Nucleoporin93 limits Yap activity to prevent endothelial cell senescence.

As the innermost lining of the vasculature, endothelial cells (ECs) are constantly subjected to systemic inflammation and particularly vulnerable to aging. Endothelial health is hence vital to prevent age-related vascular disease. Healthy ECs rely on the proper localization of transcription factors via nuclear pore complexes (NPCs) to govern cellular behavior. Emerging studies report NPC degradation with natural aging, suggesting impaired nucleocytoplasmic transport in age-associated EC dysfunction. We herein identify nucleoporin93 (Nup93), a crucial structural NPC protein, as an indispensable player in vascular protection. Endothelial Nup93 protein levels are significantly reduced in the vasculature of aged mice, paralleling observations of Nup93 loss when using in vitro models of EC senescence. The loss of Nup93 in human ECs induces cell senescence and promotes the expression of inflammatory adhesion molecules, where restoring Nup93 protein in senescent ECs reverses features of endothelial aging. Mechanistically, we find that both senescence and loss of Nup93 impair endothelial NPC transport, leading to nuclear accumulation of Yap and downstream inflammation. Pharmacological studies indicate Yap hyperactivation as the primary consequence of senescence and Nup93 loss in ECs. Collectively, our findings indicate that the maintenance of endothelial Nup93 is a key determinant of EC health, where aging targets endothelial Nup93 levels to impair NPC function as a novel mechanism of EC senescence and vascular aging.

Dynamic metabolism of endothelial triglycerides protects against atherosclerosis in mice.

Blood vessels are continually exposed to circulating lipids, and elevation of ApoB-containing lipoproteins causes atherosclerosis. Lipoprotein metabolism is highly regulated by lipolysis, largely at the level of the capillary endothelium lining metabolically active tissues. How large blood vessels, the site of atherosclerotic vascular disease, regulate the flux of fatty acids (FAs) into triglyceride-rich (TG-rich) lipid droplets (LDs) is not known. In this study, we showed that deletion of the enzyme adipose TG lipase (ATGL) in the endothelium led to neutral lipid accumulation in vessels and impaired endothelial-dependent vascular tone and nitric oxide synthesis to promote endothelial dysfunction. Mechanistically, the loss of ATGL led to endoplasmic reticulum stress-induced inflammation in the endothelium. Consistent with this mechanism, deletion of endothelial ATGL markedly increased lesion size in a model of atherosclerosis. Together, these data demonstrate that the dynamics of FA flux through LD affects endothelial cell homeostasis and consequently large vessel function during normal physiology and in a chronic disease state.

Endothelial nitric oxide synthase (eNOS) S1176 phosphorylation status governs atherosclerotic lesion formation.

Objective: We have previously demonstrated the in vivo importance of the Akt-eNOS substrate-kinase relationship, as defective postnatal angiogenesis characteristic of global Akt1-null mice is rescued when bred to 'gain-of-function' eNOS S1176D mutant mice. While multiple studies support the vascular protective role of endothelial NO generation, the causal role of Akt1-dependent eNOS S1176 phosphorylation during atherosclerotic plaque formation is not yet clear. Approach and results: We herein bred congenic 'loss-of-function' eNOS S1176A and 'gain-of-function' eNOS S1176D mutant mice to the exacerbated atherogenic Akt1-/-; ApoE-/- double knockout mice to definitively test the importance of Akt-mediated eNOS S1176 phosphorylation during atherogenesis. We find that a single amino acid substitution at the eNOS S1176 phosphorylation site yields divergent effects on atherosclerotic plaque formation, as an eNOS phospho-mimic aspartate (D) substitution at S1176 leads to favorable lipid profiles and decreased indices of atherosclerosis, even when on a proatherogenic Akt1 global deletion background. Conversely, mice harboring an unphosphorylatable mutation to alanine (S1176A) result in increased plasma lipids, increased lesion formation and cellular apoptosis, phenocopying the physiological consequence of eNOS deletion and/or impaired enzyme function. Furthermore, gene expression analyses of whole aortas indicate a combinatorial detriment from NO deficiency and Western Diet challenge, as 'loss-of-function' eNOS S1176A mice on a Western Diet present a unique expression pattern indicative of augmented T-cell activity when compared to eNOS S1176D mice. Conclusions: By using genetic epistasis approaches, we conclusively demonstrate that Akt-mediated eNOS S1176 phosphorylation and subsequent eNOS activation remains to be the most physiologically relevant method of NO production to promote athero-protective effects.

Nucleoporin93 (Nup93) Limits Yap Activity to Prevent Endothelial Cell Senescence.

Endothelial cells (ECs) form the innermost lining of the vasculature and serve a pivotal role in preventing age-related vascular disease. Endothelial health relies on the proper nucleocytoplasmic shuttling of transcription factors via nuclear pore complexes (NPCs). Emerging studies report NPC degradation with natural aging, suggesting impaired nucleocytoplasmic transport in age-related EC dysfunction. We herein identify nucleoporin93 (Nup93), a crucial structural NPC protein, as an indispensable player for vascular protection. Endothelial Nup93 protein levels are significantly reduced in the vasculature of aged mice, paralleling observations of Nup93 loss when using in vitro models of endothelial aging. Mechanistically, we find that loss of Nup93 impairs NPC transport, leading to the nuclear accumulation of Yap and downstream inflammation. Collectively, our findings indicate maintenance of endothelial Nup93 as a key determinant of EC health, where aging targets endothelial Nup93 levels to impair NPC function as a novel mechanism for EC senescence and vascular aging.

An investigation of Head Start preschool children's executive function, early literacy, and numeracy learning in the midst of the COVID-19 pandemic.

The COVID-19 pandemic's impact on preschool children's school readiness skills remains understudied. This research investigates Head Start preschool children's early numeracy, literacy, and executive function outcomes during a pandemic-affected school year. Study children (N = 336 assessed at fall baseline; N = 237-250 assessed in spring depending on outcome; fall baseline sample: mean age = 51 months; 46% Hispanic; 36% Black Non-Hispanic; 52% female) in a network of Head Start centers in four states (Nevada, New Jersey, Pennsylvania, and Wisconsin) experienced low in-person preschool exposure compared to national pre-pandemic norms. Children experienced fall to spring score gains during the pandemic-affected year of 0.05 SD in executive function, 0.27 SD in print knowledge, and 0.45-0.71 SD in early numeracy skills. Descriptively, for two of the three early numeracy domains measured, spring test score outcomes were stronger among children who attended more in-person preschool. We discuss implications for future research and policy.

Pharmacy Students' and Pharmacist Preceptors' Perceptions of the Hospital Rotation Experience during the COVID-19 Pandemic.

Background: The COVID-19 pandemic brought significant disruptions to pharmacy experiential education. To ensure the safety of students and staff, university and rotation site educators needed to make changes rapidly to adapt to the dynamic environment. Objectives: To explore the impact of the COVID-19 pandemic on pharmacy students and their preceptors during experiential rotations and to identify any barriers to learning that arose and opportunities for improvement. Methods: Two online questionnaires were developed to explore the perceptions of pharmacy students and preceptors during experiential rotations. The following topics were examined: support for rotations by the hospital and the university, perceived safety, accessibility of resources, interpersonal interactions, professional development, assessment and evaluation, and overall impressions. All Advanced Pharmacy Practice Experience students from the University of Toronto who completed 1 or more rotations at North York General Hospital during the 2020/21 academic year and their preceptors were invited to participate. Results: Sixteen and 25 questionnaires were completed by students and preceptors, respectively. Both groups agreed that they were adequately prepared for the rotations and felt safe. There was a decrease in interpersonal interactions, while the use of virtual communication tools increased. Lessons learned included the need for timely communications and access to resources for learners and preceptors, contingency plans for staff shortages and outbreaks, and workspace assessments. Conclusions: During the COVID-19 pandemic, implementation of experiential rotations was associated with many challenges, but pharmacy learners and preceptors believed the overall experience was not significantly affected.

Contexte: La pandémie de COVID-19 s'est accompagnée de perturbations importantes dans le domaine de la formation pratique en pharmacie. Les éducateurs de l'université et du lieu de stage ont dû rapidement apporter des changements pour s'adapter à l'environnement dynamique et assurer la sécurité des étudiants et du personnel. Objectifs: Étudier les effets de la pandémie de COVID-19 sur les étudiants en pharmacie et leurs précepteurs pendant les stages pratiques et identifier les obstacles qui se sont présentés ainsi que les améliorations possibles. Méthodes: Deux questionnaires en ligne ont été préparés pour étudier les perceptions des étudiants en pharmacie et des précepteurs pendant les stages pratiques. Les sujets suivants ont été examinés: le soutien de l'hôpital et de l'université pour les stages, la perception de la sécurité, l'accessibilité des ressources, les interactions interpersonnelles, le perfectionnement professionnel, l'évaluation et les impressions générales. Tous les étudiants du programme Advanced Pharmacy Practice Experience de l'Université de Toronto qui ont effectué un ou plusieurs stages à l'Hôpital général de North York au cours de l'année universitaire 2020­2021 et leurs précepteurs ont été invités à participer. Résultats: Les étudiants et les précepteurs ont répondu à 16 et 25 questionnaires, respectivement. Les deux groupes ont convenu qu'ils étaient bien préparés aux stages et qu'ils se sentaient en sécurité. On a observé une diminution des interactions interpersonnelles, tandis que l'utilisation d'outils de communication virtuels a augmenté. Les leçons tirées comprennent: la nécessité de communiquer en temps opportun et l'accès aux ressources pour les apprenants et les précepteurs; les plans d'urgence en cas de pénurie de personnel et d'épidémies; et les évaluations de l'espace de travail. Conclusions: Pendant la pandémie de COVID-19, la mise en œuvre des stages pratiques a été associée à de nombreux défis, mais les apprenants en pharmacie et les précepteurs ont estimé que l'expérience globale n'a pas été touchée de manière significative.

The seroprevalence of COVID-19 in patients living with HIV in metropolitan Detroit.

BACKGROUND: COVID-19, a novel respiratory illness caused by SARS-CoV-2, has become a global pandemic. As of December 2020, 4.8% of the 941 people living with HIV in our Ryan White clinic have tested polymerase chain reaction positive for SARS-CoV-2. The aim of our study was to estimate the seroprevalence of COVID-19 in our Ryan White people living with HIV, irrespective of known past infection. METHODS: We conducted a cross-sectional study that recruited people living with HIV in the Ryan White program at Henry Ford Hospital in Detroit, Michigan, from September 2020 through May 2021. All Ryan White patients were offered participation during clinic visits. After informed consent, patients completed a survey, and had blood sampled for SARS-CoV-2 antibody testing. RESULTS: Of the 529 individuals who completed the written survey, 504 participants were tested for SARS-CoV-2 antibody and 52 people living with HIV were COVID-19 immunoglobulin (Ig) G positive resulting in a seroprevalence of 10.3%. Among 36 persons with PCR-confirmed COVID-19, 52.8% were IgG negative. Inclusion of PCR positive but IgG-negative people living with HIV yields a COVID-19 infection prevalence of 14.1%. CONCLUSIONS: These findings suggest that passive public health-based antibody surveillance in people living with HIV significantly underestimates past infection.

Cardiac rehabilitation program: An exploration of patient experiences and perspectives on program dropout.

BACKGROUND: Cardiac rehabilitation programs (CRP) are effective evidence-based secondary prevention programs that reduce morbidity and mortality in patients with cardiovascular disease (CVD). However, participation remains suboptimal, resulting in under-treatment and greater risk for recurrent cardiac events. Understanding the reasons behind CRP dropout is urgently needed to inform the development of programs that best meet patient needs and support sustained engagement. AIMS: The aim of this study was to identify and understand factors impacting CRP dropout from the patient perspective. METHODS: A qualitative study using semi-structured interviews was undertaken to examine the experience of 23 patients who dropped out of a CRP within a large urban hospital in British Columbia, Canada. Data were coded, analyzed using the constant comparison technique, and organized thematically. RESULTS: Participants described multiple challenges when attempting to complete CRP. Analysis of the data led to the identification of three main categories: (1) challenges living with CVD, (2) perceived advantages and disadvantages of CRP, and (3) unmet needs during CRP. LINKING EVIDENCE TO ACTION: In the practice setting, assessment of readiness to engage in CRP, alongside patient preferences and engagement needs, should be undertaken for maximum CRP uptake and completion. Providing diverse modes of CRP delivery, along with exploring the impact of virtual options as compared to traditional in-person programs, will further advance the CRP evidence and may help address pervasive access barriers.

Notch1 promotes ordered revascularization through Semaphorin 3g modulation of downstream vascular patterning signalling factors.

Here we genetically and functionally addressed potential pathways of Notch signalling in mediating vascular regeneration in mouse models. We first used transgenic adult mice with either gain- or loss-of-function Notch signalling in vascular endothelial cells and monitored perfusion in the hindlimb following ischaemia induced by femoral artery ligation. Mice deficient in Notch signalling showed defective perfusion recovery and expansion of collateral arteries. Transcriptomics analysis of arterial endothelial cells in the Notch mutants identified the guidance factor Sema3g as a candidate gene mediating reperfusion downstream of Notch. Studies in the retinal circulation showed the central role of SEMA3G downstream of Notch signalling in the orderly regulation of vascular patterning. These studies in multiple vascular beds show the primacy of Notch signalling and downstream generation of guidance peptides such as SEMA3G in promoting well-ordered vascular regeneration. KEY POINTS: Notch signalling is a critical mediator of revascularization. Yet the cellular processes activated during recovery following vascular injury are incompletely understood. Here we used genetic and cellular approaches in two different vascular beds and cultured endothelial cells to address the generalizability of mechanisms. By utilizing a highly reproducible murine model of hindlimb ischaemia in transgenic mice in which Notch signalling was inhibited at the transcriptional level, we demonstrated the centrality of Notch signalling in perfusion recovery and revascularization. RNA-sequencing of Notch mutants identified class 3 Semaphorins regulated by Notch signalling as downstream targets. Studies in retinal vessels and endothelial cells showed an essential role of guidance peptide Sema3g as a modulator of angiogenesis and orderly vascular patterning. The Notch to Sema3g signalling axis functions as a feedback mechanism to sculpt the growing vasculature in multiple beds.

Immunologic resilience and COVID-19 survival advantage.

BACKGROUND: The risk of severe coronavirus disease 2019 (COVID-19) varies significantly among persons of similar age and is higher in males. Age-independent, sex-biased differences in susceptibility to severe COVID-19 may be ascribable to deficits in a sexually dimorphic protective attribute that we termed immunologic resilience (IR). OBJECTIVE: We sought to examine whether deficits in IR that antedate or are induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection independently predict COVID-19 mortality. METHODS: IR levels were quantified with 2 novel metrics: immune health grades (IHG-I [best] to IHG-IV) to gauge CD8+ and CD4+ T-cell count equilibrium, and blood gene expression signatures. IR metrics were examined in a prospective COVID-19 cohort (n = 522); primary outcome was 30-day mortality. Associations of IR metrics with outcomes in non-COVID-19 cohorts (n = 13,461) provided the framework for linking pre-COVID-19 IR status to IR during COVID-19, as well as to COVID-19 outcomes. RESULTS: IHG-I, tracking high-grade equilibrium between CD8+ and CD4+ T-cell counts, was the most common grade (73%) among healthy adults, particularly in females. SARS-CoV-2 infection was associated with underrepresentation of IHG-I (21%) versus overrepresentation (77%) of IHG-II or IHG-IV, especially in males versus females (P < .01). Presentation with IHG-I was associated with 88% lower mortality, after controlling for age and sex; reduced risk of hospitalization and respiratory failure; lower plasma IL-6 levels; rapid clearance of nasopharyngeal SARS-CoV-2 burden; and gene expression signatures correlating with survival that signify immunocompetence and controlled inflammation. In non-COVID-19 cohorts, IR-preserving metrics were associated with resistance to progressive influenza or HIV infection, as well as lower 9-year mortality in the Framingham Heart Study, especially in females. CONCLUSIONS: Preservation of immunocompetence with controlled inflammation during antigenic challenges is a hallmark of IR and associates with longevity and AIDS resistance. Independent of age, a male-biased proclivity to degrade IR before and/or during SARS-CoV-2 infection predisposes to severe COVID-19.

STRADA-mutant human cortical organoids model megalencephaly and exhibit delayed neuronal differentiation.

Genetic diseases involving overactivation of the mechanistic target of rapamycin (mTOR) pathway, so-called "mTORopathies," often manifest with malformations of cortical development (MCDs), epilepsy, and cognitive impairment. How mTOR pathway hyperactivation results in abnormal human cortical development is poorly understood. To study the effect of mTOR hyperactivity on early stages of cortical development, we focused on Pretzel Syndrome (polyhydramnios, megalencephaly, symptomatic epilepsy; PMSE syndrome), a rare mTORopathy caused by homozygous germline mutations in the STRADA gene. We developed a human cortical organoid (hCO) model of PMSE and examined morphology and size for the first 2 weeks of organoid growth, and cell type composition at weeks 2, 8, and 12 of differentiation. In the second week, PMSE hCOs enlarged more rapidly than controls and displayed an abnormal Wnt pathway-dependent increase in neural rosette structures. PMSE hCOs also exhibited delayed neurogenesis, decreased subventricular zone progenitors, increased proliferation and cell death, and an abnormal architecture of primary cilia. At week 8, PMSE hCOs had fewer deep layer neurons. By week 12, neurogenesis recovered in PMSE organoids, but they displayed increased outer radial glia, a cell type thought to contribute to the expansion of the human cerebral cortex. Together, these findings suggest that megalencephaly in PMSE arises from the expansion of neural stem cells in early corticogenesis and potentially also from increased outer radial glial at later gestational stages. The delayed neuronal differentiation in PMSE organoids demonstrates the important role the mTOR pathway plays in the maintenance and expansion of the stem cell pool.

The use of short message service (SMS) to reduce outpatient attendance in ophthalmic clinics during the coronavirus pandemic.

PURPOSE: In order to minimize the risk of transmission of coronavirus disease 2019 (COVID-19), many clinic appointments were postponed to lower patient attendance. Actively calling patients to postpone appointments is a labour-intensive process. We were the first ophthalmic clinics in Hong Kong to use short message service (SMS) to dispatch messages simultaneously to a large number of patients to offer postponement of appointments. The aim of this study is to evaluate whether SMS is an effective method to reduce outpatient attendance during the COVID-19 pandemic. METHODS: This is an observational study reviewing data on SMS messages sent to all patients attending ophthalmology clinics of a tertiary eye centre in Hong Kong. All SMS were sent at least 5 days before the scheduled appointments. The text message included an enquiry hotline for postponement of appointments and offered drug refill. The study included data from February to April 2020. Two hundred patients were invited to take part in a questionnaire on satisfaction level and reason(s) for appointment rescheduling. RESULTS: During the study period, a total of 17,028 SMS were sent. The overall response rate was 23.6%. 14.3% postponed their appointments. This led to an overall 13.9% reduction of clinic attendance. The overall satisfaction was high (96%). The main reason for postponing appointment was worries about infection risk (93.1%). CONCLUSION: SMS was an efficient and cost-effective flow-control method which was well accepted by patients and can reduce outpatient attendance. The time saved can potentially allow healthcare workers to conduct other infection control measures during the COVID-19 pandemic.

Laboratory Diagnosis of Cutaneous and Visceral Leishmaniasis: Current and Future Methods.

Leishmaniasis is a neglected tropical disease with two main clinical forms: cutaneous and visceral leishmaniasis. Diagnosis of leishmaniasis is still a challenge, concerning the detection and correct identification of the species of the parasite, mainly in endemic areas where the absence of appropriate resources is still a problem. Most accessible methods for diagnosis, particularly in these areas, do not include the identification of each one of more than 20 species responsible for the disease. Here, we summarize the main methods used for the detection and identification of leishmaniasis that can be performed by demonstration of the parasite in biological samples from the patient through microscopic examination, by in vitro culture or animal inoculation; by molecular methods through the detection of parasite DNA; or by immunological methods through the detection of parasite antigens that may be present in urine or through the detection of specific antibodies against the parasite. Potential new methods that can be applied for laboratory diagnosis of leishmaniasis are also discussed.

KICK OUT PD: Feasibility and quality of life in the pilot karate intervention to change kinematic outcomes in Parkinson's Disease.

BACKGROUND: Multiple exercise modalities and mindfulness activities are beneficial in Parkinson's Disease (PD). Karate is a martial art that combines aerobic and large-amplitude movements, balance and core training, and mindfulness, suggesting a potential benefit for individuals with PD from multiple perspectives. OBJECTIVE: To evaluate the feasibility of community-based Shotokan karate classes involving physical activity and mindfulness among individuals with mild- to moderate-stage PD, and to explore the effects of karate on objective and patient-reported outcomes. METHODS: We conducted a 10-week, unblinded trial of twice weekly, PD-specific karate classes. Feasibility was assessed by: dropout rates, adherence via attendance records, adverse effects and falls, and continued participation six months post-intervention. Participants completed pre- and post-intervention assessments of disease-related quality of life (Parkinson's Disease Questionnaire-8, PDQ-8), falls, and post-intervention assessment of change in overall wellbeing (Patient Global Impression of Change, PGIC), with exploratory measures of mobility using the Timed Up and Go (TUG), mood using the Hospital Anxiety and Depression Scale (HADS), and cognition using digit span forward and backward and the Symbol Digit Modalities Test (SDMT). RESULTS: Of 19 enrolled participants, 15 completed the study (79%). Among completers, mean adherence was 87% during the ten weeks of intervention, and 53% maintained karate participation six months later and endorsed sustained improvement, respectively. No adverse effects or change in fall frequency were detected. Among completers, 53% were women, and mean PD duration was 6 years (range 2-20). Quality of life improved to a clinically significant degree (PDQ-8: mean 25.3 (standard deviation (SD) 20.8) versus 19.3 (SD 19.6), p = 0.01, effect size 0.83). On the PGIC, 87% endorsed feeling moderately or considerably better. Mobility did not change significantly (TUG: 9.6 seconds (SD 2.23) versus 9.0 seconds (SD 1.89), p = 0.12, effect size 0.43), nor were there changes in overall physical activity, mood, or cognition (p = 0.35-0.92). CONCLUSIONS: In a small, 10-week, unblinded trial of community-based karate classes for individuals with mild and moderate PD, high adherence was noted. Quality of life and wellbeing improved significantly, without changes in exploratory outcomes of mobility or neuropsychological outcomes. The study was underpowered, particularly for the exploratory outcomes. Controlled and longitudinal investigation is warranted to confirm our pilot findings and explore the long-term effects and sustainability of karate in PD. TRIAL REGISTRATION: Clinicaltrials.gov: NCT03555695.

Large-scale death of retinal astrocytes during normal development is non-apoptotic and implemented by microglia.

Naturally occurring cell death is a fundamental developmental mechanism for regulating cell numbers and sculpting developing organs. This is particularly true in the nervous system, where large numbers of neurons and oligodendrocytes are eliminated via apoptosis during normal development. Given the profound impact of death upon these two major cell populations, it is surprising that developmental death of another major cell type-the astrocyte-has rarely been studied. It is presently unclear whether astrocytes are subject to significant developmental death, and if so, how it occurs. Here, we address these questions using mouse retinal astrocytes as our model system. We show that the total number of retinal astrocytes declines by over 3-fold during a death period spanning postnatal days 5-14. Surprisingly, these astrocytes do not die by apoptosis, the canonical mechanism underlying the vast majority of developmental cell death. Instead, we find that microglia engulf astrocytes during the death period to promote their developmental removal. Genetic ablation of microglia inhibits astrocyte death, leading to a larger astrocyte population size at the end of the death period. However, astrocyte death is not completely blocked in the absence of microglia, apparently due to the ability of astrocytes to engulf each other. Nevertheless, mice lacking microglia showed significant anatomical changes to the retinal astrocyte network, with functional consequences for the astrocyte-associated vasculature leading to retinal hemorrhage. These results establish a novel modality for naturally occurring cell death and demonstrate its importance for the formation and integrity of the retinal gliovascular network.

A Prospective Evaluation of Point of Care Ultrasound Teaching in Switzerland.

CONTEXT: As the utility of point-of-care ultrasound (POCUS) continues to expand in the medical field, there is a need for effective educational methods. In Switzerland, medical education follows the European model and lasts 6 years, focusing on preclinical training during the first 2 years. No previous studies have evaluated the optimal time for teaching ultrasound in European medical education. AIMS: The aim of this study is to provide ultrasound training to medical students in Switzerland at varying times during their clinical training to determine if the level of training plays a role in their ability to comprehend and to apply basic POCUS skills. METHODS: We performed an observational study utilizing a convenience sample of Swiss medical students between July 11, 2016 and August 6, 2016. They were taught a 2-day POCUS course by five American-trained 1st-year medical students. Following this course, students were evaluated with written and clinical examination. RESULTS: 100 Swiss medical students were enrolled in the study. A total of 59 of these students were early clinical students, and 41 students were late clinical students. A two-tailed t-test was performed and demonstrated that the late clinical students performed better than the early clinical students on the written assessment; however, no difference was found in clinical skill. CONCLUSION: Our data suggest that Swiss medical students can learn and perform POCUS after a 2-day instructional taught by trained 1st-year American medical students. No difference was found between students in early clinical training and late clinical training for the ability to perform POCUS.

Kinematic analysis of mandibular motion before and after mandibulectomy and mandibular reconstruction in dogs.

OBJECTIVE: To evaluate and quantify the kinematic behavior of canine mandibles before and after bilateral rostral or unilateral segmental mandibulectomy as well as after mandibular reconstruction with a locking reconstruction plate in ex vivo conditions. SAMPLE: Head specimens from cadavers of 16 dogs (range in body weight, 30 to 35 kg). PROCEDURE: Specimens were assigned to undergo unilateral segmental (n = 8) or bilateral rostral (8) mandibulectomy and then mandibular reconstruction by internal fixation with locking plates. Kinematic markers were attached to each specimen in a custom-built load frame. Markers were tracked in 3-D space during standardized loading conditions, and mandibular motions were quantified. Differences in mandibular range of motion among 3 experimental conditions (before mandibulectomy [ie, with mandibles intact], after mandibulectomy, and after reconstruction) were assessed by means of repeated-measures ANOVA. RESULTS: Both unilateral segmental and bilateral rostral mandibulectomy resulted in significantly greater mandibular motion and instability, compared with results for intact mandibles. No significant differences in motion were detected between mandibles reconstructed after unilateral segmental mandibulectomy and intact mandibles. Similarly, the motion of mandibles reconstructed after rostral mandibulectomy was no different from that of intact mandibles, except in the lateral direction. CONCLUSIONS AND CLINICAL RELEVANCE: Mandibular kinematics in head specimens from canine cadavers were significantly altered after unilateral segmental and bilateral rostral mandibulectomy. These alterations were corrected after mandibular reconstruction with locking reconstruction plates. Findings reinforced the clinical observations of the beneficial effect of reconstruction on mandibular function and the need for reconstructive surgery after mandibulectomy in dogs.

Methotrexate-induced iatrogenic immunodeficiency-associated lymphoproliferative disorder causing hypercalcaemia.

Hypercalcaemia is a rare but potentially life-threatening consequence of malignancies. Solid cancers, such as lymphomas, increase serum calcium primarily through parathyroid hormone-related protein or ectopic production of 1alpha-hydroxylase. We present a case of 56-year-old woman with Sjogren's syndrome and psoriasis in the setting of chronic methotrexate (MTX) use who developed worsening hypercalcaemia and symptoms suggestive of lymphoma. Pathology results diagnosed her with MTX-induced iatrogenic immunodeficiency-associated lymphoproliferative disorder (LPD). This case reminds clinicians that chronic MTX use is associated with LPDs and can ultimately lead to hypercalcaemia. The patient's MTX and other immunosuppressive medications were stopped, and her calcium corrected with fluids and calcitonin. At her 8-month follow-up postdischarge, the patient was asymptomatic with normal laboratory results and in partial clinical remission.

Characteristics of Physical Aggression in Children of Immigrant Mothers and Non-immigrant Mothers: A Cross-Sectional Analysis of the Survey of Young Canadians.

Physical aggression (PA) is important to regulate as early as the preschool years in order to ensure healthy development of children. This study aims to determine the prevalence and characteristics of PA in children of immigrant and non-immigrant mothers. Secondary data analysis was conducted using the nationwide 2010 Survey for Young Canadians, limited to children 4-9 years of age. Bivariate and multivariable logistic regression was performed, with the outcome, PA, and covariates including maternal, child, household and neighbourhood characteristics. Twenty percent of children of non-immigrant mothers and 16% of children of immigrant mothers reported PA. The only common characteristic of PA between children of non-immigrant (Adj OR 1.44, 95% CI 1.09-1.89) and immigrant mothers (Adj OR 2.08, 95% CI 1.07-4.03) was viewing violent movies/shows. The characteristics of PA differ between children of immigrant versus non-immigrant mothers therefore healthcare providers, policy makers, and researchers should be mindful to address PA in these two groups separately, and find ways to tailor current recommended coping strategies and teach children alternative ways to solve problems based on their needs.

Anaphylactoid Reaction from Trimethoprim-Sulfamethoxazole with Subsequent T-wave Inversions in a Young Patient with Dermatomyositis.

Dermatomyositis is a disease of inflammation and vasculopathy, characterized by proximal muscle weakness and classic cutaneous eruptions. Often, patients show signs of lung, esophageal, and cardiac involvement. Cardiac involvement in dermatomyositis and other inflammatory myosidities can result in conduction abnormalities, ventricular dysfunction, and hypertrophy. Some patients will become symptomatic from the sequelae of the impairment, progressing to the onset of heart failure, pericarditis, or arrhythmias. Others might remain clinically asymptomatic, with evidence of cardiac involvement of their disease seen only with electrocardiograms and imaging. A preexisting damaged myocardium is more susceptible to the damaging effects of the chemical mediators and the stress of an anaphylactic reaction. Patients with dermatomyositis often have subclinical manifestations of cardiac involvement that can predispose them to more severe and life-threatening consequences of anaphylaxis and anaphylactoid reactions. The present case report documents a patient with dermatomyositis whose disease was not complicated with cardiac involvement yet who ultimately showed lasting cardiovascular effects from an anaphylactoid reaction. This case highlights the dangers of allergic reactions in patients with inflammatory myopathies, such as dermatomyositis, as they can have more profound cardiovascular manifestations of the reactions and develop enduring changes to their myocardium.