FeNi2 S4 -A Potent Bifunctional Efficient Electrocatalyst for the Overall Electrochemical Water Splitting in Alkaline Electrolyte.

For a carbon-neutral society, the production of hydrogen as a clean fuel through water electrolysis is currently of great interest. Since water electrolysis is a laborious energetic reaction, it requires high energy to maintain efficient and sustainable production of hydrogen. Catalytic electrodes can reduce the required energy and minimize production costs. In this context, herein, a bifunctional electrocatalyst made from iron nickel sulfide (FeNi2 S4 [FNS]) for the overall electrochemical water splitting is introduced. Compared to Fe2 NiO4 (FNO), FNS shows a significantly improved performance toward both OER and HER in alkaline electrolytes. At the same time, the FNS electrode exhibits high activity toward the overall electrochemical water splitting, achieving a current density of 10 mA cm-2 at 1.63 V, which is favourable compared to previously published nonprecious electrocatalysts for overall water splitting. The long-term chronopotentiometry test reveals an activation followed by a subsequent stable overall cell potential at around 2.12 V for 20 h at 100 mA cm-2 .

Mental health and addiction health service use by physicians compared to non-physicians before and during the COVID-19 pandemic: A population-based cohort study in Ontario, Canada.

BACKGROUND: The Coronavirus Disease 2019 (COVID-19) pandemic has exacerbated mental health challenges among physicians and non-physicians. However, it is unclear if the worsening mental health among physicians is due to specific occupational stressors, reflective of general societal stressors during the pandemic, or a combination. We evaluated the difference in mental health and addictions health service use between physicians and non-physicians, before and during the COVID-19 pandemic. METHODS AND FINDINGS: We conducted a population-based cohort study in Ontario, Canada between March 11, 2017 and August 11, 2021 using data collected from Ontario's universal health system. Physicians were identified using registrations with the College of Physicians and Surgeons of Ontario between 1990 and 2020. Participants included 41,814 physicians and 12,054,070 non-physicians. We compared the first 18 months of the COVID-19 pandemic (March 11, 2020 to August 11, 2021) to the period before COVID-19 pandemic (March 11, 2017 to February 11, 2020). The primary outcome was mental health and addiction outpatient visits overall and subdivided into virtual versus in-person, psychiatrists versus family medicine and general practice clinicians. We used generalized estimating equations for the analyses. Pre-pandemic, after adjustment for age and sex, physicians had higher rates of psychiatry visits (aIRR 3.91 95% CI 3.55 to 4.30) and lower rates of family medicine visits (aIRR 0.62 95% CI 0.58 to 0.66) compared to non-physicians. During the first 18 months of the COVID-19 pandemic, the rate of outpatient mental health and addiction (MHA) visits increased by 23.2% in physicians (888.4 pre versus 1,094.7 during per 1,000 person-years, aIRR 1.39 95% CI 1.28 to 1.51) and 9.8% in non-physicians (615.5 pre versus 675.9 during per 1,000 person-years, aIRR 1.12 95% CI 1.09 to 1.14). Outpatient MHA and virtual care visits increased more among physicians than non-physicians during the first 18 months of the pandemic. Limitations include residual confounding between physician and non-physicians and challenges differentiating whether observed increases in MHA visits during the pandemic are due to stressors or changes in health care access. CONCLUSIONS: The first 18 months of the COVID-19 pandemic was associated with a larger increase in outpatient MHA visits in physicians than non-physicians. These findings suggest physicians may have had larger negative mental health during COVID-19 than the general population and highlight the need for increased access to mental health services and system level changes to promote physician wellness.

Extracellular mitochondria drive CD8 T cell dysfunction in trauma by upregulating CD39.

RATIONALE: The increased mortality and morbidity seen in critically injured patients appears associated with systemic inflammatory response syndrome (SIRS) and immune dysfunction, which ultimately predisposes to infection. Mitochondria released by injury could generate danger molecules, for example, ATP, which in turn would be rapidly scavenged by ectonucleotidases, expressed on regulatory immune cells. OBJECTIVE: To determine the association between circulating mitochondria, purinergic signalling and immune dysfunction after trauma. METHODS: We tested the impact of hepatocyte-derived free mitochondria on blood-derived and lung-derived CD8 T cells in vitro and in experimental mouse models in vivo. In parallel, immune phenotypic analyses were conducted on blood-derived CD8 T cells obtained from trauma patients. RESULTS: Isolated intact mitochondria are functional and generate ATP ex vivo. Extracellular mitochondria perturb CD8+ T cells in co-culture, inducing select features of immune exhaustion in vitro. These effects are modulated by scavenging ATP, modelled by addition of apyrase in vitro. Injection of intact mitochondria into recipient mice markedly upregulates the ectonucleotidase CD39, and other immune checkpoint markers in circulating CD8+ T cells. We note that mice injected with mitochondria, prior to instilling bacteria into the lung, exhibit more severe lung injury, characterised by elevated neutrophil influx and by changes in CD8+ T cell cytotoxic capacity. Importantly, the development of SIRS in injured humans, is likewise associated with disordered purinergic signalling and CD8 T cell dysfunction. CONCLUSION: These studies in experimental models and in a cohort of trauma patients reveal important associations between extracellular mitochondria, aberrant purinergic signalling and immune dysfunction. These pathogenic factors with immune exhaustion are linked to SIRS and could be targeted therapeutically.

Kisspeptin-10 Mitigates α-Synuclein-Mediated Mitochondrial Apoptosis in SH-SY5Y-Derived Neurons via a Kisspeptin Receptor-Independent Manner.

The hypothalamic neurohormone kisspeptin-10 (KP-10) was inherently implicated in cholinergic pathologies when aberrant fluctuations of expression patterns and receptor densities were discerned in neurodegenerative micromilieus. That said, despite variable degrees of functional redundancy, KP-10, which is biologically governed by its cognate G-protein-coupled receptor, GPR54, attenuated the progressive demise of α-synuclein (α-syn)-rich cholinergic-like neurons. Under explicitly modeled environments, in silico algorithms further rationalized the surface complementarities between KP-10 and α-syn when KP-10 was unambiguously accommodated in the C-terminal binding pockets of α-syn. Indeed, the neuroprotective relevance of KP-10's binding mechanisms can be insinuated in the amelioration of α-syn-mediated neurotoxicity; yet it is obscure whether these extenuative circumstances are contingent upon prior GPR54 activation. Herein, choline acetyltransferase (ChAT)-positive SH-SY5Y neurons were engineered ad hoc to transiently overexpress human wild-type or E46K mutant α-syn while the mitigation of α-syn-induced neuronal death was ascertained via flow cytometric and immunocytochemical quantification. Recapitulating the specificity observed on cell viability, exogenously administered KP-10 (0.1 µM) substantially suppressed wild-type and E46K mutant α-syn-mediated apoptosis and mitochondrial depolarization in cholinergic differentiated neurons. In particular, co-administrations with a GPR54 antagonist, kisspeptin-234 (KP-234), failed to abrogate the robust neuroprotection elicited by KP-10, thereby signifying a GPR54 dispensable mechanism of action. Consistent with these observations, KP-10 treatment further diminished α-syn and ChAT immunoreactivity in neurons overexpressing wild-type and E46K mutant α-syn. Overall, these findings lend additional credence to the previous notion that KP-10's binding zone may harness efficacious moieties of neuroprotective intent.

Suicide and Self-Harm Among Physicians in Ontario, Canada.

BACKGROUND: Studies of occupation-associated suicide suggest physicians may be at a higher risk of suicide compared to nonphysicians. We set out to assess the risk of suicide and self-harm among physicians and compare it to nonphysicians. METHODS: We conducted a population-based, retrospective cohort study using registration data from the College of Physicians and Surgeons of Ontario from 1990 to 2016 with a follow-up to 2017, linked to Ontario health administrative databases. Using age- and sex-standardized rates and inverse probability-weighted, cause-specific hazards regression models, we compared rates of suicide, self-harm, and a composite of either event among all newly registered physicians to nonphysician controls. RESULTS: Among 35,989 physicians and 6,585,197 nonphysicians, unadjusted suicide events (0.07% vs. 0.11%) and rates (9.44 vs. 11.55 per 100,000 person-years) were similar. Weighted analyses found a hazard ratio of 1.05 (95% confidence interval: 0.69 to 1.60). Self-harm requiring health care was lower among physicians (0.22% vs. 0.46%; hazard ratio: 0.65, 95% confidence interval: 0.52 to 0.82), as was the composite of suicide or self-harm (hazard ratio: 0.70, 95% confidence interval: 0.57 to 0.86). The composite of suicide or self-harm was associated with a history of a mood or anxiety disorder (odds ratio: 2.84, 95% confidence interval: 1.17 to 6.87), an outpatient mental health visit in the past year (odds ratio: 3.08, 95% confidence interval: 1.34 to 7.10) and psychiatry visit in the preceding year (odds ratio: 3.87, 95% confidence interval: 1.67 to 8.95). INTERPRETATION: Physicians in Ontario are at a similar risk of suicide deaths and a lower risk of self-harm requiring health care relative to nonphysicians. Risk factors associated with suicide or self-harm may help inform prevention programs.

Kisspeptin-10 Rescues Cholinergic Differentiated SHSY-5Y Cells from α-Synuclein-Induced Toxicity In Vitro.

The neuropathological substrate of dementia with Lewy bodies (DLB) is defined by the inextricable cross-seeding accretion of amyloid-ß (Aß) and α-synuclein (α-syn)-laden deposits in cholinergic neurons. The recent revelation that neuropeptide kisspeptin-10 (KP-10) is able to mitigate Aß toxicity via an extracellular binding mechanism may provide a new horizon for innovative drug design endeavors. Considering the sequence similarities between α-syn's non-amyloid-ß component (NAC) and Aß's C-terminus, we hypothesized that KP-10 would enhance cholinergic neuronal resistance against α-syn's deleterious consequences through preferential binding. Here, human cholinergic SH-SY5Y cells were transiently transformed to upsurge the mRNA expression of α-syn while α-syn-mediated cholinergic toxicity was quantified utilizing a standardized viability-based assay. Remarkably, the E46K mutant α-syn displayed elevated α-syn mRNA levels, which subsequently induced more cellular toxicity compared with the wild-type α-syn in choline acetyltransferase (ChAT)-positive cholinergic neurons. Treatment with a high concentration of KP-10 (10 µM) further decreased cholinergic cell viability, while low concentrations of KP-10 (0.01-1 µM) substantially suppressed wild-type and E46K mutant α-syn-mediated toxicity. Correlating with the in vitro observations are approximations from in silico algorithms, which inferred that KP-10 binds favorably to the C-terminal residues of wild-type and E46K mutant α-syn with CDOCKER energy scores of -118.049 kcal/mol and -114.869 kcal/mol, respectively. Over the course of 50 ns simulation time, explicit-solvent molecular dynamics conjointly revealed that the docked complexes were relatively stable despite small-scale fluctuations upon assembly. Taken together, our findings insinuate that KP-10 may serve as a novel therapeutic scaffold with far-reaching implications for the conceptualization of α-syn-based treatments.

Magnetic NiFe2 O4 Nanoparticles Prepared via Non-Aqueous Microwave-Assisted Synthesis for Application in Electrocatalytic Water Oxidation.

Phase-pure spinel-type magnetic nickel ferrite (NiFe2 O4 ) nanocrystals in the size range of 4 to 11 nm were successfully synthesized by a fast and energy-saving microwave-assisted approach. Size and accessible surface areas can be tuned precisely by the reaction parameters. Our results highlight the correlation between size, degree of inversion, and magnetic characteristics of NiFe2 O4 nanoparticles, which enables fine-tuning of these parameters for a particular application without changing the elemental composition. Moreover, the application potential of the synthesized powders for the electrocatalytic oxygen evolution reaction in alkaline media was demonstrated, showing that a low degree of inversion is beneficial for the overall performance. The most active sample reaches an overpotential of 380 mV for water oxidation at 10 mA cm-2 and 38.8 mA cm-2 at 1.7 V vs. RHE, combined with a low Tafel slope of 63 mV dec-1 .

FexNi9-xS8 (x = 3-6) as potential photocatalysts for solar-driven hydrogen production?

The efficient reduction of protons by non-noble metals under mild conditions is a challenge for our modern society. Nature utilises hydrogenases, enzymatic machineries that comprise iron- and nickel- containing active sites, to perform the conversion of protons to hydrogen. We herein report a straightforward synthetic pathway towards well-defined particles of the bio-inspired material FexNi9-xS8, a structural and functional analogue of hydrogenase metal sulfur clusters. Moreover, the potential of pentlandites to serve as photocatalysts for solar-driven H2-production is assessed for the first time. The FexNi9-xS8 materials are visible light responsive (band gaps between 2.02 and 2.49 eV, depending on the pentlandite's Fe : Ni content) and display a conduction band energy close to the thermodynamic potential for proton reduction. Despite the limited driving force, a modest activity for photocatalytic H2 has been observed. Our observations show the potential for the future development of pentlandites as photocatalysts. This work provides a basis to explore powerful synergies between biomimetic chemistry and material design to unlock novel applications in solar energy conversion.

Deciduous DPSCs Ameliorate MPTP-Mediated Neurotoxicity, Sensorimotor Coordination and Olfactory Function in Parkinsonian Mice.

Parkinson's disease (PD) is a neurodegenerative disorder defined by progressive deterioration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Dental pulp stem cells (DPSCs) have been proposed to replace the degenerated dopaminergic neurons due to its inherent neurogenic and regenerative potential. However, the effective delivery and homing of DPSCs within the lesioned brain has been one of the many obstacles faced in cell-based therapy of neurodegenerative disorders. We hypothesized that DPSCs, delivered intranasally, could circumvent these challenges. In the present study, we investigated the therapeutic efficacy of intranasally administered DPSCs in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. Human deciduous DPSCs were cultured, pre-labelled with PKH 26, and intranasally delivered into PD mice following MPTP treatment. Behavioural analyses were performed to measure olfactory function and sensorimotor coordination, while tyrosine hydroxylase (TH) immunofluorescence was used to evaluate MPTP neurotoxicity in SNpc neurons. Upon intranasal delivery, degenerated TH-positive neurons were ameliorated, while deterioration in behavioural performances was significantly enhanced. Thus, the intranasal approach enriched cell delivery to the brain, optimizing its therapeutic potential through its efficacious delivery and protection against dopaminergic neuron degeneration.

Analysis of NTPDase2 in the cell membrane using fluorescence recovery after photobleaching (FRAP).

NTPDase2, a member of the CD39/NTPDase family, is an ecto-nucleotidase anchored to the plasma membrane by two transmembrane domains, with a catalytic site facing the extracellular space and preferentially hydrolyzing nucleoside triphosphates. While NTPDase2 is expressed in many cell types, its unique functionality, mobility and dynamics at the cell membrane remain unexplored. We therefore constructed a recombinant NTPDase2 linked to the yellow fluorescent protein (EYFP) to investigate its dynamics by confocal microscopy. The present study shows that the expression of EYFP-NTPDase2 in different cell lines does not affect its proliferation, migration and adhesion to extracellular matrices (ECM). Moreover, in human embryonic kidney cells 293 (HEK293) grown on collagen type I and fibronectin, EYFP-NTPDase2 fluorescence is greater in free plasma membrane regions than in cell-cell contacts, in comparison with cells grown on other substrates. Differences in the time required for fluorescence recovery after photobleaching (FRAP) in free membrane regions and cell-cell contacts indicate that the mobility of EYFP-NTPDase2 depends on the matrix to which the cells are attached. © 2018 International Society for Advancement of Cytometry.

Effect of dental pulp stem cells in MPTP-induced old-aged mice model.

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disease caused by the loss of dopaminergic (DA-ergic) neurons in the substantia nigra (SN) and represented as a huge threat to the geriatric population. Cell replacement therapies (CRTs) have been proposed as a promising strategy to slow down or replace neuronal loss. Among the widely available cell sources, dental pulp stem cells (DPSCs) portray as an attractive source primarily due to their neural crest origin, ease of tissue procurement and less ethical hurdles. MATERIALS AND METHODS: We first demonstrated the in vitro differentiation ability of DPSCs towards DA-ergic-like cells before evaluating their neuro-protection/neuro-restoration capacities in MPTP-induced mice. Transplantation via intrathecal was performed with behavioural assessments being evaluated every fortnight. Subsequent analysis investigating their immuno-modulatory behaviour was conducted using neuronal and microglial cell lines. RESULTS: It was apparent that the behavioural parameters began to improve corresponding to tyrosine hydroxylase (TH), dopamine transporter (DAT) and dopamine decarboxylase (AADC) immunostaining in SN and striatum as early as 8-week post-transplantation (P < 0·05). About 60% restoration of DA-ergic neurons was observed at SN in MPTP-treated mice after 12-week post-transplantation. Similarly, their ability to reduce toxic effects of MPTP (DNA damages, reactive oxygen species and nitric oxide release) and regulate cytokine levels was distinctly noted (P < 0·05) upon exposure in in vitro model. CONCLUSIONS: Our results suggest that DPSCs may provide a therapeutic benefit in the old-aged PD mice model and may be explored in stem cell-based CRTs especially in geriatric population as an attempt towards 'personalized medicine'.

Regulatory T cell-derived adenosine induces dendritic cell migration through the Epac-Rap1 pathway.

Dendritic cells (DC) are one target for immune suppression by regulatory T cells (Treg), because their interaction results in reduced T cell stimulatory capacity and secretion of inhibitory cytokines in DC. We show that DC in the presence of Treg are more mobile as compared with cocultures with conventional CD4(+) T cells and form DC-Treg aggregates within 2 h of culture. The migration of DC was specifically directed toward Treg, as Treg, but not CD4(+) T cells, attracted DC in Boyden chambers. Treg deficient for the ectonucleotidase CD39 were unable to attract DC. Likewise, addition of antagonists for A2A adenosine receptors abolished the formation of DC-Treg clusters, indicating a role for adenosine in guiding DC-Treg interactions. Analysis of the signal transduction events in DC after contact to Treg revealed increased levels of cAMP, followed by activation of Epac1 and the GTPase Rap1. Subsequently activated Rap1 localized to the subcortical actin cytoskeleton in DC, providing a means by which directed locomotion of DC toward Treg is facilitated. In aggregate, these data show that Treg degrade ATP to adenosine via CD39, attracting DC by activating Epac1-Rap1-dependent pathways. As a consequence, DC-Treg clusters are formed and DC are rendered less stimulatory. This adenosine-mediated attraction of DC may therefore act as one mechanism by which Treg regulate the induction of immune responses by DC.

Does self-regulation capacity predict psychological well-being in physicians?

Despite increasing research on physician well-being, factors appearing to account for individual variation in levels of optimal functioning are largely unclear. One such factor could be self-regulation, which reflects how individuals effectively manage their thoughts, emotions and behaviours, and cope with adversity in their environment. The purpose of this study was to determine if self-regulation capacity could significantly predict psychological well-being in a sample of Canadian physicians. A total of 132 physicians completed the Scales of Psychological Well-Being and the short form of the Self-Regulation Questionnaire. Regression analyses confirmed the hypothesis that a significant amount of variance in levels of psychological well-being would be explained by self-regulation capacity. There was a particularly strong relationship between self-regulation capacity and the dimensions of purpose in life and environmental mastery, which suggests that physicians who effectively self-manage may be better able to preserve a sense of purpose and an adequate work-life balance in their daily life. Physicians today face consistently growing demands stemming from increasingly challenging work environments. Results of this study mark an important step in increasing our understanding of a potentially valuable skill that may help physicians to achieve well-being.

Distinct complexes of DNA polymerase I (Klenow fragment) for base and sugar discrimination during nucleotide substrate selection.

During each catalytic cycle, DNA polymerases select deoxyribonucleoside triphosphate (dNTP) substrates complementary to a templating base with high fidelity from a pool that includes noncomplementary dNTPs and both complementary and noncomplementary ribonucleoside triphosphates (rNTPs). The Klenow fragment of Escherichia coli DNA polymerase I (KF) achieves this through a series of conformational transitions that precede the chemical step of phosphodiester bond formation. Kinetic evidence from fluorescence and FRET experiments indicates that discrimination of the base and sugar moieties of the incoming nucleotide occurs in distinct, sequential steps during the selection pathway. Here we show that KF-DNA complexes formed with complementary rNTPs or with noncomplementary nucleotides can be distinguished on the basis of their properties when captured in an electric field atop the α-hemolysin nanopore. The average nanopore dwell time of KF-DNA complexes increased as a function of complementary rNTP concentration. The increase was less than that promoted by complementary dNTP, indicating that the rNTP complexes are more stable than KF-DNA binary complexes but less stable than KF-DNA-dNTP ternary complexes. KF-DNA-rNTP complexes could also be distinguished from KF-DNA-dNTP complexes on the basis of ionic current amplitude. In contrast to complementary rNTPs, noncomplementary dNTPs and rNTPs diminished the average nanopore dwell time of KF-DNA complexes in a concentration-dependent manner, suggesting that binding of a noncomplementary nucleotide keeps the KF-DNA complex in a less stable state. These results imply that nucleotide selection proceeds through a series of complexes of increasing stability in which substrates with the correct moiety promote the forward transitions.

Primary Care Physician Use and Frequency of Visits Among Physicians in Ontario, Canada.

Importance: Maintaining a healthy physician workforce includes the routine use of primary care physician (PCP) services; however, physicians may face barriers to attaining formal care. Objective: To analyze access to and frequency of visits to PCPs among physicians compared with nonphysicians. Design, Setting, and Participants: This population-based, retrospective cohort study used registration data from the College of Physicians and Surgeons of Ontario, Canada, from January 1, 1990, to March 31, 2018. Data for all newly practicing physicians as of March 31, 2018, were linked to Ontario health administrative databases. Data were analyzed from August 25, 2020, to August 6, 2021. Main Outcomes and Measures: The main outcomes were enrollment in a PCP practice and visits with a PCP. Generalized estimating equations compared primary care visits between physicians and nonphysicians, matched 1:5 based on age, sex, neighborhood income quintile, and health region. Results: Among 19 581 physicians (mean [SD] age, 43.99 [8.94] years; 53.27% male) matched to 97 905 nonphysicians, physicians were less likely to be enrolled with a PCP than were nonphysicians (81.8% vs 86.4%; absolute difference, 4.6%; adjusted odds ratio [OR], 0.75; 95% CI, 0.72-0.79) and had fewer primary care visits during the preceding 2 years (median [IQR], 2 [0-4] vs 4 [1-7]; adjusted relative rate ratio [RRR], 0.59; 95% CI, 0.58-0.60). Physicians aged 40 years or older and male physicians were less likely to be rostered (ages 40-44 years: OR, 0.70 [95% CI, 0.64-0.77]; male: OR, 0.60 [95% CI, 0.57-0.63]) and more likely to have a lower frequency of PCP visits (ages 40-44 years: RRR, 0.53 [95% CI, 0.51-0.56]; male: RRR, 0.50 [95% CI, 0.50-0.51]) compared with nonphysicians. Conclusions and Relevance: In this retrospective cohort study, enrollment with a PCP practice and frequency of visits were lower among physicians compared with a matched general population of nonphysicians. Individual, system, and medical cultural factors associated with these results need to be better understood so that physicians can take better care of themselves and their patients.

Physician Health Care Visits for Mental Health and Substance Use During the COVID-19 Pandemic in Ontario, Canada.

Importance: Physicians self-report high levels of symptoms of anxiety and depression, and surveys suggest these symptoms have been exacerbated by the COVID-19 pandemic. However, it is not known whether pandemic-related stressors have led to increases in health care visits related to mental health or substance use among physicians. Objective: To evaluate the association between the COVID-19 pandemic and changes in outpatient health care visits by physicians related to mental health and substance use and explore differences across physician subgroups of interest. Design, Setting, and Participants: A population-based cohort study was conducted using health administrative data collected from the universal health system (Ontario Health Insurance Plan) of Ontario, Canada, from March 1, 2017, to March 10, 2021. Participants included 34 055 physicians, residents, and fellows who registered with the College of Physicians and Surgeons of Ontario between 1990 and 2018 and were eligible for the Ontario Health Insurance Plan during the study period. Autoregressive integrated moving average models and generalized estimating equations were used in analyses. Exposures: The period during the COVID-19 pandemic (March 11, 2020, to March 10, 2021) compared with the period before the pandemic. Main Outcomes and Measures: The primary outcome was in-person, telemedicine, and virtual care outpatient visits to a psychiatrist or family medicine and general practice clinicians related to mental health and substance use. Results: In the 34 055 practicing physicians (mean [SD] age, 41.7 [10.0] years, 17 918 [52.6%] male), the annual crude number of visits per 1000 physicians increased by 27%, from 816.8 before the COVID-19 pandemic to 1037.5 during the pandemic (adjusted incident rate ratio per physician, 1.13; 95% CI, 1.07-1.19). The absolute proportion of physicians with 1 or more mental health and substance use visits within a year increased from 12.3% before to 13.4% during the pandemic (adjusted odds ratio, 1.08; 95% CI, 1.03-1.14). The relative increase was significantly greater in physicians without a prior mental health and substance use history (adjusted incident rate ratio, 1.72; 95% CI, 1.60-1.85) than in physicians with a prior mental health and substance use history. Conclusions and Relevance: In this study, the COVID-19 pandemic was associated with a substantial increase in mental health and substance use visits among physicians. Physician mental health may have worsened during the pandemic, highlighting a potential greater requirement for access to mental health services and system level change.

Liver damage and systemic inflammatory responses are exacerbated by the genetic deletion of CD39 in total hepatic ischemia.

Liver ischemia reperfusion injury is associated with both local damage to the hepatic vasculature and systemic inflammatory responses. CD39 is the dominant vascular endothelial cell ectonucleotidase and rapidly hydrolyses both adenosine triphosphate (ATP) and adenosine diphosphate to adenosine monophosphate. These biochemical properties, in tandem with 5'-nucleotidases, generate adenosine and potentially illicit inflammatory vascular responses and thrombosis. We have evaluated the role of CD39 in total hepatic ischemia reperfusion injury (IRI). Wildtype mice, Cd39-hemizygous mice (+/-) and matched Cd39-null mice (-/-); (n = 25 per group) underwent 45 min of total warm ischemia with full inflow occlusion necessitating partial hepatectomy. Soluble nucleoside triphosphate diphosphohydrolase (NTPDases) or adenosine/amrinone were administered to wildtype (n = 6) and Cd39-null mice (n = 6) in order to study protective effects in vivo. Parameters of liver injury, systemic inflammation, hepatic ATP determinations by P(31)-NMR and parameters of lung injury were obtained. All wildtype mice survived up to 7 days with minimal biochemical disturbances and minor evidence for injury. In contrast, 64% of Cd39+/- and 84% of Cd39-null mice required euthanasia or died within 4 h post-reperfusion with liver damage and systemic inflammation associated with hypercytokinemia. Hepatic ATP depletion was pronounced in Cd39-null mice posthepatic IRI. Soluble NTPDase or adenosine administration protected Cd39-deficient mice from acute reperfusion injury. We conclude that CD39 is protective in hepatic IRI preventing local injury and systemic inflammation in an adenosine dependent manner. Our data indicate that vascular CD39 expression has an essential protective role in hepatic IRI.

α-Synuclein-mediated neurodegeneration in Dementia with Lewy bodies: the pathobiology of a paradox.

Dementia with Lewy bodies (DLB) is epitomized by the pathognomonic manifestation of α-synuclein-laden Lewy bodies within selectively vulnerable neurons in the brain. By virtue of prion-like inheritance, the α-synuclein protein inexorably undergoes extensive conformational metamorphoses and culminate in the form of fibrillar polymorphs, instigating calamitous damage to the brain's neuropsychological networks. This epiphenomenon is nebulous, however, by lingering uncertainty over the quasi "pathogenic" behavior of α-synuclein conformers in DLB pathobiology. Despite numerous attempts, a monolithic "α-synuclein" paradigm that is able to untangle the enigma enshrouding the clinicopathological spectrum of DLB has failed to emanate. In this article, we review conceptual frameworks of α-synuclein dependent cell-autonomous and non-autonomous mechanisms that are likely to facilitate the transneuronal spread of degeneration through the neuraxis. In particular, we describe how the progressive demise of susceptible neurons may evolve from cellular derangements perpetrated by α-synuclein misfolding and aggregation. Where pertinent, we show how these bona fide mechanisms may mutually accentuate α-synuclein-mediated neurodegeneration in the DLB brain.

Medical student wellness in Canada: time for a national curriculum framework.

There is substantial evidence showing that medical student wellness is a worsening problem in Canada. It is apparent that medical students' wellness deteriorates throughout their training. Medical schools and their governing bodies are responding by integrating wellness into competency frameworks and accreditation standards through a combination of system- and individual-level approaches. System-level strategies that consider how policies, medical culture, and the "hidden curriculum" impact student wellness, are essential for reducing burnout prevalence and achieving optimal wellness outcomes. Individual-level initiatives such as wellness programming are widespread and more commonly used. These are often didactic, placing the onus on the student without addressing the learning environment. Despite significant progress, there is little programming consistency across schools or training levels. There is no wellness curriculum framework for Canadian undergraduate medical education that aligns with residency competencies. Creating such a framework would help align individual- and system-level initiatives and smooth the transition from medical school to residency. The framework would organize goals within relevant wellness domains, allow for local adaptability, consider basic learner needs, and be learner-informed. Physicians whose wellness has been supported throughout their training will positively contribute to the quality of patient care, work environments, and in sustaining a healthy Canadian population.

Nous disposons d'un grand nombre de données concrètes démontrant que le bien-être des étudiants en médecine au Canada se détériore tout au long de leur cheminement universitaire et que le problème s'aggrave. Alliant les approches systémique et individuelle, les facultés de médecine et leurs directions réagissent en intégrant le bien-être dans les cadres de compétences et les normes d'agrément. Les stratégies systémiques, qui tiennent compte de l'impact des politiques, de la culture médicale et du «curriculum caché¼ sur le bien-être des étudiants, sont indispensables pour prévenir l'épuisement professionnel et pour obtenir des résultats optimaux en matière de bien-être. Les initiatives au niveau individuel, comme les programmes axés sur le bien-être, sont de plus en plus répandues. Ces programmes sont souvent didactiques et ils sollicitent l'étudiant sans tenir compte de l'environnement d'apprentissage. Bien que ces initiatives aient marqué des progrès importants, il y a peu d'uniformité entre les programmes des diverses facultés et entre les niveaux de formation. Il n'y a pas de cadre pédagogique pour les programmes d'études de premier cycle axés sur le bien-être au Canada s'alignant aux compétences visées dans les programmes de résidence. La création d'un tel cadre permettrait d'harmoniser les initiatives de niveau individuel et celles de niveau systémique et de faciliter la transition de la faculté de médecine vers la résidence. Il comporterait des objectifs organisés selon les domaines de bien-être pertinents, une souplesse permettant son adaptation aux divers milieux, il tiendrait compte des besoins fondamentaux des apprenants et il serait fondé sur une consultation de ces derniers. Les médecins dont le bien-être a été soutenu tout au long de leur formation contribueront de façon positive à la qualité des soins aux patients, à leur environnement de travail et au maintien d'une population canadienne en bonne santé.

Impact of fatigue and insufficient sleep on physician and patient outcomes: a systematic review.

OBJECTIVES: For physicians in independent practice, we synthesised evidence on the (1) impacts of insufficient sleep and fatigue on health and performance, and patient safety and (2) effectiveness of interventions targeting insufficient sleep and fatigue. DESIGN: We systematically reviewed online literature. After piloting, one reviewer selected studies by title and abstract; full texts were then reviewed in duplicate. One reviewer extracted data; another verified a random 10% sample. Two reviewers assessed risk of bias. We pooled findings via meta-analysis when appropriate or narratively. DATA SOURCES: We searched Medline, Embase, PsycINFO, CINAHL and PubMed for published studies in April 2016; Medline was updated in November 2017. We searched Embase for conference proceedings, and hand-searched meeting abstracts, association and foundation websites. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: English or French language primary research studies published from 2000 to 2017 examining the effect of fatigue-related or sleep-related exposures or interventions on any outcome among physicians in independent practice and their patients. RESULTS: Of 16 154 records identified, we included 47 quantitative studies of variable quality. 28 studies showed associations between fatigue or insufficient sleep and physician health and well-being outcomes. 21 studies showed no association with surgical performance, and mixed findings for psychomotor performance, work performance and medical errors. We pooled data from six cohort studies for patient outcomes. For sleep deprived versus non-sleep deprived surgeons, we found no difference in patient mortality (n=60 436, relative risk (RR) 0.98, 95% CI 0.84 to 1.15, I2=0% (p=0.87)) nor postoperative complications (n=60 201, RR 0.99, 95% CI 0.95 to 1.03, I2=0% (p=0.45)). The findings for intraoperative complications and length of stay were considerably heterogeneous. CONCLUSIONS: Fatigue and insufficient sleep may be associated with negative physician health outcomes. Current evidence is inadequate to inform practice recommendations.