Individuals with JAK1 variants are affected by syndromic features encompassing autoimmunity, atopy, colitis, and dermatitis.

Inborn errors of immunity lead to autoimmunity, inflammation, allergy, infection, and/or malignancy. Disease-causing JAK1 gain-of-function (GoF) mutations are considered exceedingly rare and have been identified in only four families. Here, we use forward and reverse genetics to identify 59 individuals harboring one of four heterozygous JAK1 variants. In vitro and ex vivo analysis of these variants revealed hyperactive baseline and cytokine-induced STAT phosphorylation and interferon-stimulated gene (ISG) levels compared with wild-type JAK1. A systematic review of electronic health records from the BioME Biobank revealed increased likelihood of clinical presentation with autoimmunity, atopy, colitis, and/or dermatitis in JAK1 variant-positive individuals. Finally, treatment of one affected patient with severe atopic dermatitis using the JAK1/JAK2-selective inhibitor, baricitinib, resulted in clinically significant improvement. These findings suggest that individually rare JAK1 GoF variants may underlie an emerging syndrome with more common presentations of autoimmune and inflammatory disease (JAACD syndrome). More broadly, individuals who present with such conditions may benefit from genetic testing for the presence of JAK1 GoF variants.

IL4Rα and IL17A Blockade Rescue Autoinflammation in SOCS1 Haploinsufficiency.

By inhibition of JAK-STAT signaling, SOCS1 acts as a master regulator of the cytokine response across numerous tissue types and cytokine pathways. Haploinsufficiency of SOCS1 has recently emerged as a monogenic immunodysregulatory disease with marked clinical variability. Here, we describe a patient with severe dermatitis, recurrent skin infections, and psoriatic arthritis that harbors a novel heterozygous mutation in SOCS1. The variant, c.202_203delAC, generates a frameshift in SOCS1, p.Thr68fsAla*49, which leads to complete loss of protein expression. Unlike WT SOCS1, Thr68fs SOCS1 fails to inhibit JAK-STAT signaling when expressed in vitro. The peripheral immune signature from this patient was marked by a redistribution of monocyte sub-populations and hyper-responsiveness to multiple cytokines. Despite this broad hyper-response across multiple cytokine pathways in SOCS1 haploinsufficiency, the patient's clinical disease was markedly responsive to targeted IL4Rα- and IL17-blocking therapy. In accordance, the mutant allele was unable to regulate IL4Rα signaling. Further, patient cells were unresponsive to IL4/IL13 while on monoclonal antibody therapy. Together, this study reports a novel SOCS1 mutation and suggests that IL4Rα blockade may serve as an unexpected, but fruitful therapeutic target for some patients with SOCS1 haploinsufficiency.

Chimeric Peptides from Californiconus californicus and Heterodontus francisci with Antigen-Binding Capacity: A Conotoxin Scaffold to Create Non-Natural Antibodies (NoNaBodies).

Research into various proteins capable of blocking metabolic pathways has improved the detection and treatment of multiple pathologies associated with the malfunction and overexpression of different metabolites. However, antigen-binding proteins have limitations. To overcome the disadvantages of the available antigen-binding proteins, the present investigation aims to provide chimeric antigen-binding peptides by binding a complementarity-determining region 3 (CDR3) of variable domains of new antigen receptors (VNARs) with a conotoxin. Six non-natural antibodies (NoNaBodies) were obtained from the complexes of conotoxin cal14.1a with six CDR3s from the VNARs of Heterodontus francisci and two NoNaBodies from the VNARs of other shark species. The peptides cal_P98Y vs. vascular endothelial growth factor 165 (VEGF165), cal_T10 vs. transforming growth factor beta (TGF-ß), and cal_CV043 vs. carcinoembryonic antigen (CEA) showed in-silico and in vitro recognition capacity. Likewise, cal_P98Y and cal_CV043 demonstrated the capacity to neutralize the antigens for which they were designed.

Combined VNS-RNS Neuromodulation for Epilepsy.

SUMMARY: The vagus nerve stimulator (VNS) and responsive nerve stimulator (RNS) are nonpharmacological devices approved for drug-resistant epilepsy. Vagus nerve stimulator was removed before placing an RNS in clinical trials. Two cases of bilateral mesial temporal epilepsy treated concurrently with VNS and bilateral mesial temporal RNS devices were reported. In each case, the VNS device was turned off temporarily, which allowed for a direct comparison of RNS recordings and efficacy with and without simultaneous VNS stimulation. Temporary VNS cessation lead to increased clinical and electrocorticographic seizures despite continued anti-seizure drugs and RNS stimulation. In one case, VNS eliminated seizures from one epileptogenic area, whereas VNS and RNS were required to treat seizures from the contralateral mesial temporal structure. In another case, VNS effectively decreased seizure spread to the symptomatogenic zone. These cases demonstrate synergistic neuromodulation with concurrent use of VNS and RNS in intractable bitemporal epilepsy.

Ten-Week Sucralose Consumption Induces Gut Dysbiosis and Altered Glucose and Insulin Levels in Healthy Young Adults.

Sucralose consumption alters microbiome and carbohydrate metabolism in mouse models. However, there are no conclusive studies in humans. Our goals were to examine the effect of sucralose consumption on the intestinal abundance of bacterial species belonging to Actinobacteria, Bacteroidetes, and Firmicutes and explore potential associations between microbiome profiles and glucose and insulin blood levels in healthy young adults. In this open-label clinical trial, volunteers randomly drank water, as a control (n = 20), or 48 mg sucralose (n = 20), every day for ten weeks. At the beginning and the end of the study, participants were subjected to an oral glucose tolerance test (OGTT) to measure serum glucose and insulin every 15 min for 3 h and provided fecal samples to assess gut microbiota using a quantitative polymerase chain reaction. Sucralose intake altered the abundance of Firmicutes without affecting Actinobacteria or Bacteroidetes. Two-way ANOVA revealed that volunteers drinking sucralose for ten weeks showed a 3-fold increase in Blautia coccoides and a 0.66-fold decrease in Lactobacillus acidophilus compared to the controls. Sucralose consumption increased serum insulin and the area under the glucose curve compared to water. Long-term sucralose ingestion induces gut dysbiosis associated with altered insulin and glucose levels during an OGTT.

An overview of select cannabis use and supply indicators pre- and post-legalization in Canada.

BACKGROUND: Canada implemented the legalization and regulation of non-medical cannabis use, production and sale in 2018 aiming to improve public health and safety. While outcomes from legalization reforms in other jurisdictions mostly rely on US-based data have been assessed to be mixed, Canadian data are only emerging. We compiled select population-level data on key indicators to gauge initial developments from pre- to post-legalization of cannabis in Canada. METHODS: We examined indicators data focusing on the following topics: prevalence of cannabis use, frequency of use, methods/products of consumption, driving after cannabis use, and cannabis sourcing. Indicator data were obtained mostly from national and some provincial population surveys. Prevalence or percentages for the indicators pre- and post-legalization (e.g., 2017- 2020), including confidence intervals were reported, with changes noted, as available in and indicated by the data sources. RESULTS: Data suggested selected increases in cannabis use prevalence, mostly among mid- and older- but possibly also younger (e.g., under legal use age) users. Frequency of use and driving after cannabis use among active users do not appear to have changed. Methods of cannabis use show diversifying trends, with decreases in smoking and increases in alternatives use modes (e.g., edibles, vaping). There is a clearly increasing trend towards accessing cannabis from legal sources among adults, while under-legal-use-age youth do not appear to experience heightened barriers to obtaining cannabis in legalization contexts. CONCLUSIONS: Preliminary indicators on cannabis legalization in Canada show a mixed picture, some similar to US-based developments. While some use increases are observed, these do not necessarily represent indications of increases in cannabis-related harm, also since key (e.g., hospitalization or injury) data are lacking to date. There is a gradual embracing of legal supply sources of cannabis among users, which can be expected to serve public health and safety objectives. At the same time, cannabis use and access among under-age users as a principally vulnerable group do not appear to be hindered or reduced by legalization.

The Combined Use of Cytokine Serum Values with Laboratory Parameters Improves Mortality Prediction of COVID-19 Patients: The Interleukin-15-to-Albumin Ratio.

Laboratory parameters display limited accuracy in predicting mortality in coronavirus disease 2019 (COVID-19) patients, as with serum albumin. Emerging evidence suggests that cytokine serum values may enhance the predictive capacity of albumin, especially interleukin (IL)-15. We thus investigated whether the use of the IL-15-to-albumin ratio enables improving mortality prediction at hospital admission in a large group of COVID-19 patients. In this prospective cross-sectional study, we enrolled and followed up three hundred and seventy-eight patients with a COVID-19 diagnosis until hospital discharge or death. Two hundred and fifty-five patients survived, whereas one hundred and twenty-three died. Student's T-test revealed that non-survivors had a significant two-fold increase in the IL-15-to-albumin ratio compared to survivors (167.3 ± 63.8 versus 74.2 ± 28.5), a difference that was more evident than that found for IL-15 or albumin separately. Likewise, mortality prediction considerably improved when using the IL-15-to-albumin ratio with a cut-off point > 105.4, exhibiting an area under the receiver operating characteristic curve of 0.841 (95% Confidence Interval, 0.725-0.922, p < 0.001). As we outlined here, this is the first study showing that combining IL-15 serum values with albumin improves mortality prediction in COVID-19 patients.

'Resurgent', 'twin' or 'silent' epidemic? A select data overview and observations on increasing psycho-stimulant use and harms in North America.

In the early 2000s, increasing prevalence of psycho-stimulant (e.g., crack/cocaine, methamphetamine) use and related harms, including severe adverse health outcomes, was observed among - mostly marginalized - populations of persons using illicit drugs in North America, underscoring an urgent need for interventions options towards improved prevention and treatment. By about 2010, however, the 'opioid crisis', featuring unprecedented use and public health burden, had accelerated into full force in North America, largely muting attention to the psycho-stimulant issue until recently. Recent surveillance data on drug use and related mortality/morbidity from the present decade has documented a marked resurgence of psycho-stimulant use and harms especially in at-risk populations, commonly in direct combination with opioids, across North America, resulting in a 'twin epidemic' comprised of opioids and psycho-stimulants We briefly review select epidemiological data indicators for these developments from the United States and Canada; in the latter jurisdiction, related evidence has been less prevalent and systematic but corroborating the same trends. Evidently, the (widely ongoing) focus on the 'opioid epidemic' as a 'mono-type' drug problem has become an anachronism that requires urgent and appropriate correction. We then briefly consider existing, evidence-based options for - prevention and treatment - interventions targeting psycho-stimulant use and harms, which are substantially more limited and/or less efficacious than those available for problematic opioid use, while presenting major gaps and challenges. The observed resurgence of psycho-stimulants may, indirectly, relate to recent efforts towards curtailing (medical) opioid availability, thereby accelerating demand and supply for both illicit opioids and psycho-stimulants. The presently unfolding 'twin epidemic' of opioids and psycho-stimulants, combined with limited intervention resources, presents an acute challenge for public health and may crucially undermine actively extensive efforts to reduce opioid-related health harms in North America.

The Lower-Risk Cannabis Use Guidelines' (LRCUG) recommendations: How are Canadian cannabis users complying?

Canada, alongside other jurisdictions, implemented non-medical cannabis legalization in 2018, partly towards improving public health. Evidence-based 'Lower-Risk Cannabis Use Guidelines' (LRCUG), including recommendations for cannabis users on how to decrease risk-behaviors for harms, have been developed and widely disseminated in Canada since 2017. However, knowledge on users' compliance with the LRCUG is limited. We identified four major Canadian (three national, one provincial) population surveys presenting key data on cannabis-related behaviors: the National Cannabis Survey, Canadian Cannabis Survey, Canadian Tobacco, Alcohol & Drugs Survey, and CAMH Monitor. We scanned each survey for indicator data mapping onto either of the LRCUG's recommendations for the years 2017 to 2019. Relevant indicator data, albeit with varying operationalizations, were found for six of the ten LRCUG's recommendation clusters in at least some of the surveys, and were extracted and summarized. For results, substantial -- but declining -- majorities of users consumed cannabis by smoking, yet with shifts towards other use modes. Between one- to two-in-five users engaged in the risk-behaviors of using high-potency cannabis products, frequent cannabis use and cannabis-impaired driving, respectively. A small proportion of pregnant or breastfeeding women continued cannabis use during the study period. The data identified found suggested a heterogeneous picture regarding cannabis users' compliance with the LRCUG's recommendations. Non-compliance is highest for recommendations regarding modes-of-use, and applies to minorities of users for other risks factors. These sub-groups are at elevated risk for acute (e.g., accidents) or long-term (e.g., dependence) cannabis-related harms contributing to the public health burden. Appropriate targeted interventions in these areas require improvement.

Successful Detection of Unrecognized Rickettsia typhi in Pregnancy Using Cell-Free Next-Generation Sequencing.

Flea-borne (murine) typhus is caused by Rickettsia typhi. Infection in pregnant women can lead to adverse outcomes when diagnosis and treatment is delayed. We describe how next-generation sequencing (NGS) using the Karius® test was used to rapidly diagnose murine typhus in two pregnant women admitted to a large tertiary care center in Houston, Texas, when all initial testing was nondiagnostic.

'Safer opioid distribution' as an essential public health intervention for the opioid mortality crisis - Considerations, options and examples towards broad-based implementation.

•Canada experiences excessive opioid mortality, mainly from toxic opioid exposure.•Many interventions have been implemented, but are limited in reach and impact.•'Safer opioid distribution' (SOD) is a crucial preventive measure for overdose.•SOD needs to be implemented for a large, 'at-risk' opioid user population.•Other community-based public health interventions may guide SOD organization.

Induction of innate immune response in whiteleg shrimp (Litopenaeus vannamei) embryos.

The immune response of commercially relevant marine invertebrates has been extensively studied, in search of new disease-control strategies. Immune training is considered a novel approach that could help improve resistance to different pathogens. Here, we stimulated the white shrimp (Litopenaeus vannamei) during embryo development by exposure to heat-killed bacteria and evaluated their effect on hatching, larval development, and the expression of immune-related genes. In addition, we evaluated its impact on the response of shrimp nauplii during a challenge with Vibrio parahaemolyticus. We observed that the percentage of hatching and the resistance to bacterial infection increased due to the treatment of embryos with heat-killed cells of Vibrio and Bacillus. Apparently different stimuli could generate a differential pattern of gene expression, e.g., Vibrio induced a strong effector immune response whereas Bacillus elicited a protective immune profile. In addition, each response was triggered by molecular patterns detected in the environment. The results obtained in this study provide new insights for immune training to improve shrimp farming.

A CARASIL Patient from Americas with Novel Mutation and Atypical Features: Case Presentation and Literature Review.

OBJECTIVE: Reporting a novel mutation in the HTRA1 gene in a CARASIL patient from Americas. METHODS: Clinical presentation and neuroimaging were consistent with CARASIL. HTRA1 DNA sequencing was performed using advanced ("next generation") sequencing technology. The results revealed a homozygous missense mutation as c.616G>A (p.Gly206Arg) in the HTRA1 gene. RESULTS: A 24-year-old man with a history of chronic back pain presented with recurrent ischemic strokes. A diagnosis of CARASIL was made with the finding of a novel homozygous missense mutation c.616G>A in HTRA1 gene, resulting in change from Glycine to Arginine in the Serine Protease HTRA1. Brain imaging showed multiple lacunar infarcts with extensive abnormalities of the white matter that spared the external capsules. He also had unilateral decreased hearing with craniofacial asymmetry. None of the above features have been previously described in known CARASIL patients. Both parents of the proband were heterozygous for the same missense mutation. CONCLUSION: We discovered a novel missense mutation (c.616G>A) associated with a phenotype of CARASIL. This is the first genetically backed case of CARASIL in the new world. The patient's craniofacial abnormalities, including asymmetry of the head, may be related to impaired modulation of transforming growth factor-ß1, the result of loss of proteolytic activity of HTRA1. External capsules remained unaffected, despite findings of advanced changes in the rest of the cerebral white matter. Literature is briefly reviewed. The patient's history, neurological exam, neuroimaging, and genetic testing are included.