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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.

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.

Canada is experiencing an epidemic of opioid-related mortality, with increasing yet heterogeneous fatality patterns from illicit/synthetic (e.g., fentanyl) opioids. The present study examined whether differential provincial reductions in medical opioid dispensing following restrictive regulations (post-2010) were associated with differential contributions of fentanyl to opioid mortality. Annual provincial opioid dispensing totals in defined daily doses/1000 population/day, and change rates in opioid dispensing for the 10 provinces for (1) 2011–2018 and (2) “peak-year” to 2018 were derived from a pan-Canadian pharmacy-based dispensing panel. Provincial contribution rates of fentanyl to opioid-related mortality (2016–2019) were averaged. Correlation values (Pearson’s R) between provincial changes in opioid dispensing and the relative fentanyl contributions to mortality were computed for the two scenarios. The correlation between province-based changes in opioid dispensing (2011–2018) and the relative contribution of fentanyl to total opioid deaths (2016–2019) was −0.70 (t = 2.75; df = 8; p = 0.03); the corresponding correlation for opioid dispensing changes (“peak-year” to 2018) was −0.59 (t = −2.06; df = 8; p = 0.07). Provincial reductions in medical opioid dispensing indicated (near-)significant correlations with fentanyl contribution rates to opioid-related death totals. Differential reductions in pharmaceutical opioid availability may have created supply voids for nonmedical use, substituted with synthetic/toxic (e.g., fentanyl) opioids and leading to accelerated opioid mortality. Implications of these possible unintended adverse consequences warrant consideration for public health policy.

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.

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.

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-β), 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.

Inborn errors of immunity (IEIs) are genetic disorders that underlie susceptibility to infection, autoimmunity, autoinflammation, allergy and/or malignancy 1 . Incomplete penetrance is common among IEIs despite their monogenic basis 2 . Here we investigate the contribution of autosomal random monoallelic expression (aRMAE), a somatic commitment to the expression of one allele 3 , 4 , to phenotypic variability observed in families with IEIs. Using a clonal primary T cell system to assess aRMAE status of genes in healthy individuals, we find that 4.30% of IEI genes and 5.20% of all genes undergo aRMAE. Perturbing H3K27me3 and DNA methylation alters allele expression commitment, in support of two proposed mechanisms 5 , 6 for the regulation of aRMAE. We tested peripheral blood mononuclear cells from individuals with IEIs with shared genetic lesions but discordant clinical phenotypes for aRMAE. Among two relatives who were heterozygous for a mutation in PLCG2 (delEx19), an antibody deficiency phenotype corresponds to selective mutant allele expression in B cells. By contrast, among relatives who were heterozygous for a mutation in JAK1 (c.2099G>A; p.S700N), the unaffected carrier T cells predominantly expressed the wild-type JAK1 allele, whereas the affected carrier T cells exhibited biallelic expression. Allelic expression bias was also documented in phenotypically discordant family members with mutations in STAT1 and CARD11 . This study highlights the importance of considering both the genotype and the ‘transcriptotype’ in analyses of the penetrance and expressivity of monogenic disorders. Somatically determined preferential allelic expression of select genes that when mutated cause inborn errors of immunity corresponds with disease phenotypes, suggesting that the penetrance and expressivity of monogenic disorders is also dependent on the ‘transcriptotype’.

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.

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.

Introduction During the 1970s and 1980s, the Golden State Killer killed a dozen people and committed at least fifty rapes in California.1 It took over 30 years for detectives to identify and arrest Joseph James DeAngelo, a former police officer, as the Golden State Killer through a new technique called investigative genetic genealogy (IGG).2 Law enforcement reportedly used the same technique in 2022 to identify Bryan Kohberger as a suspect in the now infamous Idaho college murders case.3 Use of DNA databases has been a well-accepted law enforcement practice since the creation of the Combined DNA Index System (CODIS), the United States national DNA database, in the early 1990s.4 The investigative usage of direct-to-consumer genetic testing (DTC-GT) databases, however, is significantly different from the traditional CODIS approach.5 Notably, individuals provide their DNA to DTC-GT companies to learn about their ancestry and potential health predispositions.6 DTC-GT profiles also reveal much greater information about an individual's genetic data compared to CODIS; DTC-GT companies provide law enforcement agencies access to hundreds of thousands of DNA data points while CODIS provides access to only two dozen markers.7 The DTC-GT industry has grown to include millions of profiles, thereby changing the lives of users across the country.8 With the fast development of IGG practices in law enforcement methodology, the public is becoming increasingly ill-prepared to consent to law enforcement searches of DTC-GT databases.9 This issue is compounded by how DTC-GT companies continue to be responsible for setting their own privacy protections for consumers. Typically, a person becomes interested in taking a DNA test kit to find relatives, get insights into their health, and learn whether they have genetic variants they can pass on to their future children.13 That consumer then buys a test kit from a DTC-GT company, such as 23andMe, Ancestry, or FamilyTreeDNA, and sends back a saliva sample for lab evaluation.14 Genealogists then estimate the relationships between the consumer's DNA and others in the DTC-GT database to construct a family tree.15 Afterwards, a consumer may hire a genealogist to further construct the family tree using newspaper articles, obituaries, last name origins, and the Social Security death index.16 Consumers can also upload their DNA data file to a public platform like GEDmatch to find additional matches from other testing companies.17 IGG comes into play when law enforcement finds suspect DNA at a crime scene.18 IGG is distinguishable from traditional forensic science work because it requires a type of DNA testing that state laboratories cannot perform.19 Instead, the IGG technique combines DTC-GT DNA tests with the practice of genealogy.20 After a vendor laboratory completes a thorough analysis of the DNA sample, a forensic genealogist will enter the genetic profile into a genealogy website like GEDmatch to find potential familial relationships.21 As demonstrated in recent IGG cases, these relationships may include the potential suspect's mother or second cousin.22 Upon finding relatives, police are then able to narrow down the list of suspects and reduce the overall number of innocent relatives tested for DNA comparisons.23 Importantly, law enforcement cannot arrest a suspect solely based on familial relationships and must use other leads to support probable cause for an arrest.24 According to Christi Guerrini, a leading legal and medical scholar in genomic technologies, it is more accurate to interpret IGG as an additional tool in law enforcement's arsenal for traditional investigatory work.25 Furthermore, law enforcement agencies can use IGG to revive investigations that have gone cold, including at least 100,000 unsolved major violent crimes and 40,000 unidentified bodies in the United States alone.26 And, in tandem, IGG also has the potential to exonerate wrongfully convicted individuals.27 For the first time, in 2019, genetic genealogists exonerated an incarcerated person: [...]there is currently little regulation regarding the practice of IGG or these DTC-GT companies.34 Privacy Concerns Lack of Consumer Consent Many legal scholars argue that individuals upload their genetic information to websites like GEDmatch to find distant relatives, not to solve crimes.35 Some users choose to keep their GEDmatch profiles private for this very reason.36 They argue that even if a DNA match could assist law enforcement efforts, they do not want to be a \"genetic informant\" for a relative.37 A 2020 Consumer Reports survey supports this sentiment:38 24% of respondents who had not taken a DTC-GT DNA test were worried about the privacy of their data or genetic material.39 Additionally, 25% reported being \"extremely concerned\" about how DTC-GT companies protect the privacy of their consumers.40 Interestingly, a 2019 Pews Research Center survey suggests that approximately 48% of Americans say it is acceptable for DTC-GT companies to share consumers' DNA with law enforcement to assist with investigations.41 In fact, the aftermath of the Golden State Killer case suggests that many users do want to be genetic informants against their distant relatives.42 When it became public that investigators used GEDmatch to find the Golden State Killer, the founders worried that thousands of people would delete their accounts.43 Instead, a GEDmatch founder reported that they received \"5,000 new uploads to the site shortly after Mr. DeAngelo's arrest-a daily record. According to Ellen Clayton, a professor of law at Vanderbilt Law School, when DNA becomes available to DTC-GT companies, DNA loses any protection afforded to it by existing privacy laws.50 Consequently, there is a possibility of the misuse of DNA by downstream actors, including law enforcement officers conducting surreptitious testing for criminal investigations.51 DNA analysis is not perfect, and it can result in mistakenly implicating someone in a crime.52 For example, in 2014, Michael Usry, Jr., lived in a constant state of anxiety for a month when an IGG search linked him to a murder he did not commit.53 Law enforcement pointed to circumstantial evidence, including the fact that he was a filmmaker who made films involving homicide plotlines, and close familial markers to identify Usry as a suspect.54 Ultimately, Usry's DNA did not match the crime scene sample.55 Nonetheless, his case serves as a prime example of how IGG searches can