Novel antiinflammatory biologics shaped by parasite-host coevolution.

Parasitic helminth infections, while a major cause of neglected tropical disease burden, negatively correlate with the incidence of immune-mediated inflammatory diseases such as inflammatory bowel diseases (IBD). To evade expulsion, helminths have developed sophisticated mechanisms to regulate their host's immune responses. Controlled experimental human helminth infections have been assessed clinically for treating inflammatory conditions; however, such a radical therapeutic modality has challenges. An alternative approach is to harness the immunomodulatory properties within the worm's excretory-secretory (ES) complement, its secretome. Here, we report a biologics discovery and validation pipeline to generate and screen in vivo a recombinant cell-free secretome library of helminth-derived immunomodulatory proteins. We successfully expressed 78 recombinant ES proteins from gastrointestinal hookworms and screened the crude in vitro translation reactions for anti-IBD properties in a mouse model of acute colitis. After statistical filtering and ranking, 20 proteins conferred significant protection against various parameters of colitis. Lead candidates from distinct protein families, including annexins, transthyretins, nematode-specific retinol-binding proteins, and SCP/TAPS were identified. Representative proteins were produced in mammalian cells and further validated, including ex vivo suppression of inflammatory cytokine secretion by T cells from IBD patient colon biopsies. Proteins identified herein offer promise as novel, safe, and mechanistically differentiated biologics for treating the globally increasing burden of inflammatory diseases.

Mobile Health School Screening and Telemedicine Referral to Improve Access to Specialty Care in Rural Alaska: Integrating Mixed Methods Data to Contextualize Trial Outcomes.

OBJECTIVES: To understand factors associated with outcomes in a cluster-randomized controlled trial that evaluated a telemedicine specialty referral intervention for school hearing screenings in 15 rural Alaskan communities. DESIGN: Hearing Norton Sound was a mixed methods cluster-randomized controlled trial that compared a telemedicine specialty referral pathway (intervention) to a standard primary care referral pathway (control) for school hearing screenings. As a mixed methods trial, both quantitative and qualitative data were collected, analyzed, and integrated. Main trial results are published elsewhere, but integration of community-specific quantitative outcomes and qualitative results have not yet been reported. The constant comparative method was used to analyze qualitative data from semistructured interviews with six stakeholder groups across all 15 communities. Descriptive statistics were used to describe community-specific proportions of follow-up in both trial years. Qualitative and quantitative results were integrated to reveal relationships between contextual factors and follow-up outcomes across communities. RESULTS: The Hearing Norton Sound trial enrolled 1481 children from October 2017 to March 2019, with a total of 790 children requiring referral. Of the children who referred in the telemedicine specialty referral pathway communities (intervention), 68.5% received follow-up (268/391), compared to 32.1% (128/399) in primary care referral communities (control)(previously reported). When broken down by community, the mean proportion receiving follow-up was 75.26% (SD 22.5) and 37.9% (SD 11.4) for the telemedicine specialty referral communities and primary care referral communities, respectively. For qualitative data collection, semistructured interviews were conducted with 101 individuals between December 2018 and August 2019. Six stakeholder groups participated: elders (n = 14), parents (n = 25), children (n = 11), teachers/school staff (n = 18), principals (n = 6), and healthcare providers/clinic staff (n = 27). Six overall factors related to the outcomes of the telemedicine specialty referral pathway emerged during analysis: clinic capacity, personnel ownership and engagement, scheduling, telemedicine equipment/processes, communication, and awareness of the need for follow-up. We integrated these factors with the community-specific follow-up percentages and found associations for four of the six qualitative factors: clinic capacity, personnel ownership and engagement, communication, and awareness. An association was not seen for scheduling and telemedicine equipment/processes, which had variable relationships with the follow-up outcome. CONCLUSIONS: The Hearing Norton Sound trial demonstrated that a telemedicine specialty referral pathway can close the gap on children lost to follow up after school hearing screening. As a whole, the intervention profoundly increased the proportion of children receiving follow-up, but there was variability in outcomes within and between communities. To understand this variability, we analyzed community-specific intervention outcomes alongside community member feedback on factors related to the intervention. We identified four key factors that contributed to the success of the intervention. Attention to these factors will be essential to successful adaptation and implementation of this telemedicine specialty referral intervention and other similar interventions in future work in rural Alaska and beyond.

Community Perspectives on Hearing Loss in Rural Alaska.

OBJECTIVES: The aim of this study is to present an explanatory model of hearing loss in the Bering Strait region of Alaska in order to contextualize the results of a cluster randomized trial and propose implications for regional hearing-related health care. DESIGN: To promote ecological validity, or the generalizability of trial findings to real world experiences, qualitative methods (focus groups and interviews) were used within a mixed methods cluster randomized trial evaluating school hearing screening and follow-up processes in 15 communities in the Bering Strait region of Alaska. Focus groups were held between April and August 2017, and semistructured interviews were conducted between December 2018 and August 2019. Convenience sampling was used for six of the 11 focus groups to capture broad community feedback. Purposive sampling was used for the remaining five focus groups and for all interviews to capture a variety of experiences with hearing loss. Audio recordings of focus groups and interviews were transcribed, and both notes and transcripts were deidentified. All notes and transcripts were included in the analysis. The constant comparative method was used to develop a codebook by iteratively moving between transcripts and preliminary themes. Researchers then used this codebook to code data from all focus groups and interviews using qualitative analysis software (NVIVO 12, QSR International) and conducted thematic analyses to distill the findings presented in this article. RESULTS: Participants in focus groups (n = 116) and interviews (n = 101) shared perspectives in three domains: etiology, impact, and treatment of hearing loss. Regarding etiology, participants emphasized noise-induced hearing loss but also discussed infection-related hearing loss and various causes of ear infections. Participants described the impact of hearing loss on subsistence activities, while also detailing social, academic, and economic consequences. Participants described burdensome treatment pathways that are repetitive and often travel and time intensive. Communication breakdowns within these pathways were also described. Some participants spoke positively of increased access via onsite hearing health care services in "field clinics" as well as via telemedicine services. Others described weaknesses in these processes (infrequent field clinics and communication delays in telemedicine care pathways). Participants also described home remedies and stigma surrounding the treatment for hearing loss. CONCLUSIONS: Patient-centered health care requires an understanding of context. Explanatory models of illness are context-specific ways in which patients and their networks perceive and describe the experience of an illness or disability. In this study, we documented explanatory models of hearing loss to foster ecological validity and better understand the relevance of research findings to real-life hearing-related experiences. These findings suggest several areas that should be addressed in future implementation of hearing health care interventions elsewhere in rural Alaska, including management of repetitious treatments, awareness of infection-mediated hearing loss, mistrust, and communication breakdowns. For hearing-related health care in this region, these findings suggest localized recommendations for approaches for prevention and treatment. For community-based hearing research, this study offers an example of how qualitative methods can be used to generate ecologically valid (i.e., contextually grounded) findings.

Harnessing helminth-driven immunoregulation in the search for novel therapeutic modalities.

Parasitic helminths have coevolved with humans over millennia, intricately refining and developing an array of mechanisms to suppress or skew the host's immune system, thereby promoting their long-term survival. Some helminths, such as hookworms, cause little to no overt pathology when present in modest numbers and may even confer benefits to their human host. To exploit this evolutionary phenomenon, clinical trials of human helminth infection have been established and assessed for safety and efficacy for a range of immune dysfunction diseases and have yielded mixed outcomes. Studies of live helminth therapy in mice and larger animals have convincingly shown that helminths and their excretory/secretory products possess anti-inflammatory drug-like properties and represent an untapped pharmacopeia. These anti-inflammatory moieties include extracellular vesicles, proteins, glycans, post-translational modifications, and various metabolites. Although the concept of helminth-inspired therapies holds promise, it also presents a challenge to the drug development community, which is generally unfamiliar with foreign biologics that do not behave like antibodies. Identification and characterization of helminth molecules and vesicles and the molecular pathways they target in the host present a unique opportunity to develop tailored drugs inspired by nature that are efficacious, safe, and have minimal immunogenicity. Even so, much work remains to mine and assess this out-of-the-box therapeutic modality. Industry-based organizations need to consider long-haul investments aimed at unraveling and exploiting unique and differentiated mechanisms of action as opposed to toe-dipping entries with an eye on rapid and profitable turnarounds.

Low-dose ketamine infusions reduce opioid use in pediatric and young adult oncology patients.

BACKGROUND: Ketamine is an NMDA-receptor antagonist with analgesic and opioid-sparing properties. Although well studied in adults, more robust evidence supporting ketamine's use for pediatric pain management is needed. This retrospective study evaluates ketamine's opioid-sparing effectiveness in pediatric and young adult oncology and hematology patients. PROCEDURE: Continuous ketamine infusions administered for pain management between 2010-2020 were reviewed. Data including demographic characteristics, oncology/hematology and pain diagnoses, concurrent pain medications, and ketamine infusions' dose and duration were collected. Opioid consumption data based on delivery via patient-controlled analgesia were collected 1 day before (D1), all days during (cumulatively named D2), and 1 day after (D3) ketamine infusions and calculated as morphine-equivalent doses (mg/kg/day). Data were reported for the entire study group as well as for distinct oncology and end-of-life categories, and short-term acute pain circumstances which included vaso-occlusive crises in hematology patients. Side effects were reviewed. RESULTS: Significantly lower daily opioid consumption was noted in the oncology group, while decreases were not significant in the end-of-life group and in the overall study population. The acute pain group did not show an opioid reduction associated with the ketamine infusions. A largely tolerable side-effect profile was observed, with no differences among each group's incidence. CONCLUSIONS: Ketamine infusions were associated with significantly reduced opioid consumption for oncology patients. The opioid-sparing effects of ketamine may vary according to clinical diagnoses and circumstances of use. Overall, low-dose ketamine infusions present an acceptable safety profile in pediatric and young adult patients; nevertheless, individual risks and benefits should be considered.

Novel cholinesterase paralogs of Schistosoma mansoni have perceived roles in cholinergic signalling and drug detoxification and are essential for parasite survival.

Cholinesterase (ChE) function in schistosomes is essential for orchestration of parasite neurotransmission but has been poorly defined with respect to the molecules responsible. Interrogation of the S. mansoni genome has revealed the presence of three ChE domain-containing genes (Smche)s, which we have shown to encode two functional acetylcholinesterases (AChE)s (Smache1 -smp_154600 and Smache2 -smp_136690) and a butyrylcholinesterase (BChE) (Smbche1 -smp_125350). Antibodies to recombinant forms of each SmChE localized the proteins to the tegument of adults and schistosomula and developmental expression profiling differed among the three molecules, suggestive of functions extending beyond traditional cholinergic signaling. For the first time in schistosomes, we identified ChE enzymatic activity in fluke excretory/secretory (ES) products and, using proteomic approaches, attributed this activity to the presence of SmAChE1 and SmBChE1. Parasite survival in vitro and in vivo was significantly impaired by silencing of each smche, either individually or in combination, attesting to the essential roles of these molecules. Lastly, in the first characterization study of a BChE from helminths, evidence is provided that SmBChE1 may act as a bio-scavenger of AChE inhibitors as the addition of recombinant SmBChE1 to parasite cultures mitigated the effect of the anti-schistosome AChE inhibitor 2,2- dichlorovinyl dimethyl phosphate-dichlorvos (DDVP), whereas smbche1-silenced parasites displayed increased sensitivity to DDVP.

Phyllosphere Community Assembly and Response to Drought Stress on Common Tropical and Temperate Forage Grasses.

Grasslands represent a critical ecosystem important for global food production, soil carbon storage, and water regulation. Current intensification and expansion practices add to the degradation of grasslands and dramatically increase greenhouse gas emissions and pollution. Thus, new ways to sustain and improve their productivity are needed. Research efforts focus on the plant-leaf microbiome, or phyllosphere, because its microbial members impact ecosystem function by influencing pathogen resistance, plant hormone production, and nutrient availability through processes including nitrogen fixation. However, little is known about grassland phyllospheres and their response to environmental stress. In this study, globally dominant temperate and tropical forage grass species were grown in a greenhouse under current climate conditions and drought conditions that mimic future climate predictions to understand if (i) plant host taxa influence microbial community assembly, (ii) microbial communities respond to drought stress, and (iii) phyllosphere community changes correlate to changes in plant host traits and stress-response strategies. Community analysis using high-resolution sequencing revealed Gammaproteobacteria as the dominant bacterial class, which increased under severe drought stress on both temperate and tropical grasses while overall bacterial community diversity declined. Bacterial community diversity, structure, and response to drought were significantly different between grass species. This community dependence on plant host species correlated with differences in grass species traits, which became more defined under drought stress conditions, suggesting symbiotic evolutionary relationships between plant hosts and their associated microbial community. Further understanding these strategies and the functions microbes provide to plants will help us utilize microbes to promote agricultural and ecosystem productivity in the future. IMPORTANCE Globally important grassland ecosystems are at risk of degradation due to poor management practices compounded by predicted increases in severity and duration of drought over the next century. Finding new ways to support grassland productivity is critical to maintaining their ecological and agricultural benefits. Discerning how grassland microbial communities change in response to climate stress will help us understand how plant-microbe relationships may be useful to sustainably support grasslands in the future. In this study, phyllosphere community diversity and composition were significantly altered under drought conditions. The significance of our research is demonstrating how severe climate stress reduces bacterial community diversity, which previously was directly associated with decreased plant productivity. These findings guide future questions about functional plant-microbe interactions under stress conditions, greatly enhancing our understanding of how bacteria can increase food security by promoting grassland growth and resilience.

Maple syrup urine disease: Clinical outcomes, metabolic control, and genotypes in a screened population after four decades of newborn bloodspot screening in the Republic of Ireland.

Since 1972, 18 patients (10 females/8 males) have been detected by newborn bloodspot screening (NBS) with neonatal-onset maple syrup urine disease (MSUD) in Ireland. Patients were stratified into three clusters according to clinical outcome at the time of data collection, including developmental, clinical, and IQ data. A fourth cluster comprised of two early childhood deaths; a third patient died as an adult. We present neuroimaging and electroencephalography together with clinical and biochemical data. Incidence of MSUD (1972-2018) was 1 in 147 975. Overall good clinical outcomes were achieved with 15/18 patients alive and with essentially normal functioning (with only the lowest performing cluster lying beyond a single SD on their full scale intelligence quotient). Molecular genetic analysis revealed genotypes hitherto not reported, including a possible digenic inheritance state for the BCKDHA and DBT genes in one family. Treatment has been based on early implementation of emergency treatment, diet, close monitoring, and even dialysis in the setting of acute metabolic decompensation. A plasma leucine ≥400 µmol/L (outside therapeutic range) was more frequently observed in infancy or during adolescence, possibly due to infections, hormonal changes, or noncompliance. Children require careful management during metabolic decompensations in early childhood, and this represented a key risk period in our cohort. A high level of metabolic control can be achieved through diet with early implementation of a "sick day" regime and, in some cases, dialysis as a rescue therapy. The Irish cohort, despite largely classical phenotypes, achieved good outcomes in the NBS era, underlining the importance of early diagnosis and skilled multidisciplinary team management.

Identification and Characterization of a Peptide from the Stony Coral Heliofungia actiniformis.

Marine organisms produce a diverse range of toxins and bioactive peptides to support predation, competition, and defense. The peptide repertoires of stony corals (order Scleractinia) remain relatively understudied despite the presence of tentacles used for predation and defense that are likely to contain a range of bioactive compounds. Here, we show that a tentacle extract from the mushroom coral, Heliofungia actiniformis, contains numerous peptides with a range of molecular weights analogous to venom profiles from species such as cone snails. Using NMR spectroscopy and mass spectrometry we characterized a 12-residue peptide (Hact-1) with a new sequence (GCHYTPFGLICF) and well-defined ß-hairpin structure stabilized by a single disulfide bond. The sequence is encoded within the genome of the coral and expressed in the polyp body tissue. The structure present is common among toxins and venom peptides, but Hact-1 does not show activity against select examples of Gram-positive and Gram-negative bacteria or a range of ion channels, common properties of such peptides. Instead, it appears to have a limited effect on human peripheral blood mononuclear cells, but the ecological function of the peptide remains unknown. The discovery of this peptide from H. actiniformis is likely to be the first of many from this and related species.

Patterns of sport participation for youth with autism spectrum disorder and intellectual disability.

BACKGROUND: Little is known about sport participation in youth with Autism Spectrum Disorder (ASD). The current study examined sport characteristics (frequency, diversity, positive social experiences [PSE]) for youth with ASD and intellectual disability compared to youth with intellectual disability alone and explored the personal and contextual correlates of involvement. METHOD: Parents (N = 409) completed an online survey, and multiple mediation analyses were used to examine the factors that explained the relationships between sport involvement in youth with ASD and intellectual disability. RESULTS: No significant main effects of ASD status were found for frequency or diversity, but youth with intellectual disability alone had higher scores for PSE compared to youth with ASD and intellectual disability. Sociocommunicative abilities, coach relationship and resources mediated the relationship between ASD status and PSE. CONCLUSIONS: A better understanding of the factors related to sport is essential for allowing families, service providers and policy makers to improve involvement for youth with ASD.

Noninvasive continuous cardiac output and cerebral perfusion monitoring in term infants with neonatal encephalopathy: assessment of feasibility and reliability.

BackgroundNoninvasive hemodynamic monitoring of infants with neonatal encephalopathy (NE) undergoing therapeutic hypothermia (TH) would be a potentially useful clinical tool. We aimed to assess the feasibility and reliability of noninvasive cardiac output monitoring (NICOM) and near-infrared spectroscopy (NIRS) in this cohort.MethodsNICOM and NIRS were commenced to measure cardiac output (CO), systemic vascular resistance (SVR), blood pressure (BP), and cerebral regional oxygen saturations (SctO2) during TH and rewarming. NICOM measures of CO were also compared with simultaneous echocardiography-derived CO (echo-CO).ResultsTwenty infants with a median gestation of 40 weeks were enrolled. There was a strong correlation between NICOM- and echo-CO (r2=0.79, P<0.001). NICOM-CO was systematically lower than echo-CO with a bias of 27% (limits of agreement 3-51%). NICOM illustrated lower CO during TH, which increased during rewarming. SctO2 increased over the first 30 h of TH and stayed high for the remainder of the study. There was a rise in SVR over the first 30 h of TH and a decrease during rewarming (all P<0.05).ConclusionsNoninvasive hemodynamic assessment of infants with NE is feasible and illustrates potentially important changes. Larger studies are needed to assess the clinical applicability of those methods in this cohort.

A Mokken analysis of the literacy in musculoskeletal problems questionnaire.

BACKGROUND: Limited health literacy is known to impact on medication adherence, hospital readmission and potentially poorer health outcomes. The literature on the health literacy of those with musculoskeletal conditions suggests greater functional limitations and increased pain levels. There are a number of measures of health literacy. One that specifically relates to musculoskeletal complaints is the Literacy in Musculoskeletal Problems (LiMP) questionnaire. The LiMP contains 9 multiple choice items that cover anatomy, musculoskeletal conditions and the diagnosis of musculoskeletal complaints. The aim of the study was to evaluate the dimensionality and internal structure of the LiMP in patients attending for osteopathy care at a student-led clinic, as a potential measure of musculoskeletal health literacy. METHOD: Three hundred and sixty-one (n = 361) new patients attending the Victoria University Osteopathy Clinic completed the LiMP and a demographic and health information questionnaire prior to their initial consultation. Mokken scale analysis, a nonparametric item response theory approach, was used to evaluate the dimensionality and structure of the LiMP in this population, to ascertain whether the questionnaire was measuring a single latent construct - musculoskeletal health literacy. McDonald's omega and Cronbach's alpha were calculated as the reliability estimations. The relationship between the LiMP and a single item screen of health literacy was also undertaken. RESULTS: The 9 items on the LiMP did not form a Mokken scale and the reliability estimations were below an acceptable level (alpha and omega <0.45). LiMP items 5 and 8 were more likely to be answered correctly by those with higher health literacy (p < 0.05), however the effect sizes were small (<0.20). CONCLUSION: Calculation of a total score for the LiMP, as advocated by the original authors, is not supported based on data in the present study. Further research is required to explore the relationship of the LiMP items to demographic and clinical data, and to other broader measures of health literacy. Further research may also develop a health literacy measure that is specific to patients seeking manual therapy care for musculoskeletal complaints.

EMS Provider Perceptions on Termination of Resuscitation in a Large, Urban EMS System.

OBJECTIVE: Despite the value of out-of-hospital Termination of Resuscitation (TOR) and the scientific evidence in favor of this practice, TOR has not been uniformly adopted or consistently practiced in EMS systems. Previous focus group studies have identified multiple barriers to implementation of out of hospital TOR but existing literature on EMS provider perceptions is limited. We sought to identify EMS providers' perceived barriers to performing out-of-hospital TOR in a large urban EMS system. METHODS: The Chicago EMS System is a regional collaborative of EMS physicians, nurses and provider agencies, including the Chicago Fire Department (CFD), which provides exclusive emergency response for 9-1-1 calls in Chicago. CFD is an urban, fire-based EMS agency with a tiered response, with fire-fighter EMTs and paramedics providing initial care, and single role paramedics providing supplemental care and transport. A 2-page written survey was distributed to understand providers' experiences with managing OHCA and perceived barriers to TOR to inform subsequent improvements in protocol development and education. RESULTS: Of 3500 EMS providers that received the survey, 2309 were completed (66%). Survey respondent demographics were fire-fighter/EMTB (69%), fire-fighter/paramedic (14%), and single role paramedic (17%). The most frequent barrier to field TOR was scene safety (86%). The most common safety issue identified was family reaction to TOR (68%) and many providers felt threatened by family when trying to perform TOR (38%). Providers with a higher career numbers of OHCA were more likely to have felt threatened by the family (OR 6.70, 95% CI 2.99-15.00) and single role paramedics were more likely than FF/EMTBs to have felt threatened (OR 3.34, 95% CI 2.65-4.22). Barriers to delivering a death notification after TOR, include being uncomfortable or threatened with possible family reaction (52%) and family asking to continue the resuscitation (45%). There was lack of formal prior death notification training, the majority learned from colleagues through on the job training. CONCLUSIONS: Our study identifies scene safety, death notification delivery, and lack of formal training in death notification as barriers that EMS providers face while performing TOR in a large urban EMS system. These findings informed educational and operational initiatives to overcome the identified provider level issues and improve compliance with TOR policies.

A Pilot Randomized Controlled Trial of the Feasibility of a Multicomponent Delirium Prevention Intervention Versus Usual Care in Acute Stroke.

BACKGROUND: Delirium after acute stroke is a serious complication. Numerous studies support a benefit of multicomponent interventions in minimizing delirium-related complications in at-risk patients, but this has not been reported in acute stroke patients. The purpose of this study was to explore the feasibility of conducting a randomized (delirium care) versus usual standardized stroke care (usual care) in reducing delirium in acute stroke. OBJECTIVE: This pilot study assessed the feasibility of (1) enrollment within the 48-hour window when delirium risk is greatest, (2) measuring cognitive function using the Montreal Cognitive Assessment, (3) delivering interventions 7 days per week, and (4) determining delirium incidence in stroke-related cognitive dysfunction. METHODS: A 2-group randomized controlled trial was conducted. Patients admitted with ischemic and hemorrhagic strokes and 50 years or older, English speaking, and without delirium on admit were recruited, consented, and randomized to usual care or delirium care groups. RESULTS: Data from 125 subjects (delirium care, n = 59; usual care, n = 66) were analyzed. All Montreal Cognitive Assessment subscales were completed by 86% of subjects (delirium care, mean [SD], 18.14 [6.03]; usual care, mean [SD], 17.61 [6.29]). Subjects in the delirium care group received a mean of 6.10 therapeutic activities (range, 2-23) and daily medication review by a clinical pharmacist using anticholinergic drug calculations. Delirium incidence was 8% (10/125), 3 in the delirium care group and 7 in the usual care group. CONCLUSION: Findings support the feasibility of delivering a multicomponent delirium prevention intervention in acute stroke and warrants testing intervention effects on delirium outcomes and anticholinergic medication administration.

Understanding Special Olympics Experiences from the Athlete Perspectives Using Photo-Elicitation: A Qualitative Study.

BACKGROUND: Many individuals with intellectual disabilities experience challenges to participating in organized sport, despite its known benefits. The aim of this qualitative study was to understand the experiences of participating in sport (Special Olympics) from the perspectives of athletes with intellectual disabilities. METHODS: Five participants (13-33 years of age) took part in a photo-elicitation project during a 1-month period. RESULTS: Our thematic analysis of participant photographs and descriptions revealed the following athlete themes: 'Connectedness' and 'Training in Sport'. CONCLUSION: Photo-elicitation was a useful and important tool in assisting athlete participants to communicate their motivations to participate in sport in ways that using traditional verbal interviewing would not.

Comparisons of Allergenic and Metazoan Parasite Proteins: Allergy the Price of Immunity.

Allergic reactions can be considered as maladaptive IgE immune responses towards environmental antigens. Intriguingly, these mechanisms are observed to be very similar to those implicated in the acquisition of an important degree of immunity against metazoan parasites (helminths and arthropods) in mammalian hosts. Based on the hypothesis that IgE-mediated immune responses evolved in mammals to provide extra protection against metazoan parasites rather than to cause allergy, we predict that the environmental allergens will share key properties with the metazoan parasite antigens that are specifically targeted by IgE in infected human populations. We seek to test this prediction by examining if significant similarity exists between molecular features of allergens and helminth proteins that induce an IgE response in the human host. By employing various computational approaches, 2712 unique protein molecules that are known IgE antigens were searched against a dataset of proteins from helminths and parasitic arthropods, resulting in a comprehensive list of 2445 parasite proteins that show significant similarity through sequence and structure with allergenic proteins. Nearly half of these parasite proteins from 31 species fall within the 10 most abundant allergenic protein domain families (EF-hand, Tropomyosin, CAP, Profilin, Lipocalin, Trypsin-like serine protease, Cupin, BetV1, Expansin and Prolamin). We identified epitopic-like regions in 206 parasite proteins and present the first example of a plant protein (BetV1) that is the commonest allergen in pollen in a worm, and confirming it as the target of IgE in schistosomiasis infected humans. The identification of significant similarity, inclusive of the epitopic regions, between allergens and helminth proteins against which IgE is an observed marker of protective immunity explains the 'off-target' effects of the IgE-mediated immune system in allergy. All these findings can impact the discovery and design of molecules used in immunotherapy of allergic conditions.

One to Watch: A Germ Cell Tumor Arising in an Undescended Testicle in Rubinstein-Taybi Syndrome.

A male preterm infant was born with dysmorphic features consistent with Rubinstein-Taybi syndrome (RTS). An undescended right testicle was noted on examination. At 5 months of age he developed a palpable right-sided abdominal mass and an elevated alpha-fetoprotein. Histology revealed a malignant germ cell neoplasm arising within the undescended testis. This is the first reported case of a germ cell tumor occurring in a pediatric patient with RTS. Urologic abnormalities occur in approximately 52% of RTS patients, of which cryptorchidism is the commonest. Given the frequency of undescended testes in this population, closer screening may be warranted.

A Comprehensive Allele Specific Expression Resource for the Equine Transcriptome.

Background: Allele-specific expression (ASE) analysis provides a nuanced view of cis-regulatory mechanisms affecting gene expression. Results: An equine ASE analysis was performed, using integrated Iso-seq and short-read RNA sequencing data from four healthy Thoroughbreds (2 mares and 2 stallions) across 9 tissues from the Functional Annotation of Animal Genomes (FAANG) project. Allele expression was quantified by haplotypes from long-read data, with 42,900 allele expression events compared. Within these events, 635 (1.48%) demonstrated ASE, with liver tissue containing the highest proportion. Genetic variants within ASE events were in histone modified regions 64.2% of the time. Validation of allele-specific variants, using a set of 66 equine liver samples from multiple breeds, confirmed that 97% of variants demonstrated ASE. Conclusions: This valuable publicly accessible resource is poised to facilitate investigations into regulatory variation in equine tissues. Our results highlight the tissue-specific nature of allelic imbalance in the equine genome.