3D stem-like spheroids-on-a-chip for personalized combinatorial drug testing in oral cancer.

BACKGROUND: Functional drug testing (FDT) with patient-derived tumor cells in microfluidic devices is gaining popularity. However, the majority of previously reported microfluidic devices for FDT were limited by at least one of these factors: lengthy fabrication procedures, absence of tumor progenitor cells, lack of clinical correlation, and mono-drug therapy testing. Furthermore, personalized microfluidic models based on spheroids derived from oral cancer patients remain to be thoroughly validated. Overcoming the limitations, we develop 3D printed mold-based, dynamic, and personalized oral stem-like spheroids-on-a-chip, featuring unique serpentine loops and flat-bottom microwells arrangement. RESULTS: This unique arrangement enables the screening of seven combinations of three drugs on chemoresistive cancer stem-like cells. Oral cancer patients-derived stem-like spheroids (CD 44+) remains highly viable (> 90%) for 5 days. Treatment with a well-known oral cancer chemotherapy regimen (paclitaxel, 5 fluorouracil, and cisplatin) at clinically relevant dosages results in heterogeneous drug responses in spheroids. These spheroids are derived from three oral cancer patients, each diagnosed with either well-differentiated or moderately-differentiated squamous cell carcinoma. Oral spheroids exhibit dissimilar morphology, size, and oral tumor-relevant oxygen levels (< 5% O2). These features correlate with the drug responses and clinical diagnosis from each patient's histopathological report. CONCLUSIONS: Overall, we demonstrate the influence of tumor differentiation status on treatment responses, which has been rarely carried out in the previous reports. To the best of our knowledge, this is the first report demonstrating extensive work on development of microfluidic based oral cancer spheroid model for personalized combinatorial drug screening. Furthermore, the obtained clinical correlation of drug screening data represents a significant advancement over previously reported personalized spheroid-based microfluidic devices. Finally, the maintenance of patient-derived spheroids with high viability under oral cancer relevant oxygen levels of less than 5% O2 is a more realistic representation of solid tumor microenvironment in our developed device.

Health Literacy in Oculofacial Plastic Surgery: A Literature Review.

Patient satisfaction following oculofacial cosmetic procedures depends on preoperative expectations, which may be influenced by online material. Patients with poor health literacy are particularly vulnerable to misinformation and low-quality resources. However, few studies have evaluated the quality of online information on common oculofacial plastic surgeries and procedures. This study aimed to review the literature on the readability and quality of online material related to oculofacial plastic surgery. We conducted a systematic search of the PubMed/MEDLINE database and included 10 studies in our review. Among the readability scores reported in these studies, the lowest was 10, representing a tenth-grade reading level. Furthermore, the online materials were often rated as "poor" quality based on multiple grading scales. Our systematic review of the literature demonstrates that online materials covering common oculofacial plastic surgery procedures are consistently of poor quality and exceed the recommended readability level. Therefore, considering these online materials that influence patient expectations could enable oculofacial plastic surgeons to better tailor their preoperative counseling.

Impacts of morally distressing experiences on the mental health of Canadian health care workers during the COVID-19 pandemic.

Background: Research is urgently needed to understand health care workers' (HCWs') experiences of moral-ethical dilemmas encountered throughout the COVID-19 pandemic, and their associations with organizational perceptions and personal well-being. This research is important to prevent long-term moral and psychological distress and to ensure that workers can optimally provide health services. Objective: Evaluate associations between workplace experiences during COVID-19, moral distress, and the psychological well-being of Canadian HCWs. Method: A total of 1362 French- and English-speaking Canadian HCWs employed during the COVID-19 pandemic were recruited to participate in an online survey. Participants completed measures reflecting moral distress, perceptions of organizational response to the pandemic, burnout, and symptoms of psychological disorders, including depression, anxiety, and posttraumatic stress disorder (PTSD). Results: Structural equation modelling showed that when organizational predictors were considered together, resource adequacy, positive work life impact, and ethical work environment negatively predicted severity of moral distress, whereas COVID-19 risk perception positively predicted severity of moral distress. Moral distress also significantly and positively predicted symptoms of depression, anxiety, PTSD, and burnout. Conclusions: Our findings highlight an urgent need for HCW organizations to implement strategies designed to prevent long-term moral and psychological distress within the workplace. Ensuring availability of adequate resources, reducing HCW risk of contracting COVID-19, providing organizational support regarding individual priorities, and upholding ethical considerations are crucial to reducing severity of moral distress in HCWs.

Antecedentes: Se necesita con urgencia investigaciones para comprender las experiencias de los dilemas éticos y morales que los trabajadores de la salud encontraron durante la pandemia de la COVID-19 y su asociación con las percepciones de la organización y el bienestar personal. Esta investigación es importante para prevenir la angustia moral y psicológica a largo plazo y para asegurar que los trabajadores de la salud puedan proveer de manera óptima los servicios de salud.Objetivo: Evaluar la asociación entre las experiencias en el lugar de trabajo durante la COVID-19, la angustia moral y el bienestar psicológico de los trabajadores de salud canadienses.Métodos: Se reclutó a un total de 1362 trabajadores de salud canadienses, que hablaban francés e inglés y que fueron contratados durante la pandemia de la COVID-19, para participar en un cuestionario en línea. Los participantes completaron mediciones que reflejaban la angustia moral, la percepción de la respuesta de la organización a la pandemia, el burnout y los síntomas de trastornos psicológicos, que incluían a la depresión, a la ansiedad y al trastorno de estrés postraumático (TEPT).Resultados: El modelo de ecuaciones estructurales mostró que cuando los predictores de la organización se consideraban en conjunto ­ los recursos adecuados, el impacto positivo en la vida laboral y un ambiente de trabajo ético ­, predijeron negativamente la gravedad de la angustia moral, mientras que la percepción del riesgo de contraer la COVID-19 predijo positivamente la gravedad de la angustia moral. La angustia moral también predijo de manera significativa y positiva los síntomas de la depresión, la ansiedad, el TEPT y el burnout.Conclusiones: Nuestros hallazgos resaltan la urgente necesidad de que las organizaciones de trabajadores de salud implementen estrategias diseñadas para prevenir la angustia moral y psicológica a largo plazo en el lugar de trabajo. El asegurar la disponibilidad de los recursos adecuados, el reducir el riesgo de que los trabajadores de salud contraigan la COVID-19, el proveer un soporte organizacional adecuado según las prioridades individuales y el respetar las consideraciones éticas son fundamentales para reducir la gravedad de la angustia moral en los trabajadores de salud.

Presentation and outcomes of orbital cellulitis caused by Group F Streptococcus.

PURPOSE: To compare the presentation and outcomes of patients with orbital cellulitis requiring surgical intervention caused by the Group F Streptococcus (GFS) versus other bacteria. We hypothesize that patients with GFS infections have a more severe presentation and worse clinical outcomes compared to infections by other bacteria. METHODS: After Institutional Review Board approval at a large academic institutional center, 70 patients with culture-positive orbital cellulitis who required surgical intervention were identified. Clinical examinations before and after surgery as well as preoperative imaging with computed tomography and/or magnetic resonance imaging were reviewed. The study measures were preoperative and postoperative vision, motility, involved sinus disease, complications, and total hospital length of stay. Multiple imputation was used for missing data. Characteristics of patients were compared using Chi-square and Wilcoxon rank-sum. RESULTS: Nineteen patients (27%) had positive cultures for GFS and 51 patients (73%) had positive cultures for other bacterial species. There was no significant difference in visual acuity, motility, or inflammatory markers in patients with GFS compared to other patients. Patients with GFS were noted to have more sinus involvement on presentation compared to patients with other bacterial infections (P = 0.007). CONCLUSION: GFS associated orbital cellulitis is associated with significantly more sinus involvement, but has similar outcomes as orbital cellulitis from other bacterial species.

A novel design of microfluidic platform for metronomic combinatorial chemotherapy drug screening based on 3D tumor spheroid model.

For treating cancer at various stages, chemotherapy drugs administered in combination provide better treatment results with lower side effects compared to single-drug therapy. However, finding the potential drug combinations has been challenging due to the large numbers of possible combinations from approved drugs and the failure of in vitro 2D well plate-based cancer models. 3D spheroid-based high-throughput microfluidic platforms recapitulate some of the important features of native tumor tissue and offer a promising alternative to evaluate the combinatory effects of the drugs. This study develops a novel polydimethylsiloxane (PDMS) based microfluidic design with a dynamic environment and strategically placed U-shaped wells for testing all seven possible combinations (three single-drug treatments, three pairwise combinations, treatment with all three drugs) of three chemotherapy drugs (Paclitaxel, Vinorelbine, and Etoposide) on lung tumor spheroids. The design of U-shaped wells has been validated with computational results. Firstly, we test all combinations of drugs on the conventional well plate in static conditions with 3D tumor spheroids. Based on static drug testing results, we show a proof-of-concept by testing the most effective drug combination on the microfluidic device in a dynamic environment. The concentration of the drugs used in combination falls below the maximum tolerated dose (MTD) of the individual drugs, towards low dose metronomic (LDM) chemotherapy. LDM combinatorial chemotherapy identified in this study can potentially lower toxicity and provide better treatment results in cancer patients. The device can be further used to culture patient-specific tumor spheroids and identify synergistic drug combinations for personalized medicine.

Exploring the Well-being of Health Care Workers During the COVID-19 Pandemic: Protocol for a Prospective Longitudinal Study.

BACKGROUND: Health care workers (HCWs) have experienced several stressors associated with the COVID-19 pandemic. Structural stressors, including extended work hours, redeployment, and changes in organizational mandates, often intersect with interpersonal and personal stressors, such as caring for those with COVID-19 infections; worrying about infection of self, family, and loved ones; working despite shortages of personal protective equipment; and encountering various difficult moral-ethical dilemmas. OBJECTIVE: The paper describes the protocol for a longitudinal study seeking to capture the unique experiences, challenges, and changes faced by HCWs during the COVID-19 pandemic. The study seeks to explore the impact of COVID-19 on the mental well-being of HCWs with a particular focus on moral distress, perceptions of and satisfaction with delivery of care, and how changes in work structure are tolerated among HCWs providing clinical services. METHODS: A prospective longitudinal design is employed to assess HCWs' experiences across domains of mental health (depression, anxiety, posttraumatic stress, and well-being), moral distress and moral reasoning, work-related changes and telehealth, organizational responses to COVID-19 concerns, and experiences with COVID-19 infections to self and to others. We recruited HCWs from across Canada through convenience snowball sampling to participate in either a short-form or long-form web-based survey at baseline. Respondents to the baseline survey are invited to complete a follow-up survey every 3 months, for a total of 18 months. RESULTS: A total of 1926 participants completed baseline surveys between June 26 and December 31, 2020, and 1859 participants provided their emails to contact them to participate in follow-up surveys. As of July 2021, data collection is ongoing, with participants nearing the 6- or 9-month follow-up periods depending on their initial time of self-enrollment. CONCLUSIONS: This protocol describes a study that will provide unique insights into the immediate and longitudinal impact of the COVID-19 pandemic on the dimensions of mental health, moral distress, health care delivery, and workplace environment of HCWs. The feasibility and acceptability of implementing a short-form and long-form survey on participant engagement and data retention will also be discussed. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/32663.

Facile Route for 3D Printing of Transparent PETg-Based Hybrid Biomicrofluidic Devices Promoting Cell Adhesion.

3D printing has emerged as a promising fabrication technique for microfluidic devices, overcoming some of the challenges associated with conventional soft lithography. Filament-based polymer extrusion (popularly known as fused deposition modeling (FDM)) is one of the most accessible 3D printing techniques available, offering a wide range of low-cost thermoplastic polymer materials for microfluidic device fabrication. However, low optical transparency is one of the significant limitations of extrusion-based microfluidic devices, rendering them unsuitable for cell culture-related biological applications. Moreover, previously reported extrusion-based devices were largely dependent on fluorescent dyes for cell imaging because of their poor transparency. First, we aim to improve the optical transparency of FDM-based microfluidic devices to enable bright-field microscopy of cells. This is achieved using (1) transparent polymer filament materials such as poly(ethylene terephthalate) glycol (PETg), (2) optimized 3D printing process parameters, and (3) a hybrid approach by integrating 3D printed microfluidic devices with cast poly(dimethylsiloxane) (PDMS) blocks. We begin by optimizing four essential 3D printing process parameters (layer height, printing speed, cooling fan speed, and extrusion flow), affecting the overall transparency of 3D printed devices. Optimized parameters produce exceptional optical transparency close to 80% in 3D printed PETg devices. Next, we demonstrate the potential of FDM-based 3D printing to fabricate transparent micromixing devices with complex planar and nonplanar channel networks. Most importantly, cells cultured on native 3D printed PETg surfaces show excellent cell attachment, spreading, and proliferation during 3 days of culture without extracellular matrix coating or surface treatment. Next, we introduce L929 cells inside hybrid PETg-PDMS biomicrofluidic devices as a proof of concept. We demonstrate that 3D printed hybrid biomicrofluidic devices promote cell adhesion, allow bright-field microscopy, and maintain high cell viability for 3 days. Finally, we demonstrate the applicability of the proposed fabrication approach for developing 3D printed microfluidic devices from other FDM-compatible transparent polymers such as polylactic acid (PLA) and poly(methyl methacrylate) (PMMA).

The evidence for using tenofovir disoproxil fumarate plus lamivudine as a nucleoside analogue backbone for the treatment of HIV.

This article evaluates the evidence supporting use of the tenofovir disoproxil fumarate (TDF) plus lamivudine (3 â€‹TC) combination as a dual nucleoside backbone within a triple drug antiretroviral regimen. Key trials that assess the relative efficacy, safety and resistance profile of 3 â€‹TC and emtricitabine (FTC) are discussed. Clinical use of 3 â€‹TC and FTC with two tenofovir prodrugs -TDF and tenofovir alafenamide (TAF) - is presented. Recommendations from various international guidelines for the construction of triple and emerging dual regimens are summarised. In conclusion, data suggest the therapeutic equivalence of 3 â€‹TC and FTC, especially when 3 â€‹TC is combined with TDF.

Delayed periorbital hemorrhage in oculoplastic surgery patients on oral anticoagulants.

Periorbital hemorrhage is a potentially sight threatening surgical complication. The effect of new oral anticoagulants (NOACs) on hemorrhagic events after periorbital surgery has not been investigated. We describe four cases of severe delayed postoperative hemorrhage associated with NOACs, in addition to three cases in patients on traditional antithrombotic agents. Time of delayed hemorrhage ranged from postoperative day 2 to 6. Six patients required surgical intervention to achieve control of bleeding, and two patients required transfusion of blood products. Risk factors and management of this rare complication are discussed.

The BEACON study: protocol for a cohort study as part of an evaluation of the effectiveness of smartphone-assisted problem-solving therapy in men who present with intentional self-harm to emergency departments in Ontario.

BACKGROUND: Patients who present to emergency departments after intentional self-harm are at an increased risk of dying by suicide. This applies particularly to men, who represent nearly two-thirds of those who die by suicide in Ontario. One way of potentially addressing this gap is to offer a course of blended problem-solving therapy, comprised of a brief course of evidence-based psychotherapy for individuals at risk for suicide, facilitated by the use of a patient-facing smartphone application and a clinician-facing "dashboard." This approach has the potential to combine the benefits of face-to-face therapy and technology to create a novel intervention. METHODS: This is a cohort study nested within a larger pragmatic multicentre pre- and post-design cluster randomised trial. Suicidal ideation assessed by the Beck Scale for Suicide Ideation is the primary outcome variable. Secondary outcome measures include depression (Patient Health Questionnaire-9), anxiety (Generalized Anxiety Disorder 7-item scale), post-traumatic stress disorder (Primary Care PTSD Screen), health-related quality of life (EuroQol 5-dimension 5-level questionnaire), meaning in life (Experienced Meaning in Life Scale), perceived social supports (Multidimensional Scale of Perceived Social Support), alcohol use (Alcohol Use Disorders Identification Test), drug use (Drug Abuse Screening Test Short Form 10), problem-solving skills (Social Problem-Solving Inventory-Revised Short Form), and self-reported healthcare costs, as well as health service use measured using Ontario administrative health data. A process evaluation will also be conducted following study completion. DISCUSSION: The cohort study will test whether better adherence to the intervention results in better outcomes. The value of the cohort study design is that we can examine in more detail certain subgroups or other variables that are not available in the larger cluster randomised trial. This trial will aim to improve standards by informing best practice in management of men who self-harm and present to hospitals in Ontario. TRIAL REGISTRATION: ClinicalTrials.gov , NCT03473535 . Registered on March 22, 2018.

Intraorbital Graphite Foreign Body With a Delayed Presentation of Optic Neuropathy.

Traumatic penetrating injuries to the orbit from pencils, while uncommon, have a plethora of presentations, both acute and delayed. With the most incidents occurring in the pediatric population where obtaining a detailed history is difficult, the ability to effectively evaluate and diagnose these injuries is cumbersome, yet important. The authors report a patient who presented with optic neuropathy, blepharoptosis, and strabismus 10 months after an orbital injury with pencil graphite.

A Report of Intracranial Meningioma Recurring as Ectopic Orbital Meningioma Associated With Basal Encephalocele.

The authors describe a rare case of recurrent ectopic meningioma associated with sphenoid encephalocele in the medial anterior orbit of a 52-year-old man with a history of a resected intracranial meningioma. Typical features of ectopic meningioma are reviewed as well as potential etiologies of this very rare recurrence of intracranial meningioma in the orbit. Treatment is typically surgical excision.The authors report a rare case of recurrent orbital ectopic meningioma in the right medial canthus of a 52-year-old man.

Effect of Time to Operative Intervention on Motility Outcomes Following Orbital Floor Fracture Repair in Children.

PURPOSE: To evaluate the relationship between time to surgical intervention and extraocular motility outcomes in children following repair of an orbital floor fracture with inferior rectus entrapment. METHODS: After institution review board's approval, a retrospective, consecutive case series of 28 children with unilateral orbital floor fractures entrapping the inferior rectus muscle was conducted. Clinical examinations and CT images were performed on all children. The main outcomes measures were postoperative motility measurements. RESULTS: Eleven patients underwent surgery within 24 hours of reported injury, while 17 patients underwent surgery after 24 hours. There was no statistically significant difference in average age at the time of surgery (p = 0.47) or average preoperative motility scores (p = 1.0) between the 2 groups. Patients who underwent surgery within 24 hours of reported injury had an improved likelihood of recovery (log hazard ratio = 0.469; 95% confidence interval, -0.42 to 1.36). CONCLUSIONS: Our exploratory study suggests that surgical reduction of inferior rectus entrapment in pediatric orbital floor fractures within 24 hours from the time of injury shows an improved, but nonstatistically significant, likelihood of recovery in motility deficits with earlier surgical intervention.

An abnormal ocular motor manifestation of Joubert syndrome.

Joubert syndrome is a congenital neurodevelopmental disorder primarily affecting the midbrain and hindbrain. It is characterized by ataxia, hypotonia, and developmental delay as well as apnea or abnormal ocular motor function. We describe and present a video of a child with Joubert syndrome with an alternating skew deviation in primary position rather than on lateral gaze, which is a more characteristic phenotype of this condition.

Neuroepithelial Cyst of the Optic Nerve in a Newborn.

Cystic lesions of the optic nerve are uncommon findings that have been associated with neoplasms, systemic disorders, or described as idiopathic. They have been described in a wide range of ages, with few congenital cysts having been described in infants. Surgical excision of these lesions may lead to significant morbidity as previously reported cases often involved transection of the optic nerve. The authors describe a unique case of a newborn with a rare neuroepithelial cyst of the intraorbital optic nerve that was successfully excised while sparing the optic nerve, ultimately resulting in the resolution of an afferent pupillary defect. This case demonstrates that careful surgical excision of a benign optic nerve cyst can be performed without significant morbidity to potentially preserve vision.

Congenital Tonic Pupils Associated With Congenital Central Hypoventilation Syndrome and Hirschsprung Disease.

Autonomic dysfunction can be associated with pupillary abnormalities. We describe a rare association of tonic pupils, congenital central hypoventilation syndrome, and Hirschsprung disease in a newborn with a mutation in the PHOX2B gene, a key regulator of neural crest cells. Hirschsprung disease is characterized by the congenital absence of neural crest-derived intrinsic ganglion cells. Tonic pupils may result from an abnormality of the ciliary ganglion, another structure of neural crest origin. The close association of these conditions in this child suggests a common abnormality in neural crest migration and differentiation.