promotes tumor immune surveillance.

Cyclic dinucleotide (CDN) agonists of the STimulator of InterferoN Genes (STING) pathway have shown immune activation and tumor clearance in pre-clinical models. However, CDNs administered intratumorally also promote STING activation leading to direct cytotoxicity of many cell types in the tumor microenvironment (TME), systemic inflammation due to rapid tumor extravasation of the CDN, and immune ablation in the TME. These result in a failure to establish immunological memory. ExoSTING, an engineered extracellular vesicle (EV) exogenously loaded with CDN, enhances the potency of CDN and preferentially activates antigen presenting cells in the TME. Following intratumoral injection, exoSTING was retained within the tumor, enhanced local Th1 responses and recruitment of CD8+ T cells, and generated systemic anti-tumor immunity to the tumor. ExoSTING at therapeutically active doses did not induce systemic inflammatory cytokines, resulting in an enhanced therapeutic window. ExoSTING is a novel, differentiated therapeutic candidate that leverages the natural biology of EVs to enhance the activity of CDNs.

A versatile platform for generating engineered extracellular vesicles with defined therapeutic properties.

Extracellular vesicles (EVs) are an important intercellular communication system facilitating the transfer of macromolecules between cells. Delivery of exogenous cargo tethered to the EV surface or packaged inside the lumen are key strategies for generating therapeutic EVs. We identified two "scaffold" proteins, PTGFRN and BASP1, that are preferentially sorted into EVs and enable high-density surface display and luminal loading of a wide range of molecules, including cytokines, antibody fragments, RNA binding proteins, vaccine antigens, Cas9, and members of the TNF superfamily. Molecules were loaded into EVs at high density and exhibited potent in vitro activity when fused to full-length or truncated forms of PTGFRN or BASP1. Furthermore, these engineered EVs retained pharmacodynamic activity in a variety of animal models. This engineering platform provides a simple approach to functionalize EVs with topologically diverse macromolecules and represents a significant advance toward unlocking the therapeutic potential of EVs.

Exosome Surface Display of IL12 Results in Tumor-Retained Pharmacology with Superior Potency and Limited Systemic Exposure Compared with Recombinant IL12.

The promise of IL12 as a cancer treatment has yet to be fulfilled with multiple tested approaches being limited by unwanted systemic exposure and unpredictable pharmacology. To address these limitations, we generated exoIL12, a novel, engineered exosome therapeutic that displays functional IL12 on the surface of an exosome. IL12 exosomal surface expression was achieved via fusion to the abundant exosomal surface protein PTGFRN resulting in equivalent potency in vitro to recombinant IL12 (rIL12) as demonstrated by IFNγ production. Following intratumoral injection, exoIL12 exhibited prolonged tumor retention and greater antitumor activity than rIL12. Moreover, exoIL12 was significantly more potent than rIL12 in tumor growth inhibition. In the MC38 model, complete responses were observed in 63% of mice treated with exoIL12; in contrast, rIL12 resulted in 0% complete responses at an equivalent IL12 dose. This correlated with dose-dependent increases in tumor antigen-specific CD8+ T cells. Rechallenge studies of exoIL12 complete responder mice showed no tumor regrowth, and depletion of CD8+ T cells completely abrogated antitumor activity of exoIL12. Following intratumoral administration, exoIL12 exhibited 10-fold higher intratumoral exposure than rIL12 and prolonged IFNγ production up to 48 hours. Retained local pharmacology of exoIL12 was further confirmed using subcutaneous injections in nonhuman primates. This work demonstrates that tumor-restricted pharmacology of exoIL12 results in superior in vivo efficacy and immune memory without systemic IL12 exposure and related toxicity. ExoIL12 is a novel cancer therapeutic candidate that overcomes key limitations of rIL12 and thereby creates a therapeutic window for this potent cytokine.

Scale insect genus names and their families in the scale insects (Hemiptera: Sternorrhyncha: Coccomorpha), a supplement.

A list of genus names in the scale insects published between 2014 and the end of 2019 is provided; it follows on from an earlier comprehensive list of the names published between 1758 and the end of 2013. Each genus name and its type species are assigned to one of the 53 scale insect families now recognised.

The status of three species names in the mealybug genus Rastrococcus Ferris (Hemiptera: Coccomorpha: Pseudococcidae).

This paper attempts to establish the correct status of three species names in the mealybug genus Rastrococcus Ferris (Hemiptera: Coccomorpha: Pseudococcidae). At present, 31 species are included in the genus (García Morales et al. 2019). The natural distribution of the species is southern Asia and Australasia, but two species have been introduced into Africa and one of them has reached French Guiana.

A psychological intervention (ConquerFear) for treating fear of cancer recurrence: Views of study therapists regarding sustainability.

OBJECTIVE: ConquerFear is a metacognitive intervention for fear of cancer recurrence (FCR) with proven efficacy immmediately and 6 months post-treatment. This qualitative study documented barriers and facilitators to the sustainability of ConquerFear from the perspective of study therapists. METHODS: Fourteen therapists who had delivered ConquerFear in a randomised controlled trial completed a semi-structured phone interview, reaching theoretical saturation. Themes from thematic analysis were mapped to the Promoting Action on Research Implementation in Health Services (PARiHS) implementation framework. RESULTS: Participants were 13 males and one female with, on average, 14 years psycho-oncology experience. Nine over-arching themes were identified, falling into three domains, which when present, were facilitators, and if absent, were barriers: evidence (intervention credibility, experienced efficacy, perceived need for intervention); context (positive attitude to and capacity for survivorship/FCR care, favourable therapist orientation and flexibility, strong referral pathways); and facilitation of implementation (intervention/service fit, intervention/patient fit, and training, support, and provided resources). CONCLUSIONS: ConquerFear is a sustainable intervention in routine clinical practise. Facilitators included a sound evidence base; a receptive context; good fit between the intervention, therapist orientation, and patient need; and flexibility of delivery. Where absent, these factors served as barriers. These results have implications for enhancing uptake of psycho-oncology interventions in routine care.

Trials with proxy-reported outcomes registered on the Australian New Zealand Clinical Trials Registry (ANZCTR).

AIMS: A proxy is someone other than a patient who reports a patient's outcomes as if they are the patient. Due to known discordance with patient reports, proxies are often not recommended in clinical trials; however, proxies may be needed in certain research contexts. We aimed to identify and describe trials registered on the Australian New Zealand Clinical Trials Registry (ANZCTR) with proxy-reported endpoints. METHODS: ANZCTR was systematically searched from inception (2005) to 31 March 2017 for trials with proxy-reported endpoints. Primary and secondary endpoints for each trial retrieved by the search were individually coded (proxy-reported: yes/no), and trials with confirmed proxy-reported endpoints were included in the analysis. RESULTS: Of 13,666 registered trials, 469 (3.4%) included a proxy-reported endpoint (867 individual proxy-reported endpoints in total: 62% family member proxy, 22% health professional). Proxy endpoint inclusion did not significantly increase over time (r = 0.18, p = 0.59). Mental health (11.5%), stroke (10.3%) and neurological (8.3%) trials had the highest proportion of trials using proxies. Of the 469 trials, 123 (26.2%) studies involved paediatric patients. DISCUSSION: Proxy-reported endpoints are included in a small but notable number of studies, which may indicate other types of outcomes are used for patients unable to self-report, or that these patients are under-researched.

Revision of the soft scale genus Paralecanium (Hemiptera: Coccomorpha: Coccidae) with the introduction of three new genera and twenty new species.

The soft scale insect genus Paralecanium Cockerell (Hemiptera: Coccomorpha: Coccidae), mainly characterised by the possession of fan-shaped marginal setae, has never been revised and most of the species currently recognised were described in the early part of the twentieth century. The present revision is based on the morphology of the adult females and redescribes and illustrates all 34 species or subspecies previously included in the genus. These three subspecies have been raised to full specific rank, namely P. expansum javanicum (Green) to P. javanicum (Green) stat. n.; P. expansum rotundum (Green) to P. rotundum (Green) stat. n. and P. frenchii macrozamiae (Fuller) to P. macrozamiae (Fuller) stat. n. Of the remaining previously recognised species, three have been made junior synonyms: P. album Takahashi is here considered to be a junior synonym of P. metallicum (Green), syn. n.; P. angkorense Takahashi is considered to be a junior synonym ofP. cocophyllae Banks, syn. n.; and P. limbatum Green is considered to be a junior synonym of P. geometricum (Green), syn. n. Paralecanium marianum Cockerell from Brazil is clearly not closely related to Paralecanium and so a new genus, Mariacoccus Hodgson Williams gen. n., has been introduced to take it and the adult female is redescribed and illustrated; comparison of the adult female of M. marianus with that of Coccus lizeri (Fonseca) showed that the latter species is a junior synonym of M. marianus (Cockerell), syn. n. Based on the morphology of the above species and on the new species mentioned below, two new genera have been introduced: Insularicoccus Hodgson Williams gen. n. (type species P. carolinensis Beardsley), and Discochiton Hodgson Williams gen. n. (type species D. martini Hodgson, spec. n.). This brings the number of soft scale genera with fan-shaped marginal setae to three. Diagnoses of each of these 3 genera are presented, along with a key to the genera based on adult female morphology. The species that have been left in Paralecanium Cockerell are: P. calophylli (Green), P. frenchii (Maskell), P. geometricum (Green), P. hainanense Takahashi, P. machili Takahashi, P. macrozamiae (Fuller), P. maculatum Takahashi, P. marginatum (Green), P. maritimum (Green), P. minutum Takahashi, P. neomaritimum Takahashi, P. ovatum Morrison, P. pahanense Takahashi, P. peradeniyense (Green), P. planum (Green) and P. zonatum (Green). The species transferred to Discochiton as comb. n. are: P. album Takahashi, P. cocophyllae Banks, P. expansum (Green), P. javanicum (Green), P. luzonicum Cockerell, P. malainum Takahashi, P. mancum (Green), P. metallicum (Green), P. milleri Takahashi, P. pseudexpansum (Green), P. quadratum (Green), P. rotundum (Green),P. trifasciatum (Green) and P. vacuum Morrison. The only species transferred to Insularicoccus is the type species, namelyP. carolinense (Beardsley), comb. n. In addition, adult females of the following 11 new species are described and illustrated in the genus Paralecanium (as defined here) spec. n.: P. acinaces Hodgson, P. busoense Hodgson, P. claviseta Hodgson, P. comperei Hodgson, P. cypripedium Hodgson, P. elongatum Hodgson, P. leei Hodgson, P. morobeense Hodgson, P. neoguineense Hodgson, P. palawanense Hodgson and P. vacerra Hodgson. In addition, the following 8 species are described and illustrated as Discochiton spec. n.: D. browni Hodgson, D. crenulatum Hodgson, D. diplodiscus Hodgson, D. martini Hodgson, D. papillatum Hodgson, D. paucipedis Hodgson, D. sarawakense Hodgson and D. seychellarum Williams Hodgson, and 1 species of Insularicoccus is described as new and illustrated, namely I. syzygium Hodgson spec. n. Keys, based on adult female morphology, are provided for separation of all the species in each genus. As part of this revision, the morphological characters used to diagnose species in this group of genera are re-evaluated and a number of new characters found; greater emphasis has been placed on some character-states, so the basic morphology of this group of genera is also described. Lectotypes have been designated for 22 species, namely: Lecanium calophylli Green; L. expansum Green; L. expansum javanicum Green; L. expansum metallicum Green; L. expansum rotundum Green; rotundum Green; L. geometricum Green; L. limbatum Green; L. mancum Green; L. marginatum Green; L. maritimum Green; L. peradeniyense Green; L. planum Green; L. pseudexpansum Green; L. quadratum Green; L. trifasciatum Green and L. zonatum Green. Also: Paralecanium album Takahashi; P. hainanense Takahashi; P. malianum Takahashi; P. marianum Cockerell; P. neomaritimum Takahashi and P. vacuum Morrison. Finally, an example of the first-instar nymphs, second-instar males and second/third instar females of both Paralecanium and Discochiton are described and illustrated and compared with those already known in the tribe Paralecaniini.

Doubling the known endemic species diversity of New Caledonian armored scale insects (Hemiptera, Diaspididae).

Fourteen species of armored scale insects are known only from New Caledonia. Here, the adult female of fourteen more are described: Agrophaspisansevatae sp. n., Aonidiamontikoghis sp. n. , Aonidiapauca sp. n., Fernaldannawhita sp. n., Furcaspiscostulariae sp. n., Greeniellacasuarinae sp. n., Greenielladacrydiae sp. n., Lepidosaphesmonticola sp. n., Leptaspispege gen. et sp. n., Leucaspismontikoghis sp. n., Melanaspisnothofagi sp. n., Neomorganianothofagi sp. n., Pseudaonidiadugdali sp. n., and Pseudaonidiayateensis sp. n. We note that the diversity of New Caledonian armored scale insects appears to have resulted more from trans-oceanic dispersal than in situ speciation.

Correction to: Trials with patient-reported outcomes registered on the Australian New Zealand Clinical Trials Registry (ANZCTR).

In the original publication of the article, the sentence "The ANZCTR is the fifth largest trial registry internationally, with 21,330 registered trials as at January 2018 [5]" in the Introduction section was published incorrectly.

Trials with patient-reported outcomes registered on the Australian New Zealand Clinical Trials Registry (ANZCTR).

AIMS: It is important to understand the number, types and regions of trials that include patient-reported outcomes (PROs) to appreciate how patient experiences have been considered in studies of health and interventions. Twenty-seven percent of trials registered with ClinicalTrials.gov (2007-2013) included PROs; however, a regional breakdown was not provided and no reviews have been conducted of the Australia New Zealand Clinical Trials Registry (ANZCTR). We aimed to identify trials registered with ANZCTR with PRO endpoints and describe their characteristics. METHODS: ANZCTR was systematically searched from inception (2005) to 31 March 2017 for trials with PRO endpoints. Search terms included PRO measures listed in Patient-Reported Outcomes Quality of Life Instrument Database and Grid-Enabled Measures, as well as generic PRO terms (e.g. "quality of life" (QOL)). Trial endpoints were individually coded using an established framework to identify trials with PROs for the analysis. RESULTS: Of 13,666 registered trials, 6168 (45.1%) included a PRO. The proportion of studies including PROs increased between 2006 and 2016 (r = 0.74, p = 0.009). Among the 6168 trials, there were 17,961 individual PRO endpoints, including symptoms/functional outcomes/condition-specific QOL (65.6%), generic QOL (13.2%), patient-reported experiences (9.9%), patient-reported behaviours (7.9%). Mental health was the most common category (99.8% included PROs), followed by physical medicine/rehabilitation (65.6%), musculoskeletal (63.5%), public health (63.1%), and cancer (54.2%). DISCUSSION: Our findings suggest growing use of PROs in the assessment of health and interventions in ANZ. Our review identifies trial categories with limited patient-reported information and provides a basis for future work on the impact of PRO findings in clinical care.