LSD increases sleep duration the night after microdosing.

Microdosing psychedelic drugs at a level below the threshold to induce hallucinations is an increasingly common lifestyle practice. However, the effects of microdosing on sleep have not been previously reported. Here, we report results from a Phase 1 randomized controlled trial in which 80 healthy adult male volunteers received a 6-week course of either LSD (10 µg) or placebo with doses self-administered every third day. Participants used a commercially available sleep/activity tracker for the duration of the trial. Data from 3231 nights of sleep showed that on the night after microdosing, participants in the LSD group slept an extra 24.3 min per night (95% Confidence Interval 10.3-38.3 min) compared to placebo-with no reductions of sleep observed on the dosing day itself. There were no changes in the proportion of time spent in various sleep stages or in participant physical activity. These results show a clear modification of the physiological sleep requirements in healthy male volunteers who microdose LSD. The clear, clinically significant changes in objective measurements of sleep observed are difficult to explain as a placebo effect. Trial registration: Australian New Zealand Clinical Trials Registry: A randomized, double-blind, placebo-controlled trial of repeated microdoses of lysergic acid diethylamide (LSD) in healthy volunteers; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=381476 ; ACTRN12621000436875.

Development of an integrated milestone assessment tool across multiple early-adopter programs for breaking bad news: a pilot project.

BACKGROUND: The transition of the Accreditation Council for Graduate Medical Education (ACGME) to milestone assessment creates opportunities for collaboration and shared assessments across graduate medical programs. Breaking bad news is an essential communication skill that is a common milestone across almost every medical specialty. The purpose of this study was to develop and pilot an integrated milestone assessment (IMA) tool for breaking bad news using ACGME milestone criteria and to compare the IMA tool with the existing SPIKES protocol. METHODS: The IMA tool was created using sub-anchors in professionalism and interpersonal communication skills that are applicable to every specialty and to the ability to break bad news. Two cases of breaking bad news, designed to be "easy" and "intermediate" in difficulty, were used to assess basic skills in breaking bad news in first-year medical residents from six residency specialties. Eight standardized patients were trained to portray the cases in sessions held in November 2013 and May 2014. Standardized patients completed an assessment checklist to evaluate each resident's performance in breaking bad news based on their use of the SPIKES protocol and IMA tool. Residents answered post-encounter questions about their training and comfort in breaking bad news. The association between SPIKES and IMA scores was investigated by simple linear regression models and Spearman rank correlations. RESULTS: There were 136 eligible medical residents: 108 (79.4%) participated in the first session and 97 (71.3%) participated in the second session, with 96 (70.6%) residents participating in both sessions. Overall, we were able to identify residents that performed at both extremes of the assessment criteria using the integrated milestone assessment (IMA) and the SPIKES protocol. Interestingly, residents rated themselves below "comfortable" on average. CONCLUSION: We developed an integrated milestone assessment (IMA) that was better than the SPIKES protocol at assessing the skill of breaking bad news. This collaborative assessment tool can be used as supplement tool in the era of milestone transformation. We aim assess our tool in other specialties and institutions, as well as assess other shared milestones across specialties.

A longitudinal field study of commercial honey bees shows that non-native probiotics do not rescue antibiotic treatment, and are generally not beneficial.

Probiotics are widely used in agriculture including commercial beekeeping, but there is little evidence supporting their effectiveness. Antibiotic treatments can greatly distort the gut microbiome, reducing its protective abilities and facilitating the growth of antibiotic resistant pathogens. Commercial beekeepers regularly apply antibiotics to combat bacterial infections, often followed by an application of non-native probiotics advertised to ease the impact of antibiotic-induced gut dysbiosis. We tested whether probiotics affect the gut microbiome or disease prevalence, or rescue the negative effects of antibiotic induced gut dysbiosis. We found no difference in the gut microbiome or disease markers by probiotic application or antibiotic recovery associated with probiotic treatment. A colony-level application of the antibiotics oxytetracycline and tylosin produced an immediate decrease in gut microbiome size, and over the longer-term, very different and persistent dysbiotic effects on the composition and membership of the hindgut microbiome. Our results demonstrate the lack of probiotic effect or antibiotic rescue, detail the duration and character of dysbiotic states resulting from different antibiotics, and highlight the importance of the gut microbiome for honeybee health.

A dominance of Mu class glutathione transferases within the equine tapeworm Anoplocephala perfoliata.

The most common equine tapeworm, Anoplocephala perfoliata, has often been neglected amongst molecular investigations and has been faced with limited treatment options. However, the recent release of a transcriptome dataset has now provided opportunities for in-depth analysis of A. perfoliata protein expression. Here, global, and sub-proteomic approaches were utilized to provide a comprehensive characterization of the A. perfoliata soluble glutathione transferases (GST) (ApGST). Utilizing both bioinformatics and gel-based proteomics, GeLC and 2D-SDS PAGE, the A. perfoliata 'GST-ome' was observed to be dominated with Mu class GST representatives. In addition, both Sigma and Omega class GSTs were identified, albeit to a lesser extent and absent from affinity chromatography approaches. Moreover, 51 ApGSTs were localized across somatic (47 GSTs), extracellular vesicles (EVs) (Whole: 1 GST, Surface: 2 GSTs) and EV depleted excretory secretory product (ESP) (9 GSTs) proteomes. In related helminths, GSTs have shown promise as novel anthelmintic or vaccine targets for improved helminth control. Thus, provides potential targets for understanding A. perfoliata novel infection mechanisms, host­parasite relationships and anthelmintic treatments.

An open-label pilot trial assessing tolerability and feasibility of LSD microdosing in patients with major depressive disorder (LSDDEP1).

BACKGROUND: Globally, an estimated 260 million people suffer from depression [1], and there is a clear need for the development of new, alternative antidepressant therapies. In light of problems with the tolerability and efficacy of available treatments [2], a global trend is emerging for patients to self-treat depression with microdoses of psychedelic drugs such as lysergic acid diethylamide (LSD) and psilocybin [3]. Beyond anecdotal reports from those who self-medicate in this way, few clinical trials have evaluated this practice. In our recently published phase 1 study in healthy volunteers [4], we determined that LSD microdosing was relatively safe and well tolerated in that cohort. Furthermore, the data demonstrated that conducting such microdosing trials is broadly feasible, with excellent adherence and compliance to the regimen observed. In this open-label pilot trial of patients with major depressive disorder (LSDDEP1), we will test the tolerability and feasibility of an 8-week regimen of LSD microdosing in this patient group prior to a larger subsequent randomised controlled trial (LSDDEP2). METHODS: Twenty patients meeting the DSM-5 criteria for major depressive disorder will receive an 8-week LSD microdosing treatment regimen. The treatment protocol will use a sublingual formulation of LSD (MB-22001) delivered twice per week under a titration schedule using a dose of 5-15 µg. Tolerability will be assessed by quantifying the percentage of participants who withdraw from the trial due to adverse events attributable to the treatment regimen, while feasibility will be assessed by quantifying the percentage of attended clinic visits once enrolled. To determine whether there is any antidepressant response to the LSD microdosing regimen, MADRS scores will be assessed at baseline and 2, 4, 6, and 8 weeks after the commencement of the regimen. DISCUSSION: The results of LSDDEP1 will provide valuable information regarding the tolerability and feasibility of a proposed LSD microdosing regimen in patients with MDD. Such information is critically important to optimise trial design prior to commencing a subsequent and more resource-intensive randomised controlled trial. TRIAL REGISTRATION: ANZCTR, ACTRN12623000486628. Registered on 12 May 2023.

Law enforcement information gathering in the emergency department: Legal and ethical background and practical approaches.

In the course of legal investigations, law enforcement officers may enlist emergency department (ED) personnel to gather information or forensic evidence, often with the intent of building cases against a patient. These situations create ethical conflicts between the emergency physician's obligations to the patient and society. This paper provides an overview of the ethical and legal considerations in ED forensic evidence collection and the general principles that emergency physicians should apply in these situations.

Evidence of Immune Modulators in the Secretome of the Equine Tapeworm Anoplocephala perfoliata.

Anoplocephala perfoliata is a neglected gastro-intestinal tapeworm, commonly infecting horses worldwide. Molecular investigation of A. perfoliata is hampered by a lack of tools to better understand the host-parasite interface. This interface is likely influenced by parasite derived immune modulators released in the secretome as free proteins or components of extracellular vesicles (EVs). Therefore, adult RNA was sequenced and de novo assembled to generate the first A. perfoliata transcriptome. In addition, excretory secretory products (ESP) from adult A. perfoliata were collected and EVs isolated using size exclusion chromatography, prior to proteomic analysis of the EVs, the EV surface and EV depleted ESP. Transcriptome analysis revealed 454 sequences homologous to known helminth immune modulators including two novel Sigma class GSTs, five α-HSP90s, and three α-enolases with isoforms of all three observed within the proteomic analysis of the secretome. Furthermore, secretome proteomics identified common helminth proteins across each sample with known EV markers, such as annexins and tetraspanins, observed in EV fractions. Importantly, 49 of the 454 putative immune modulators were identified across the secretome proteomics contained within and on the surface of EVs in addition to those identified in free ESP. This work provides the molecular tools for A. perfoliata to reveal key players in the host-parasite interaction within the horse host.

Modulation of Rumen Microbes Through Extracellular Vesicle Released by the Rumen Fluke Calicophoron daubneyi.

Parasite derived extracellular vesicles (EVs) have been proposed to play key roles in the establishment and maintenance of infection. Calicophoron daubneyi is a newly emerging parasite of livestock with many aspects of its underpinning biology yet to be resolved. This research is the first in-depth investigation of EVs released by adult C. daubneyi. EVs were successfully isolated using both differential centrifugation and size exclusion chromatography (SEC), and morphologically characterized though transmission electron microscopy (TEM). EV protein components were characterized using a GeLC approach allowing the elucidation of comprehensive proteomic profiles for both their soluble protein cargo and surface membrane bound proteins yielding a total of 378 soluble proteins identified. Notably, EVs contained Sigma-class GST and cathepsin L and B proteases, which have previously been described in immune modulation and successful establishment of parasitic flatworm infections. SEC purified C. daubneyi EVs were observed to modulate rumen bacterial populations by likely increasing microbial species diversity via antimicrobial activity. This data indicates EVs released from adult C. daubneyi have a role in establishment within the rumen through the regulation of microbial populations offering new routes to control rumen fluke infection and to develop molecular strategies to improve rumen efficiency.

Ethical issues and obligations with undocumented immigrants relying on emergency departments for dialysis.

Undocumented immigrants with end-stage renal disease in the United States are uniquely disadvantaged in their ability to access dialysis. This article examines the unique circumstances of the medical condition and healthcare system, including the relevant legal and regulatory influences that largely relegate undocumented immigrants to relying on emergency-only dialysis through a hospital's Emergency Medical Treatment and Labor Act obligations. We explore the ethical implications of this current state, emphasizing the adverse effects on patients and staff alike. We also review necessary actions that range from the actions an individual emergency physician to changes needed in federal policy.

Is it safer at the beach? Spatial and temporal analyses of beachgoer behaviors during the COVID-19 pandemic.

Tourism localities worldwide continue to grapple with how best to sustain coastal visitation during the COVID-19 pandemic. Emerging epidemiological science illustrates the risk of disease transmission is lower outdoors than indoors, and exposure is likely lower in outdoor, coastal environments due to dispersion and dilution of respiratory droplets through regular air flow. That said, it remains unclear how beachgoer behavior affects the likelihood of disease transmission. During summer 2020, we analyzed publicly-available beachcam video data and collected unmanned aerial vehicle (UAV) imagery at the recreational beach oceanfront in Virginia Beach, U.S.A. Data were collected over 24 days, documenting tourists' and recreationists' behaviors related to the public health guidance from the U.S. Centers for Disease Control, Commonwealth of Virginia Department of Public Health and City of Virginia Beach. Specifically, using a sample test area of beach and adjoining boardwalk, we investigated diurnal patterns of beach and boardwalk use, the location and density of use, as well as the presence of face coverings (i.e., masks) on boardwalk users. Results from beachcam analyses indicate a curvilinear trend in beach use, peaking in the mid-afternoon, while boardwalk use remained consistent throughout the day. Beachcam observations were corroborated by UAV photography and spatial analysis, indicating concentrated use of the beach adjoining shoreline above high tide, with onethird of the landward adjacent upper beach vacant. Among boardwalk pedestrians, few (8.7%) were observed wearing facial coverings. These findings point to both indirect and direct strategies coastal managers can implement to communicate when, where, and how to reduce the potential for transmission while accessing beach amenities during the COVID-19 pandemic.

Compositional cyber-physical epidemiology of COVID-19.

The COVID-19 pandemic has posed significant challenges globally. Countries have adopted different strategies with varying degrees of success. Epidemiologists are studying the impact of government actions using scenario analysis. However, the interactions between the government policy and the disease dynamics are not formally captured. We, for the first time, formally study the interaction between the disease dynamics, which is modelled as a physical process, and the government policy, which is modelled as the adjoining controller. Our approach enables compositionality, where either the plant or the controller could be replaced by an alternative model. Our work is inspired by the engineering approach for the design of Cyber-Physical Systems. Consequently, we term the new framework Compositional Cyber-Physical Epidemiology. We created different classes of controllers and applied these to control the disease in New Zealand and Italy. Our controllers closely follow government decisions based on their published data. We not only reproduce the pandemic progression faithfully in New Zealand and Italy but also show the tradeoffs produced by differing control actions.

Polyomic tools for an emerging livestock parasite, the rumen fluke Calicophoron daubneyi; identifying shifts in rumen functionality.

BACKGROUND: Diseases caused by parasitic flatworms of rumen tissues (paramphistomosis) are a significant threat to global food security as a cause of morbidity and mortality in ruminant livestock in subtropical and tropical climates. Calicophoron daubneyi is currently the only paramphistome species commonly infecting ruminant livestock in temperate European climates. However, recorded incidences of C. daubneyi infection in European livestock have been increasing over the last decade. Whilst clinical paramphistomosis caused by adult worms has not been confirmed in Europe, fatalities have been attributed to severe haemorrhagic enteritis of the small intestine resulting from the migration of immature paramphistomes. Large numbers of mature adults can reside in the rumen, yet to date, the impact on rumen fermentation, and consequently on productivity and economic management of infected livestock, have not been resolved. Limited publicly available nucleotide and protein sequences for C. daubneyi underpin this lack of biological and economic understanding. Here we present for the first time a de novo assembled transcriptome, with functional annotations, for adult C. daubneyi, which provides a reference database for protein and nucleotide sequence identification to facilitate fundamental biology, anthelmintic, vaccine and diagnostics discoveries. RESULTS: This dataset identifies a number of genes potentially unique to C. daubneyi and, by comparison to an existing transcriptome for the related Paramphistomum cervi, identifies novel genes which may be unique to the paramphistome group of platyhelminthes. Additionally, we present the first coverage of the excretory/secretory and soluble somatic proteome profiles for adult C. daubneyi and identify the release of extracellular vesicles from adult C. daubneyi parasites during in vitro, ex-host culture. Finally, we have performed the first analysis of rumen fluke impacting upon rumen fermentation parameters using an in vitro gas production study resulting in a significant increase in propionate production. CONCLUSIONS: The resulting data provide a discovery platform (transcriptome, proteomes, EV isolation pipeline and in vitro fermentation system) to further study C. daubneyi-host interaction. In addition, the acetate: propionate ratio has been demonstrated to decrease with rumen fluke infection suggesting that acidotic conditions in the rumen may occur.

A Parametric Computational Model of the Action Potential of Pacemaker Cells.

OBJECTIVE: A flexible, efficient, and verifiable pacemaker cell model is essential to the design of real-time virtual hearts that can be used for closed-loop validation of cardiac devices. A new parametric model of pacemaker action potential is developed to address this need. METHODS: The action potential phases are modeled using hybrid automaton with one piecewise-linear continuous variable. The model can capture rate-dependent dynamics, such as action potential duration restitution, conduction velocity restitution, and overdrive suppression by incorporating nonlinear update functions. Simulated dynamics of the model compared well with previous models and clinical data. CONCLUSION: The results show that the parametric model can reproduce the electrophysiological dynamics of a variety of pacemaker cells, such as sinoatrial node, atrioventricular node, and the His-Purkinje system, under varying cardiac conditions. SIGNIFICANCE: This is an important contribution toward closed-loop validation of cardiac devices using real-time heart models.

An intracardiac electrogram model to bridge virtual hearts and implantable cardiac devices.

Virtual heart models have been proposed to enhance the safety of implantable cardiac devices through closed loop validation. To communicate with a virtual heart, devices have been driven by cardiac signals at specific sites. As a result, only the action potentials of these sites are sensed. However, the real device implanted in the heart will sense a complex combination of near and far-field extracellular potential signals. Therefore many device functions, such as blanking periods and refractory periods, are designed to handle these unexpected signals. To represent these signals, we develop an intracardiac electrogram (IEGM) model as an interface between the virtual heart and the device. The model can capture not only the local excitation but also far-field signals and pacing afterpotentials. Moreover, the sensing controller can specify unipolar or bipolar electrogram (EGM) sensing configurations and introduce various oversensing and undersensing modes. The simulation results show that the model is able to reproduce clinically observed sensing problems, which significantly extends the capabilities of the virtual heart model in the context of device validation.

The Photovoltaic Heat Island Effect: Larger solar power plants increase local temperatures.

While photovoltaic (PV) renewable energy production has surged, concerns remain about whether or not PV power plants induce a "heat island" (PVHI) effect, much like the increase in ambient temperatures relative to wildlands generates an Urban Heat Island effect in cities. Transitions to PV plants alter the way that incoming energy is reflected back to the atmosphere or absorbed, stored, and reradiated because PV plants change the albedo, vegetation, and structure of the terrain. Prior work on the PVHI has been mostly theoretical or based upon simulated models. Furthermore, past empirical work has been limited in scope to a single biome. Because there are still large uncertainties surrounding the potential for a PHVI effect, we examined the PVHI empirically with experiments that spanned three biomes. We found temperatures over a PV plant were regularly 3-4 °C warmer than wildlands at night, which is in direct contrast to other studies based on models that suggested that PV systems should decrease ambient temperatures. Deducing the underlying cause and scale of the PVHI effect and identifying mitigation strategies are key in supporting decision-making regarding PV development, particularly in semiarid landscapes, which are among the most likely for large-scale PV installations.

Navigating Ethical Conflicts Between Advance Directives and Surrogate Decision-Makers' Interpretations of Patient Wishes.

There is little guidance on what clinicians should do when advance directives (or living wills, specifically) are challenged, particularly when surrogate decision-makers' interpretations of patients' wishes conflict with the living will. In our commentary, we make a controversial argument suggesting that overriding living wills can be ethically preferable to the alternative of strictly adhering to them. We propose four ethical considerations for determining whether it is ethically supportable to override living wills.

Ethical Issues in Emergency Psychiatry.

The care of patients with a psychiatric emergency is fraught with ethical challenges. Applying ethical reasoning to clinical challenges may help to improve care. Emergency providers should assess decision-making capacity using 4 criteria: communication, understanding, appreciation, and reasoning. Maintaining patient confidentiality is a strong imperative for emergency physicians and should be protected unless compelling additional concerns take precedence. The goal of involuntary treatment should be to protect patients from harm that they would not be exposed to were they capable of autonomous decision making, not dangerous, or not impaired by their psychiatric illness using the least restrictive means possible.

"Systematizing" ethics consultation services.

While valuable work has been done addressing clinical ethics within established healthcare systems, we anticipate that the projected growth in acquisitions of community hospitals and facilities by large tertiary hospitals will impact the field of clinical ethics and the day-to-day responsibilities of clinical ethicists in ways that have yet to be explored. Toward the goal of providing clinical ethicists guidance on a range of issues that they may encounter in the systematization process, we discuss key considerations and potential challenges in implementing system-wide ethics consultation services. Specifically, we identify four models for organizing, developing, and enhancing ethics consultation activities within a system created through acquisitions: (1) train-the-trainer, (2) local capacity-building, (3) circuit-riding, and (4) consolidated accountability. We note each model's benefits and challenges. To our knowledge, this is the first paper to consider the broader landscape of issues affected by consolidation. We anticipate that clinical ethicists, volunteer consultants, and hospital administrators will benefit from our recommendations.