A framework for automated conflict detection and resolution in medical guidelines.

Common chronic conditions are routinely treated following standardised procedures known as clinical guidelines. For patients suffering from two or more chronic conditions, known as multimorbidity, several guidelines have to be applied simultaneously, which may lead to severe adverse effects when the combined recommendations and prescribed medications are inconsistent or incomplete. This paper presents an automated formal framework to detect, highlight and resolve conflicts in the treatments used for patients with multimorbidities focusing on medications. The presented extended framework has a front-end which takes guidelines captured in a standard modelling language and returns the visualisation of the detected conflicts as well as suggested alternative treatments. Internally, the guidelines are transformed into formal models capturing the possible unfoldings of the guidelines. The back-end takes the formal models associated with multiple guidelines and checks their correctness with a theorem prover, and inherent inconsistencies with a constraint solver. Key to our approach is the use of an optimising constraint solver which enables us to search for the best solution that resolves/minimises conflicts according to medication efficacy and the degree of severity in case of harmful combinations, also taking into account their temporal overlapping. The approach is illustrated throughout with a real medical example.

Sry requires a CAG repeat domain for male sex determination in Mus musculus.

SRY, the mammalian Y-chromosomal sex-determining gene, encodes a protein characterized by a DNA-binding and -bending domain referred to as the HMG box. Despite the pivotal role of this gene, only the HMG box region has been conserved through evolution, suggesting that SRY function depends solely on the HMG box and therefore acts as an architectural transcription factor. In mice (genus Mus) Sry also includes a large CAG trinucleotide repeat region encoding a carboxy-terminal glutamine-rich domain that acts as a transcriptional trans-activator in vitro. The absence of this or any other potential trans-activating domain in other mammals, however, has raised doubts as to its biological relevance. To test directly whether the glutamine-rich region is required for Sry function in vivo, we created truncation mutations of the Mus musculus musculus Sry gene and tested their ability to induce testis formation in XX embryos using a transgenic mouse assay. Sry constructs that encode proteins lacking the glutamine-rich region were unable to effect male sex determination, in contrast to their wild-type counterparts. We conclude that the glutamine-rich repeat domain of the mouse Sry protein has an essential role in sex determination in vivo, and that Sry may act via a fundamentally different biochemical mechanism in mice compared with other mammals.

Expression of a linear Sry transcript in the mouse genital ridge.

Sry is the Y-chromosomal gene that is pivotal in the determination of sex in mammals, however the structure of the Sry transcript produced in the embryo has not been determined. We show here that the transcript expressed in the developing mouse gonad at the sex determining stage of development is linear, polyadenylated and encoded by a single exon, in contrast to the circular, apparently untranslated transcript produced in adult testes. The linear transcript was not detected in any other fetal tissue nor in any adult tissue tested, and was expressed only in the genital ridge portion of the urogenital ridge. The spatial and temporal profile of Sry expression suggests that its role in the mouse fetus is limited to initiating Sertoli cell development during testis determination.

Spatial proximity and access to buprenorphine or methadone treatment for opioid use disorder in a sample of people misusing opioids in Southern California.

BACKGROUND: In response to the opioid crisis, over the last 10 years substantial strides have been made to increase the availability of evidence-based treatments for opioid use disorder, in particular buprenorphine maintenance, in the United States. Despite these worthwhile efforts, uptake rates of evidence-based treatment remain relatively low. As part of a broader study of opioid misuse, we examined proximity to evidence-based treatment as a potential barrier to treatment access. METHODS: In 2017-2018, we surveyed 218 individuals misusing prescription opioids or using street opioids in three Southern Californian counties. The study calculated driving distance from place of residence to the closest treatment provider offering buprenorphine or methadone treatment for opioid use disorders. RESULTS: Median distance to providers was 3.8 km (2.4 miles). Seventy one (33%) participants had received some form of treatment in the last 3 months; however, only 26 (40%) of these had received buprenorphine or methadone maintenance treatment. Participants receiving treatment at the time of their interview were traveling an average 16.8 km (10.4 miles) to reach treatment, indicating that as a group this population was both willing and able to seek and engage with treatment. CONCLUSIONS: In the suburban and exurban communities in which our study was based, our findings suggest that simple physical proximity to providers of evidence-based treatment for opioid use disorder is no longer a critical barrier. Other barriers to uptake of buprenorphine or methadone maintenance treatment clearly remain and need to be addressed. DISCLAIMER: Findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

Emerging synthetic cannabinoids detected by a drug checking service in Toronto, Canada.

BACKGROUND: Toronto's Drug Checking Service (DCS) provides people who use drugs with information on the chemical composition of their substances and conducts real-time monitoring of the unregulated drug supply. Presented are first known data of three newly detected synthetic cannabinoids (SCs) in Toronto, Ontario. METHODS: The present data are from samples analyzed between April and November 2020. Samples were collected at partnering harm reduction agencies in Toronto and analyzed using gas or liquid chromatography-mass spectrometry. An intake survey queried about the sample characteristics on submission, including expected drug(s). RESULTS: Samples were analyzed between 1 April and 20 November 2020 (N = 19), which marks the period immediately following imposed COVID-19 border and movement restrictions in Canada. The newly detected, unexpected SCs were ACHMINACA (n = 15), AB-FUBINACA (n = 3), and 4-fluoro-MDMB-BUTINACA (n = 1). Fentanyl was expected in 74% (n = 14). Most SCs were detected in samples containing fentanyl or related analogues (n = 18; 95%), or benzodiazepine-related drugs (i.e., etizolam and flualprazolam) (n = 15; 79%). CONCLUSIONS: This information can inform overdose prevention efforts and drug market monitoring of SCs in Toronto and regions served by the same drug trafficking routes. The detection of SCs during a period marked by COVID-19-related restrictions can contribute to efforts to identify global drug market trends during this time.

Antihypertensive effectiveness of aliskiren for the 'real-world' management of hypertension: multilevel modelling of 180-day blood pressure outcomes (the Belgian DRIVER Study).

AIMS: The 'DRIVER' study was designed to investigate the 'real-world' effectiveness of aliskiren-based treatment of hypertension. This article reports the 180-day blood pressure (BP) outcomes, and the multilevel (physician- and patient-level) determinants thereof. METHODS AND RESULTS: DRIVER was a prospective, observational, open-label, multi-centre, pharmaco-epidemiologic study of hypertensive patients treated with aliskiren in whom prior treatment failed or was not tolerated. 2070 patients (enrolled by 426 physicians) were enrolled; 1695 patients (81.9%) completed the 180-day aliskiren treatment period. Mean patient age was 64.2 ± 12.1 years; 53.7% were men, 25.3% diabetic and 40.7% had a high or very high cardiovascular (CV) risk. At 180 days, the mean ± SD reductions in systolic and diastolic BP were -22.9 ± 16.7 mmHg and -10.5 ± 10.9 mmHg respectively (both p < .001). 2007 and 2009 guideline-defined BP control was achieved in 36.4% and 56.3% of patients, respectively (both p < .001). 64.2% of eligible patients had a reduction in CV risk (p < .001). A physician-level class effect was responsible for 22.8% and 28.1% of variability in systolic and diastolic BP, respectively, for 20.1% of variability in BP control, and for 16.1% of variability in the reduction of CV risk. Both patient- (e.g. adherence) and physician-related factors (e.g. age and knowledge) were significant in profiling best response to treatment with aliskiren. Adverse events reported in this article were consistent with the aliskiren scientific leaflet. CONCLUSION: Aliskiren is safe and effective in reducing BP, improving BP control and reducing global CV risk in a 'real-world' setting and for patients in whom prior treatment failed or was not tolerated. Optimising treatment adherence and strategic medical education may be ways of improving BP outcomes in patients with hypertension.

"I wanted to close the chapter completely and I feel like that [carrying naloxone] would keep it open a little bit": Refusal to carry naloxone among newly-abstinent opioid users and 12-step identity.

BACKGROUND: 12-step programs aim to address drug-related harms, like opioid overdose, via abstinence. However, abstaining from opioids can diminish tolerance, which increases risk for overdose death upon resumption. A recent study found that desire to abstain from drugs inhibited willingness to participate in take-home naloxone programming, which was linked to perceptions of harm reduction strategies being tied to drug use. In the present study, we uncovered a similar phenomenon occurring among newly-abstinent participants who were refusing to carry naloxone. METHODS: This study is an analysis of broader qualitative data collected throughout Southern California among persons who use opioids, including those recently abstinent. Preliminary analysis revealed that those newly abstinent refused to accept naloxone at the end of interviews, and so we began probing about this (N=44). We used thematic analysis and author positionality to explicate the emergent phenomenon and applied social identity theory to conceptualize findings. RESULTS: Mechanisms underlying naloxone refusal included its tie to a drug-using identity that newly-abstinent participants were attempting to retire. Carrying naloxone was also viewed as pointless due to doubt of witnessing an overdose again. Furthermore, the thought of being equipped with naloxone was not believed to be congruent with an abstinent identity, e.g. "me carrying it [naloxone] is making me feel like I'm going to be hanging out with people that are doing it [using drugs]." CONCLUSION: Recent detoxification heightens vulnerability to overdose, which other newly-abstinent peers might be positioned to respond to as bonds are formed through 12-step identity formation. However, naloxone is often refused by this group due to perceived 12-step identity clash. While some treatment spaces distribute naloxone, 12-step identity associated behavioral expectations appear to conflict with this strategy. Reframing these disconnects is essential for expanding the lifesaving naloxone community safety net.

Comparison of acid- versus heat-treatment for immune complex dissociation and detection of Dirofilaria immitis antigen in canine plasma.

Annual antigen testing is a mainstay for diagnosing infection with Dirofiliaria immitis in dogs; yet, it has been documented that some heartworm-infected dogs and cats test false-negative for antigen due to the presence of antigen-antibody complexes. Several studies have reported the use of heat as a reliable means of immune-complex dissociation (ICD) in recent years; however, the data regarding the use of acid as a reliable method of ICD for D. immitis detection are limited. The objective of this study was to compare an acid-based form of ICD to the more established and evaluated method of heat-based ICD in experimentally infected and non-infected dogs. Plasma from class A dogs experimentally infected ∼4 months prior with D. immitis (infected; n = 24) and dogs reared indoors with no history of exposure to mosquitoes (non-infected; n = 75) were evaluated for presence of D. immitis antigen (DiroCHEK® Heartworm antigen test kit). Each sample was divided into three aliquots for testing: [1] Control plasma (no acid- or heat-treatment), [2] acid-treated plasma (trichloroacetic acid (TCA), incubation, centrifugation for 5 min at 16,000 X g, buffer), and [3] heat-treated plasma (104 °C followed by centrifugation at 16,000 X g). Treatments for each aliquot were performed and tested in triplicate; results were determined both visually (color change) and by spectrophotometric analysis (optical density [OD] value). Of the 24 infected dogs, 0/24 tested positive for antigen in the absence of acid- or heat-treatment. Those same plasma samples following processing by either acid- or heat-treatment yielded 18/24 (75.0%) and 19/24 (79.2%) antigen-positive results, respectively. Of the 75 plasma samples from non-infected dogs, neither acid- nor heat-treatment of plasma caused any false-positive color changes or spectrophotometric values. These results indicate that acid as a means of ICD reliably allowed for the detection of D. immitis antigen in infected plasma while not inducing false-positive results in non-infected plasma samples.

"Generally, you get 86'ed because you're a liability": An application of Integrated Threat Theory to frequently witnessed overdoses and social distancing responses.

While rates of opioid overdose deaths in North American have increased exponentially in recent years, most overdoses are not fatal, especially when witnesses are present and can intervene. Previous research has found that some people who use drugs [PWUDs] trained in overdose response might cut social ties with frequent overdosers, leading to more solitary opioid use and risk of death if someone overdoses alone. To examine the phenomenon of social distancing of people who overdose frequently, we used data from fifty-two in-depth qualitative interviews collected in Southern California with PWUDs who had recently witnessed an opioid overdose. Transcripts were reviewed and coded thematically, using the Integrated Threat Theory (ITT) to conceptualize the observed phenomenon. ITT outlines how realistic and symbolic threats are experienced by a group. We found that while some participants acknowledged the role of adulterated street drugs in overdoses, individualized blame was nonetheless imposed. Accusations of careless drug use practices fostered negative stereotyping towards frequent overdosers. This was attributed to the need to summon 911 for rescue, which often resulted in police dispatch. The intergroup relationship between police and PWUDs is precarious as police pose realistic threats onto PWUDs - such as incarceration, eviction, and manslaughter charges - leading to intragroup anxiety among PWUDs about future overdose events, and labelled frequent overdosers as liabilities. These threats, and inter/intra-group conflict, explained one reason how and why non-fatal overdoses led to social distancing events. People who overdose frequently were also accused of breaking the norm of drug user surreptitiousness; a symbolic threat that endangered the group due to police exposure. Social distancing might dampen exposure to the protective effect of peer-led interventions such as take-home naloxone programs, increasing risk of overdose death. This phenomenon highlights how intergroup dynamics are driving intragroup processes. Suggestions for tailoring public health interventions are discussed.

Transitioning from pharmaceutical opioids: A discrete-time survival analysis of heroin initiation in suburban/exurban communities.

INTRODUCTION: Research identifying pathways to heroin use has typically been conducted among urban populations. This study examined heroin initiation following pharmaceutical opioid use in three suburban/exurban Southern California counties. METHODS: Interviewer-administered surveys collected data among 330 participants (65.9 % male; 63.9 % non-Hispanic white) whose initial use of any opioid was a pharmaceutical opioid. Retrospective discrete-time survival analysis identified predictors of heroin initiation, measured as self-reported age of first heroin use. RESULTS: Median age of first pharmaceutical opioid use was 17 years; 50.6 % initially acquired pharmaceutical opioids from an illicit source, 56.7 % first used pharmaceutical opioids for recreational purposes, and 86 % initiated heroin use. Average time from first pharmaceutical opioid use to first heroin use was 8.2 years. Drug/alcohol treatment (adjusted Hazard Ratio [aHR]: 0.67, 95 % CI: 0.50, 0.88) was associated with delayed time to heroin initiation. Obtaining opioids from non-medical sources (aHR: 2.21, 95 % CI: 1.55, 3.14) was associated with accelerated time to heroin initiation. Reporting supply problems with obtaining pharmaceutical opioids (e.g., unable to acquire pharmaceutical opioids) was associated with accelerated time to heroin initiation, but the magnitude of this effect was dependent on one's history of methamphetamine use (p < 0.05). CONCLUSIONS: Time to heroin initiation following pharmaceutical opioid use was accelerated among those reporting supply problems and delayed among those with exposure to substance use treatment. Interventions interrupting supply of opioids might benefit from coordination with evidence-based medication-assisted treatment to minimize the risk of transitioning to heroin use, particularly among those with a long history of non-prescribed pharmaceutical opioid use.

Mice null for sox18 are viable and display a mild coat defect.

We have previously shown that Sox18 is expressed in developing vascular endothelium and hair follicles during mouse embryogenesis and that point mutations in Sox18 are the underlying cause of cardiovascular and hair follicle defects in ragged (Ra) mice. Here we describe the analysis of Sox18(-/-) mice produced by gene targeting. Despite the profound defects seen in Ra mice, Sox18(-/-) mice have no obvious cardiovascular defects and only a mild coat defect with a reduced proportion of zigzag hairs. A reduction in the amount of pheomelanin pigmentation in hair shafts was also observed; later-forming hair follicles showed a reduced subapical pheomelanin band, giving Sox18(-/-) mice a slightly darker appearance than Sox18(+/+) and Sox18(+/-) siblings. Sox18(-/-) mice are viable and fertile and show no difference in the ability to thrive relative to littermates. Because of the mild effect of the mutation on the phenotype of Sox18(-/-) mice, we conclude that the semidominant nature of the Ra mutations is due to a trans-dominant negative effect mediated by the mutant SOX18 proteins rather than haploinsufficiency as has been observed for other SOX genes. Due to the similarity of SOX18 to other subgroup F SOX proteins, SOX7 and -17, and the overlap in expression of these genes, functional redundancy amongst these SOX proteins could also account for the mild phenotype of Sox18(-/-) mice.

Rapid discrimination of Echinococcus species and strains using a polymerase chain reaction-based RFLP method.

Echinococcus species and genetically distinct strains of Echinococcus granulosus can be rapidly and reliably identified using a polymerase chain reaction (PCR)-linked restriction fragment length polymorphism (RFLP) method which surveys the sequence of a rapidly evolving region of the ribosomal DNA (rDNA) unit. Internal transcribed spacer 1 (ITS1) of the rDNA repeat was amplified from various isolates and the product was digested with one of a number of 4-base cutting restriction enzymes. Characteristic patterns were produced when samples within various species and strain groups were analysed. This method offers an objective, simple, highly sensitive and rapid approach for the discrimination of Echinococcus isolates and for study of other parasite complexes.

Genetic variants within the genus Echinococcus identified by mitochondrial DNA sequencing.

The pattern of species and strain variation within the genus Echinococcus is complex and controversial. In an attempt to characterise objectively the various species and strains, the sequence of a region of the mitochondrial cytochrome c oxidase subunit I (CO1) gene was determined for 56 Echinococcus isolates. Eleven different genotypes were detected, including 7 within Echinococcus granulosus, and these were used to categorise the isolates. The 4 generally accepted Echinococcus species were clearly distinguishable using this approach. In addition, the consensus view of the strain pattern within E. granulosus, based on a variety of criteria of differentiation, was broadly upheld. Very little variation was detected within Echinococcus multilocularis. Remarkable intra-strain homogeneity was found at the DNA sequence level. This region of the rapidly evolving mitochondrial genome is useful as a marker of species and strain identity and as a preliminary indication of evolutionary divergence within the genus Echinococcus.

Dppa3 is a marker of pluripotency and has a human homologue that is expressed in germ cell tumours.

We identified a transcript named 11M2 on the basis of its strong male-specific expression pattern in the developing mouse gonad. 11M2 was found to be expressed by gonad primordial germ cells (PGCs) of both sexes and down-regulated in female PGCs as they enter prophase I of the first meiotic division, similar to the expression of OCT4. Mouse EST analysis revealed expression only in early-stage embryos, embryonic stem cells and pre-meiotic germ cells. 11M2 corresponds to a recently reported gene variously known as PGC7, STELLA or DPPA3. We have identified the human orthologue of DPPA3 and find by human EST analysis that it is expressed in human testicular germ cell tumours but not in normal human somatic tissues. The expression patterns of mouse and human DPPA3, in undifferentiated embryonic cells, embryonic germ cells and adult germ cell tumours, together suggest a role for this gene in maintaining cell pluripotentiality.

NADH dehydrogenase 1 gene sequences compared for species and strains of the genus Echinococcus.

Nucleotide sequences of a 471 bp region of the mitochondrial NADH dehydrogenase 1 gene were obtained for 59 Echinococcus isolates including representatives of each of the 4 recognised species. Ten distinct genotypes were detected among these isolates, including 6 within E. granulosus. This information complements and extends knowledge of inter- and intraspecific variation within Echinococcus and should prove useful in phylogenetic studies.

Molecular genetic approaches to parasite identification: their value in diagnostic parasitology and systematics.

A wide range of approaches is available to parasitologists to aid in specific parasite identification and to formulate phylogenetic relationships. This review emphasises the usefulness of molecular genetic techniques, especially DNA-based procedures, in addressing problems of identification, characterisation and phylogeny of parasites. It should be stressed that an understanding of the various DNA approaches, techniques and target genes most likely to be effective in addressing key issues in diagnostic parasitology and systematics is still developing. Nevertheless, DNA methods clearly have great potential with regard to specificity and sensitivity, and applications will increase further with technological advance. Indeed, because of the minimal requirements for material, PCR-based methods especially should prove of immense value in future studies with parasites.

A reconsideration of the Echinococcus granulosus strain situation in Australia following RFLP analysis of cystic material.

Restriction fragment length polymorphism (RFLP) analysis, previously shown to be a relatively simple and reproducible method for distinguishing discrete strains of E. granulosus, could not discriminate between E. granulosus originating from central Queensland macropod marsupials, Australian mainland sheep or United Kingdom sheep. Furthermore, sheep cyst material from Tasmania and the Australian mainland was indistinguishable using this approach. As a result of this DNA analysis, the existence of three distinct strains of E. granulosus in Australia, previously described on the basis of morphological, biochemical and developmental differences, may require re-evaluation.

Genetic characterization of the Asian Taenia, a newly described taeniid cestode of humans.

Recent studies on the epidemiologic pattern of taeniasis in Southeast Asia have indicated the existence of a third form of human Taenia, distinguishable from Taenia saginata and T. solium. Originally termed Taiwan Taenia, and first described in Taiwanese aboriginals, this newly recognized taeniid is now generally referred to as Asian Taenia since it has since been recorded in a number of other Asian countries. Here we have used a genetic yardstick approach to determine whether the Asian Taenia should most appropriately be considered as a new, distinct species or as a subspecies, strain, or variant of T. saginata, which previous studies have shown it closely resembles. Sequence variation in the 28S rRNA and mitochondrial cytochrome c oxidase I (COI) genes of a range of taeniid cestodes and the COI and rDNA internal transcribed spacer I polymerase chain reaction (PCR) restriction fragment length polymorphism (RFLP) pattern differences in the Asian Taenia, T. saginata, and T. solium were used as markers of genetic identity. The PCR-RFLP approaches proved useful for rapid and unambiguous discrimination of Asian Taenia from the other two human species, whereas the mitochondrial and nuclear sequence comparisons indicate that the Asian Taenia is much more closely related to T. saginata than recognized taeniid species are to each other. The results support earlier conclusions that the Asian Taenia is a genetically distinct entity but is closely related to T. saginata, and suggest that its taxonomic classification as a subspecies or strain of T. saginata is more appropriate than formal designation as a new species. The very close relationship between Asian Taenia and T. saginata has public health implications in that the Asian form is unlikely to be an important cause of human cysticercosis because T. saginata cysticercosis, if it occurs at all in humans, is an extremely rare phenomenon.

Molecular examination of the sympatry and distribution of sheep and camel strains of Echinococcus granulosus in Kenya.

Previous studies have shown that camel and sheep strains of the cystic hydatid parasite Echinococcus granulosus occur in Kenya. We examined 208 larval isolates and 40 worm samples of E. granulosus from various hosts in Kenya using restriction fragment length polymorphism analysis of a segment of ribosomal DNA amplified by the polymerase chain reaction. This was in an effort to determine whether additional strains of E. granulosus occur in Kenya, to examine the level of genetic heterogeneity within the sheep/dog and camel/dog strains previously identified, and to map out their intermediate host range and geographic distribution in Kenya. We confirmed the existence of the two strains in Kenya and showed that the distribution of the camel strain appears restricted to the Turkana region, where camels are kept as livestock. The intermediate host range for both strains seems to be similar except that humans appear refractory to infection with the camel strain. We have also shown that although the life-cycle patterns of the two strains overlap both geographically and in intermediate and definitive hosts, the strains maintain their homogeneous genetic identity.