Proteoglycan inhibition of canonical BMP-dependent cartilage maturation delays endochondral ossification.

During endochondral ossification, chondrocytes secrete a proteoglycan (PG)-rich extracellular matrix that can inhibit the process of cartilage maturation, including expression of Ihh and Col10a1. Because bone morphogenetic proteins (BMPs) can promote cartilage maturation, we hypothesized that cartilage PGs normally inhibit BMP signalling. Accordingly, BMP signalling was evaluated in chondrocytes of wild-type and PG mutant (fam20b-/-) zebrafish and inhibited with temporal control using the drug DMH1 or an inducible dominant-negative BMP receptor transgene (dnBMPR). Compared with wild type, phospho-Smad1/5/9, but not phospho-p38, was increased in fam20b-/- chondrocytes, but only after they secreted PGs. Phospho-Smad1/5/9 was decreased in DMH1-treated or dnBMPR-activated wild-type chondrocytes, and DMH1 also decreased phospho-p38 levels. ihha and col10a1a were decreased in DMH1-treated or dnBMPR-activated chondrocytes, and less perichondral bone formed. Finally, early ihha and col10a1a expression and early perichondral bone formation of fam20b mutants were rescued with DMH1 treatment or dnBMPR activation. Therefore, PG inhibition of canonical BMP-dependent cartilage maturation delays endochondral ossification, and these results offer hope for the development of growth factor therapies for skeletal defects of PG diseases.

Repurposing General Anesthetic Drugs to Treat Depression: A New Frontier for Anesthesiologists in Neuropsychiatric Care.

During the last 100 years, the role of anesthesiologists in psychiatry has focused primarily on facilitating electroconvulsive therapy and mitigating postoperative delirium and other perioperative neurocognitive disorders. The discovery of the rapid and sustained antidepressant properties of ketamine, and early results suggesting that other general anesthetic drugs (including nitrous oxide, propofol, and isoflurane) have antidepressant properties, has positioned anesthesiologists at a new frontier in the treatment of neuropsychiatric disorders. Moreover, shared interest in understanding the biologic underpinnings of anesthetic drugs as psychotropic agents is eroding traditional academic boundaries between anesthesiology and psychiatry. This article presents a brief overview of anesthetic drugs as novel antidepressants and identifies promising future candidates for the treatment of depression. The authors issue a call to action and outline strategies to foster collaborations between anesthesiologists and psychiatrists as they work toward the common goals of repurposing anesthetic drugs as antidepressants and addressing mood disorders in surgical patients.

The heart of anaesthesiology: revitalising humanism in the age of technology.

Technological innovation has greatly aided modern medicine, and anaesthesiology in particular, but also contributes to dehumanising influences that promote physician burnout and dissatisfaction among patients. Here we advocate for a profound reaffirmation of humanistic principles-empathy, compassion, and communication-in perioperative medicine. We propose adaptable strategies to bolster humanism in practice, such as curricular offerings, simulation training, role modelling, and recognition. As perioperative technologies continue to evolve, the threat of depersonalisation in anaesthetic care looms, making commitments to humanism a crucial precondition for healing in the communities in which we work and live.

Cognitive deficits after general anaesthesia in animal models: a scoping review.

BACKGROUND: It remains controversial whether general anaesthetic drugs contribute to perioperative neurocognitive disorders in adult patients. Preclinical studies have generated conflicting results, likely because of differing animal models, study protocols, and measured outcomes. This scoping review of preclinical studies addressed the question: 'Do general anaesthetic drugs cause cognitive deficits in adult animals that persist after the drugs have been eliminated from the brain?' METHODS: Reports of preclinical studies in the MEDLINE database published from 1953 to 2021 were examined. A structured review process was used to assess original studies of cognitive behaviours, which were measured after treatment (≥24 h) with commonly used general anaesthetic drugs in adult animals. RESULTS: The initial search yielded 380 articles, of which 106 were fully analysed. The most frequently studied animal model was male (81%; n=86/106) rodents (n=106/106) between 2-3 months or 18-20 months of age. Volatile anaesthetic drugs were more frequently studied than injected drugs, and common outcomes were memory behaviours assessed using the Morris water maze and fear conditioning assays. Cognitive deficits were detected in 77% of studies (n=82/106) and were more frequent in studies of older animals (89%), after inhaled anaesthetics, and longer drug treatments. Limitations of the studies included a lack of physiological monitoring, mortality data, and risk of bias attributable to the absence of randomisation and blinding. CONCLUSIONS: Most studies reported cognitive deficits after general anaesthesia, with age, use of volatile anaesthetic drugs, and duration of anaesthesia as risk factors. Recommendations to improve study design and guide future research are presented.

Steering clear of Akrasia: An integrative review of self-binding Ulysses Contracts in clinical practice.

In many jurisdictions, legal frameworks afford patients the opportunity to make prospective medical decisions or to create directives that contain a special provision forfeiting their own ability to object to those decisions at a future time point, should they lose decision-making capacity. These agreements have been described with widely varying nomenclatures, including Ulysses Contracts, Odysseus Transfers, Psychiatric Advance Directives with Ulysses Clauses, and Powers of Attorney with Special Provisions. As a consequence of this terminological heterogeneity, it is challenging for healthcare providers to understand the terms and uses of these agreements and for ethicists to engage with the nuances of clinical decision-making with such unique provisions surrounding patient autonomy. In theory, prospective self-binding agreements may safeguard patient's "authentic" wishes from future "inauthentic" changes of mind. In practice, it is unclear what may be comprised within these agreements or how-and to what effect-they are used. The primary focus of this integrative review is to curate the existing literature describing Ulysses Contracts (and analogous decisions) used in the clinical arena, in order to empirically synthesize their shared essence and provide insights into the traditional components of these agreements when used in practice, the requirements of their consent processes, and the outcomes of their utilization.

Economic Evaluation Associated With Clinical-Grade Mobile App-Based Digital Therapeutic Interventions: Systematic Review.

BACKGROUND: Digital therapeutics (DTx), a class of software-based clinical interventions, are promising new technologies that can potentially prevent, manage, or treat a spectrum of medical disorders and diseases as well as deliver unprecedented portability for patients and scalability for health care providers. Their adoption and implementation were accelerated by the need for remote care during the COVID-19 pandemic, and awareness about their utility has rapidly grown among providers, payers, and regulators. Despite this, relatively little is known about the capacity of DTx to provide economic value in care. OBJECTIVE: This study aimed to systematically review and summarize the published evidence regarding the cost-effectiveness of clinical-grade mobile app-based DTx and explore the factors affecting such evaluations. METHODS: A systematic review of economic evaluations of clinical-grade mobile app-based DTx was conducted following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 guidelines. Major electronic databases, including PubMed, Cochrane Library, and Web of Science, were searched for eligible studies published from inception to October 28, 2022. Two independent reviewers evaluated the eligibility of all the retrieved articles for inclusion in the review. Methodological quality and risk of bias were assessed for each included study. RESULTS: A total of 18 studies were included in this review. Of the 18 studies, 7 (39%) were nonrandomized study-based economic evaluations, 6 (33%) were model-based evaluations, and 5 (28%) were randomized clinical trial-based evaluations. The DTx intervention subject to assessment was found to be cost-effective in 12 (67%) studies, cost saving in 5 (28%) studies, and cost-effective in 1 (6%) study in only 1 of the 3 countries where it was being deployed in the final study. Qualitative deficiencies in methodology and substantial potential for bias, including risks of performance bias and selection bias in participant recruitment, were identified in several included studies. CONCLUSIONS: This systematic review supports the thesis that DTx interventions offer potential economic benefits. However, DTx economic analyses conducted to date exhibit important methodological shortcomings that must be addressed in future evaluations to reduce the uncertainty surrounding the widespread adoption of DTx interventions. TRIAL REGISTRATION: PROSPERO International Prospective Register of Systematic Reviews CRD42022358616; https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022358616.

Cardiac Investigation Trends Among Primary Care Physicians: A Paradigm Shift.

OBJECTIVE: While numerous recent guidelines support coronary computed tomography angiography (CTA) as a first-line test for stable chest pain, it remains underutilized by primary care physicians (PCPs). We aimed to evaluate cardiac investigation ordering practices following education sessions, as well as the total number of downstream tests and time to diagnosis for patients presenting with stable chest pain. METHODS: A retrospective chart review was completed for eligible patients assessed at the Women's College Hospital Family Practice Health Centre between 2017 and 2019 following the education sessions. The outcome measures were first-choice cardiac investigation, additional downstream testing, time from presentation to first investigation, and time to final diagnosis. RESULTS: 419 patients were included in the final analysis (74.70% female; mean age 61 ± 11 years). Coronary CTA requests by PCPs increased between 2017 and 2019 (18 vs 72 tests; P < .0001). When coronary CTA was the first-line test, patients were less likely to receive additional downstream testing when compared to those receiving other first-line investigations (P < .0001). Coronary CTA was associated with longer time to diagnosis than stress echocardiography (47 ± 45 vs 27 ± 36 days; P = .0068) due to limited availability of coronary CTA appointment times. There was no significant difference in time to final diagnosis among the cardiac imaging modalities observed in the cohort (P = .0623). CONCLUSION: Utilization of coronary CTA as the first-line test for stable chest pain increased following our education sessions targeting PCPs. Coronary CTA was associated with less downstream testing compared to other non-invasive cardiac investigations.

The Effects of Dexmedetomidine on Perioperative Neurocognitive Outcomes After Cardiac Surgery: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

OBJECTIVE: The purpose of this systematic review and meta-analysis is to examine the effect of DEX on delayed dNCR (cognitive dysfunction ≥ 1 week postoperative) after cardiac surgery. BACKGROUND: DEX has salutary effects on cognitive outcomes following cardiac surgery, however, studies are limited by inconsistent assessment tools, timing, and definitions of dysfunction. It is imperative to identify accurate point estimates of effect of DEX on clinically relevant changes in cognitive function. METHODS: Randomized trials of adults undergoing cardiac surgery comparing perioperative DEX to placebo or alternate sedation and assessing cognitive function ≥ 1 week postoperative were included. Data was abstracted by three reviewers independently and in parallel according to PRISMA guidelines. The primary outcome is dNCR. To classify as dNCR, cognitive function must decrease by at least the minimal clinically important difference or accepted alternate measure (eg, Reliable Change Index ≥1.96). Bias was assessed with the Cochrane Collaboration tool. Data was pooled using a random effects model. RESULTS: Nine trials (942 participants) were included in qualitative analysis, of which seven were included in the meta-analysis of dNCR. DEX reduced the incidence of dNCR (OR 0.39, 95% CI 0.25-0.61, P < 0.0001) compared to placebo/no DEX. There was no difference in the incidence of delirium (OR 0.69, 95% CI 0.35-1.34, P = 0.27) or incidence of hemodynamic instability (OR 1.14, 95% CI 0.59-2.18, P = 0.70) associated with perioperative DEX. CONCLUSIONS: DEX reduced the incidence of dNCR 1 week after cardiac surgery. Although this meta-analysis demonstrates short term cognitive outcomes are improved after cardiac surgery with perioperative DEX, future trials examining long term cognitive outcomes, using robust cognitive assessments, and new perioperative neurocognitive disorders nomenclature with objective diagnostic criteria are necessary.

An ethical analysis of clinical triage protocols and decision-making frameworks: what do the principles of justice, freedom, and a disability rights approach demand of us?

BACKGROUND: The expectation of pandemic-induced severe resource shortages has prompted authorities to draft and update frameworks to guide clinical decision-making and patient triage. While these documents differ in scope, they share a utilitarian focus on the maximization of benefit. This utilitarian view necessarily marginalizes certain groups, in particular individuals with increased medical needs. MAIN BODY: Here, we posit that engagement with the disability critique demands that we broaden our understandings of justice and fairness in clinical decision-making and patient triage. We propose the capabilities theory, which recognizes that justice requires a range of positive capabilities/freedoms conducive to the achievement of meaningful life goals, as a means to do so. Informed by a disability rights critique of the clinical response to the pandemic, we offer direction for the construction of future clinical triage protocols which will avoid ableist biases by incorporating a broader apprehension of what it means to be human. CONCLUSION: The clinical pandemic response, codified across triage protocols, should embrace a form of justice which incorporates a vision of pluralistic human capabilities and a valuing of positive freedoms.

Clinical Outcomes of Children With Adrenocortical Carcinoma in the Context of Germline TP53 Status.

Adrenocortical carcinoma (ACC) is a rare, aggressive malignancy of the adrenal cortex. This study characterizes a single-institution cohort of children treated for ACC, and explores the relationship between clinical outcomes of ACC and germline TP53 mutation status. We performed a retrospective chart review of 23 consecutive pediatric patients with ACC treated at The Hospital for Sick Children, Toronto, Canada, between 1977 and 2017. Clinical, biochemical, radiologic, pathologic, and genetic data were collected for each patient. ACC diagnosis followed a bimodal age distribution of 0 to 6 (n=17) and 12+ (n=6) years, with a female:male ratio of 3.6:1. Ten of 20 patients tested for germline TP53 status carried a pathogenic (9) or likely pathogenic (1) variant, including all but 1 male patient. Only 3 patients died of ACC-related causes, each 5 months post-diagnosis. When treated with resection and combination chemotherapy, carriers of germline TP53 mutations may respond more favorably than their wild-type counterparts. In addition, the survival of patients reported in our cohort with high-stage ACC was appreciably greater than previously described (100.0% for stage II, 50.0% for stage III, and 42.9% for stage IV), favoring aggressive intervention in these patient populations.

Access-site complications in ultrasound-guided endovascular thrombectomy: a single-institution retrospective cohort study.

OBJECTIVE: Mechanical endovascular thrombectomy (EVT) is an increasingly relied-on treatment for clot retrieval in the context of ischemic strokes, which otherwise are associated with significant morbidity and mortality. Despite several known risks associated with this procedure, there is a high degree of technical heterogeneity across both centers and operators. The most common procedural complications occur at the point of transfemoral access (the common femoral artery), and include access-site hematomas, dissections, and pseudoaneurysms. Other interventional fields have previously popularized the use of ultrasound to enhance the anatomical localization of structures relevant to vascular access and thereby reducing access-site complications. In this study, the authors aimed to describe the ultrasound-guided EVT technique performed at a large, quaternary neurovascular referral center, and to characterize the effects of ultrasound guidance on access-site complications. METHODS: A retrospective chart review of all patients treated with EVT at a single center between January 2013 and August 2020 was performed. Patients in this cohort were treated using a universal, unique, ultrasound-guided, single-wall puncture technique, which bears several theoretical advantages over the standard technique of arterial puncture via palpation. RESULTS: There were 479 patients treated with EVT within the study period. Twenty patients in the cohort were identified as having experienced some form of access-site complication. Eight (1.67%) of these patients experienced minor access-site complications, all of which were groin hematomas and none of which were clinically significant, as defined by requiring surgical or interventional management or transfusion. The remaining 12 patients experienced arterial dissection (n = 5), arterial pseudoaneurysm (n = 4), retroperitoneal hematoma (n = 2), or arterial occlusion (n = 1), with only 1.04% (5/479) requiring surgical or interventional management or transfusion. CONCLUSIONS: The authors found an overall reduction in total access-site complications as well as minor access-site complications in the study cohort compared with previously published randomized controlled trials and observational studies in the recent literature. The findings suggested that there may be a role for routine use of ultrasound-guided puncture techniques in EVT to decrease rates of complications.

Regulating Death: A Brief History of Medical Assistance in Dying.

Unique reports of suicide and euthanasia date back more than 2 millennia, reflecting evolving philosophies of death and dying as expressions of the mores dominating a given era. One longstanding theme in the history of decisions to die has been staunch opposition founded in religious claims that one's body is a trust from the divine (and therefore not wholly in their ownership). The role of the physician has also been traditionally estranged from participation in such decisions, dating back to rudimentary conceptions of medical ethics in the Hippocratic notion primum non nocere ('first, do no harm'). However, fundamental principles in the modern philosophy of medicine lend support to the idea that physicians can be justified in actions which cause some harm, in so far as they are acting to fulfil a greater ethical imperative. This brief historical review explores the inception of modern North American medical assistance in dying (MAiD) policy through a series of critical case studies in the unfolding of its practice. Medically assisted dying has presently been legalised in Canada and some United States jurisdictions, but with critical caveats surrounding circumstances of mature minors, advance directives and mental illness as participants' sole underlying medical condition. While the modern regulations surrounding MAiD continue to take shape, the palliative care community is well-positioned to both guide and scrutinise the ethics of this practice.

Coerced consent in clinical research: study protocol for a randomized controlled trial.

BACKGROUND: Despite the low-risk nature of participation in most clinical anesthesia trials, subject recruitment on the same day as surgery is often restricted due to the concerns of researchers and local research ethics boards that same-day consent may not afford adequate time and opportunity for patients to weigh and make decisions, as well as perceptions of patient vulnerability immediately prior to surgery that could impact the voluntary nature and the rigor of the informed consent process. However, specialties such as anesthesiology, critical care, interventional radiology, and emergency medicine have a varied pattern of practice and patient acquaintance that does not typically afford the luxury of time or, in many cases, advance consent for participation in research. Indeed, the initial encounter between anesthesiologists and patients undergoing elective procedures routinely occurs on the day of surgery. Concerns of coercion related to same-day consent for clinical anesthesia research trials have not been borne out in the literature, and represent a significant obstacle to clinical researchers, as well as to the patients who are denied opportunities for potential benefit through participation in research studies. METHODS: We describe the protocol for a prospective randomized controlled trial examining the voluntariness of patient consent, solicited either in advance of surgery or on the same day, to participate in an anesthesia research study at Women's College Hospital. One hundred fourteen patients scheduled to undergo ambulatory anterior cruciate ligament repair facilitated by general anesthesia with an adductor canal block will be randomized for recruitment either (a) in the pre-operative assessment clinic before the day of surgery or (b) on the day of surgery, to be approached for consent to participate in a fabricated research study of adjunct medications in adductor canal blocks. Regardless of allocation, patients in both groups will receive the same routine standard of care and will complete a post-operative questionnaire to signal perceptions of undue influence in the process of providing informed consent for the fabricated trial. DISCUSSION: This study will inform trial design and practice guidelines surrounding the amount of time patients ought to be afforded in order to make durable decisions to participate (or not) in clinical research studies. This is expected to impact trial recruitment in a variety of clinical settings where researchers have only brief opportunities to interface with patients. TRIAL REGISTRATION: The trial was registered prospectively on the Open Science Framework (OSF), registration #46twc, on 2023-Mar-17.