Drug Legalization: The Importance of Asking the Right Question Symposium on Drug Decriminalization

As a policy analysis, this article\u27s central argument is that that the costs imposed by markets in licit psychoactives are significantly greater than those imposed by drug prohibition

Affine and Projective Tree Metric Theorems

The tree metric theorem provides a combinatorial four-point condition that characterizes dissimilarity maps derived from pairwise compatible split systems. A related weaker four point condition characterizes dissimilarity maps derived from circular split systems known as Kalmanson metrics. The tree metric theorem was first discovered in the context of phylogenetics and forms the basis of many tree reconstruction algorithms, whereas Kalmanson metrics were first considered by computer scientists, and are notable in that they are a non-trivial class of metrics for which the traveling salesman problem is tractable. We present a unifying framework for these theorems based on combinatorial structures that are used for graph planarity testing. These are (projective) PC-trees, and their affine analogs, PQ-trees. In the projective case, we generalize a number of concepts from clustering theory, including hierarchies, pyramids, ultrametrics, and Robinsonian matrices, and the theorems that relate them. As with tree metrics and ultrametrics, the link between PC-trees and PQ-trees is established via the Gromov product

Sometimes you have to take the person and show them how : adapting behavioral activation for peer recovery specialist-delivery to improve methadone treatment retention

BACKGROUND: Despite efficacy of medication for opioid use disorder, low-income, ethno-racial minoritized populations often experience poor opioid use disorder treatment outcomes. Peer recovery specialists, individuals with lived experience of substance use and recovery, are well-positioned to engage hard-to-reach patients in treatment for opioid use disorder. Traditionally, peer recovery specialists have focused on bridging to care rather than delivering interventions. This study builds on research in other low-resource contexts that has explored peer delivery of evidence-based interventions, such as behavioral activation, to expand access to care. METHODS: We sought feedback on the feasibility and acceptability of a peer recovery specialist-delivered behavioral activation intervention supporting retention in methadone treatment by increasing positive reinforcement. We recruited patients and staff at a community-based methadone treatment center and peer recovery specialist working across Baltimore City, Maryland, USA. Semi-structured interviews and focus groups inquired about the feasibility and acceptability of behavioral activation, recommendations for adaptation, and acceptability of working with a peer alongside methadone treatment. RESULTS: Participants (N = 32) shared that peer recovery specialist-delivered behavioral activation could be feasible and acceptable with adaptations. They described common challenges associated with unstructured time, for which behavioral activation could be particularly relevant. Participants provided examples of how a peer-delivered intervention could fit well in the context of methadone treatment, emphasizing the importance of flexibility and specific peer qualities. CONCLUSIONS: Improving medication for opioid use disorder outcomes is a national priority that must be met with cost-effective, sustainable strategies to support individuals in treatment. Findings will guide adaptation of a peer recovery specialist-delivered behavioral activation intervention to improve methadone treatment retention for underserved, ethno-racial minoritized individuals living with opioid use disorder

5. The PROTECT Trial: A Cluster Randomized Clinical Trial of Universal Decolonization with Chlorhexidine and Nasal Povidone Iodine Versus Standard of Care for Prevention of Infections and Hospital Readmissions among Nursing Home Residents

Abstract Background Nursing home (NH) residents are at high infection and hospital readmission risk. Colonization with multidrug-resistant organisms (MDROs) is common. In ICU and post-hospital discharge settings, decolonization has reduced infection rates. However, the effectiveness of this strategy in NHs is unclear. Methods We performed a cluster randomized trial of 1:1 universal decolonization (decol) vs standard of care bathing (control) in 28 California NHs. After an 18 month baseline evaluation of hospitalization rates due to infection and MDRO prevalence, NHs were randomized to decol or control. Decol consisted of 1) chlorhexidine bathing; 2) nasal povidone iodine bid on admission x 5d and then M-F biweekly x 18 mo. Primary outcome was the probability that a transfer to a hospital was due to infection. Secondary outcome was the probability that a NH discharge was to a hospital. Results Four of 28 NHs dropped from the trial (3 decol, 1 control). Mean facility baseline of hospital transfers due to infection was 58% and 57% in the control and decol groups. In the intervention period, proportions were 57% and 48% in the control and decol groups. When accounting for clustering within NHs, hospital transfers due to infection had an OR of 0.91 (95% CI: 0.82-1.02) in the control group and an OR of 0.73 (95% CI: 0.56-0.95) in the decol group when comparing intervention to baseline period. For the primary outcome, decol had a 18% greater impact v. control (P=0.005, Fig. A). Baseline proportion of NH discharges due to hospitalization was 37% and 39% in the control and decol groups. In the intervention period, proportions were 36% and 33%. When accounting for clustering within NHs, the proportion of discharges due to hospitalization had an OR of 1.14 (95% CI: 1.06-1.22) in the control group and 0.91 (CI: 0.77-1.07) in the decol group when comparing the intervention period to the baseline period. For the secondary outcome, decol had a 23% greater impact v. control (P< 0.0001, Fig. B). In this figure, each nursing home is represented by a circle. The size of the circle represents the amount of contributed patient days to the trial. The groups represent “as randomized” categories. Panel A) compares the probability that a transfer to a hospital was due to infection; panel B) compares the probability that a nursing home discharge was to a hospital. The y-axis represents the odds ratio of these probabilities comparing the baseline to the intervention period. The p values represent the significance of the difference between groups (the trial effect). Conclusion Universal NH decolonization with chlorhexidine and nasal iodophor significantly reduced the proportion of transfers to hospitals due to infection and discharges due to hospitalization. Our findings suggest that NH decolonization reduces serious infections and can decrease morbidity in this vulnerable population. Disclosures Loren G. Miller, MD, MPH, Medline (Grant/Research Support, Other Financial or Material Support, Contributed product) Stryker (Other Financial or Material Support, Contributed product) Xttrium (Other Financial or Material Support, Contributed product) James A. McKinnell, MD, Medline (Grant/Research Support) Raveena Singh, MA, Medline (Other Financial or Material Support, Conducted studies in which participating hospitals and nursing homes received contributed antiseptic and cleaning products) Stryker (Sage) (Other Financial or Material Support, Conducted studies in which participating hospitals and nursing homes received contributed antiseptic products) Xttrium (Other Financial or Material Support, Conducted studies in which participating hospitals and nursing homes received contributed antiseptic products) Gabrielle Gussin, MS, Medline (Other Financial or Material Support, Conducted studies in which participating hospitals and nursing homes received contributed antiseptic and cleaning products) Stryker (Sage) (Other Financial or Material Support, Conducted studies in which participating hospitals and nursing homes received contributed antiseptic products) Xttrium (Other Financial or Material Support, Conducted studies in which participating hospitals and nursing homes received contributed antiseptic products) Ken Kleinman, PhD, Medline (Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic products) Molnlycke (Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic products) Raheeb Saavedra, AS, Medline (Other Financial or Material Support, Conducted studies in which participating hospitals and nursing homes received contributed antiseptic and cleaning products) Stryker (Sage) (Other Financial or Material Support, Conducted studies in which participating hospitals and nursing homes received contributed antiseptic products) Xttrium (Other Financial or Material Support, Conducted studies in which participating hospitals and nursing homes received contributed antiseptic products) Lauren Heim, MPH, Medline (Other Financial or Material Support, Conducted clinical trials and studies in which participating hospitals and nursing homes received contributed antiseptic and cleaning products) Molnlycke (Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic product) Stryker (Sage) (Other Financial or Material Support, Conducted clinical trials and studies in which participating hospitals and nursing homes received contributed antiseptic product) Xttrium (Other Financial or Material Support, Conducted clinical trials and studies in which participating hospitals and nursing homes received contributed antiseptic product) Shruti K. Gohil, MD, MPH, Medline (Other Financial or Material Support, Co-Investigator in studies in which participating hospitals and nursing homes received contributed antiseptic and cleaning products) Molnycke (Other Financial or Material Support, Co-Investigator in studies in which participating hospitals and nursing homes received contributed antiseptic and cleaning products) Stryker (Sage) (Other Financial or Material Support, Co-Investigator in studies in which participating hospitals and nursing homes received contributed antiseptic and cleaning products) Susan S. Huang, MD, MPH, Medline (Other Financial or Material Support, Conducted studies in which participating hospitals and nursing homes received contributed antiseptic and cleaning products) Molnlycke (Other Financial or Material Support, Conducted studies in which participating hospitals and nursing homes received contributed antiseptic and cleaning products) Stryker (Sage) (Other Financial or Material Support, Conducted studies in which participating hospitals and nursing homes received contributed antiseptic and cleaning products)Xttrium (Other Financial or Material Support, Conducted studies in which participating hospitals and nursing homes received contributed antiseptic and cleaning products

The effect of LRRK2 loss-of-function variants in humans

Analysis of large genomic datasets, including gnomAD, reveals that partial LRRK2 loss of function is not strongly associated with diseases, serving as an example of how human genetics can be leveraged for target validation in drug discovery. Human genetic variants predicted to cause loss-of-function of protein-coding genes (pLoF variants) provide natural in vivo models of human gene inactivation and can be valuable indicators of gene function and the potential toxicity of therapeutic inhibitors targeting these genes(1,2). Gain-of-kinase-function variants in LRRK2 are known to significantly increase the risk of Parkinson's disease(3,4), suggesting that inhibition of LRRK2 kinase activity is a promising therapeutic strategy. While preclinical studies in model organisms have raised some on-target toxicity concerns(5-8), the biological consequences of LRRK2 inhibition have not been well characterized in humans. Here, we systematically analyze pLoF variants in LRRK2 observed across 141,456 individuals sequenced in the Genome Aggregation Database (gnomAD)(9), 49,960 exome-sequenced individuals from the UK Biobank and over 4 million participants in the 23andMe genotyped dataset. After stringent variant curation, we identify 1,455 individuals with high-confidence pLoF variants in LRRK2. Experimental validation of three variants, combined with previous work(10), confirmed reduced protein levels in 82.5% of our cohort. We show that heterozygous pLoF variants in LRRK2 reduce LRRK2 protein levels but that these are not strongly associated with any specific phenotype or disease state. Our results demonstrate the value of large-scale genomic databases and phenotyping of human loss-of-function carriers for target validation in drug discovery.Peer reviewe

Polygenic prediction of educational attainment within and between families from genome-wide association analyses in 3 million individuals

Publisher Copyright: © 2022, The Author(s).We conduct a genome-wide association study (GWAS) of educational attainment (EA) in a sample of ~3 million individuals and identify 3,952 approximately uncorrelated genome-wide-significant single-nucleotide polymorphisms (SNPs). A genome-wide polygenic predictor, or polygenic index (PGI), explains 12–16% of EA variance and contributes to risk prediction for ten diseases. Direct effects (i.e., controlling for parental PGIs) explain roughly half the PGI’s magnitude of association with EA and other phenotypes. The correlation between mate-pair PGIs is far too large to be consistent with phenotypic assortment alone, implying additional assortment on PGI-associated factors. In an additional GWAS of dominance deviations from the additive model, we identify no genome-wide-significant SNPs, and a separate X-chromosome additive GWAS identifies 57.Peer reviewe

Molecular and Physiological Changes in the SpaceX Inspiration4 Civilian Crew

Human spaceflight has historically been managed by government agencies, such as in the NASA Twins Study1, but new commercial spaceflight opportunities have opened spaceflight to a broader population. In 2021, the SpaceX Inspiration4 mission launched the first all-civilian crew to low Earth orbit, which included the youngest American astronaut (aged 29), new in-flight experimental technologies (handheld ultrasound imaging, smartwatch wearables and immune profiling), ocular alignment measurements and new protocols for in-depth, multi-omic molecular and cellular profiling. Here we report the primary findings from the 3-day spaceflight mission, which induced a broad range of physiological and stress responses, neurovestibular changes indexed by ocular misalignment, and altered neurocognitive functioning, some of which match those of long-term spaceflight2, but almost all of which did not differ from baseline (pre-flight) after return to Earth. Overall, these preliminary civilian spaceflight data suggest that short-duration missions do not pose a significant health risk, and moreover present a rich opportunity to measure the earliest phases of adaptation to spaceflight in the human body at anatomical, cellular, physiological and cognitive levels. Finally, these methods and results lay the foundation for an open, rapidly expanding biomedical database for astronauts3, which can inform countermeasure development for both private and government-sponsored space missions

Genome-wide association and epidemiological analyses reveal common genetic origins between uterine leiomyomata and endometriosis

Abstract: Uterine leiomyomata (UL) are the most common neoplasms of the female reproductive tract and primary cause for hysterectomy, leading to considerable morbidity and high economic burden. Here we conduct a GWAS meta-analysis in 35,474 cases and 267,505 female controls of European ancestry, identifying eight novel genome-wide significant (P < 5 × 10−8) loci, in addition to confirming 21 previously reported loci, including multiple independent signals at 10 loci. Phenotypic stratification of UL by heavy menstrual bleeding in 3409 cases and 199,171 female controls reveals genome-wide significant associations at three of the 29 UL loci: 5p15.33 (TERT), 5q35.2 (FGFR4) and 11q22.3 (ATM). Four loci identified in the meta-analysis are also associated with endometriosis risk; an epidemiological meta-analysis across 402,868 women suggests at least a doubling of risk for UL diagnosis among those with a history of endometriosis. These findings increase our understanding of genetic contribution and biology underlying UL development, and suggest overlapping genetic origins with endometriosis

Functional illness in primary care: dysfunction versus disease

<p>Abstract</p> <p>Background</p> <p>The Biopsychosocial Model aims to integrate the biological, psychological and social components of illness, but integration is difficult in practice, particularly when patients consult with medically unexplained physical symptoms or functional illness.</p> <p>Discussion</p> <p>This Biopsychosocial Model was developed from General Systems Theory, which describes nature as a dynamic order of interacting parts and processes, from molecular to societal. Despite such conceptual progress, the biological, psychological, social and spiritual components of illness are seldom managed as an integrated whole in conventional medical practice. This is because the biomedical model can be easier to use, clinicians often have difficulty relinquishing a disease-centred approach to diagnosis, and either dismiss illness when pathology has been excluded, or explain all undifferentiated illness in terms of psychosocial factors. By contrast, traditional and complementary treatment systems describe reversible functional disturbances, and appear better at integrating the different components of illness. Conventional medicine retains the advantage of scientific method and an expanding evidence base, but needs to more effectively integrate psychosocial factors into assessment and management, notably of 'functional' illness. As an aid to integration, pathology characterised by structural change in tissues and organs is contrasted with dysfunction arising from disordered physiology or psychology that may occur independent of pathological change.</p> <p>Summary</p> <p>We propose a classification of illness that includes orthogonal dimensions of pathology and dysfunction to support a broadly based clinical approach to patients; adoption of which may lead to fewer inappropriate investigations and secondary care referrals and greater use of cognitive behavioural techniques, particularly when managing functional illness.</p