Cholesteryl Ester Transfer Protein Influences High-Density Lipoprotein Levels and Survival in Sepsis.

RATIONALE: High-density lipoprotein (HDL) cholesterol (HDL-C) levels decline during sepsis, and lower levels are associated with worse survival. However, the genetic mechanisms underlying changes in HDL-C during sepsis, and whether the relationship with survival is causative, are largely unknown. OBJECTIVES: We hypothesized that variation in genes involved in HDL metabolism would contribute to changes in HDL-C levels and clinical outcomes during sepsis. METHODS: We performed targeted resequencing of HDL-related genes in 200 patients admitted to an emergency department with sepsis (Early Infection cohort). We examined the association of genetic variants with HDL-C levels, 28-day survival, 90-day survival, organ dysfunction, and need for vasopressor or ventilatory support. Candidate variants were further assessed in the VASST (Vasopressin versus Norepinephrine Infusion in Patients with Septic Shock Trial) cohort (n = 632) and St. Paul's Hospital Intensive Care Unit 2 (SPHICU2) cohort (n = 203). MEASUREMENTS AND MAIN RESULTS: We identified a rare missense variant in CETP (cholesteryl ester transfer protein gene; rs1800777-A) that was associated with significant reductions in HDL-C levels during sepsis. Carriers of the A allele (n = 10) had decreased survival, more organ failure, and greater need for organ support compared with noncarriers. We replicated this finding in the VASST and SPHICU2 cohorts, in which carriers of rs1800777-A (n = 35 and n = 12, respectively) had significantly reduced 28-day survival. Mendelian randomization was consistent with genetically reduced HDL levels being a causal factor for decreased sepsis survival. CONCLUSIONS: Our results identify CETP as a critical regulator of HDL levels and clinical outcomes during sepsis. These data point toward a critical role for HDL in sepsis.

Copper (II) complexes of bidentate ligands exhibit potent anti-cancer activity regardless of platinum sensitivity status.

Insensitivity to platinum, either through inherent or acquired resistance, is a major clinical problem in the treatment of many solid tumors. Here, we explored the therapeutic potential of diethyldithiocarbamate (DDC), pyrithione (Pyr), plumbagin (Plum), 8-hydroxyquinoline (8-HQ), clioquinol (CQ) copper complexes in a panel of cancer cell lines that differ in their sensitivity to platins (cisplatin/carboplatin) using a high-content imaging system. Our data suggest that the copper complexes were effective against both platinum sensitive (IC50 ~ 1 µM platinum) and insensitive (IC50 > 5 µM platinum) cell lines. Furthermore, copper complexes of DDC, Pyr and 8-HQ had greater therapeutic activity compared to the copper-free ligands in all cell lines; whereas the copper-dependent activities of Plum and CQ were cell-line specific. Four of the copper complexes (Cu(DDC)2, Cu(Pyr)2, Cu(Plum)2 and Cu(8-HQ)2) showed IC50 values less than that of cisplatin in all tested cell lines. The complex copper DDC (Cu(DDC)2) was selected for in vivo evaluation due to its low nano-molar range activity in vitro and the availability of an injectable liposomal formulation. Liposomal (Cu(DDC)2) was tested in a fast-growing platinum-resistant A2780-CP ovarian xenograft model and was found to achieve a statistically significant reduction (50%; p < 0.05) in tumour size. This work supports the potential use of copper-based therapeutics to treat cancers that are insensitive to platinum drugs.

Isolated Intracranial Hypertension as a Presentation of Pediatric Lyme Borreliosis: A Case Report and Literature Review.

BACKGROUND: It is extremely rare for Lyme borreliosis to present solely with features of increased intracranial pressure. The treatment of pediatric Lyme neuroborreliosis with oral versus intravenous antibiotics remains controversial. METHODS: Case report and literature review. RESULTS: A 13-year-old male presented with five days of binocular diplopia, several weeks of headache, and a history of multiple tick bites six weeks prior. His examination showed a left eye abduction deficit and bilateral optic disc edema. Magnetic resonance imaging (MRI) of the brain with contrast showed tortuosity of the optic nerves, prominence of the optic nerve sheaths, and enhancement of the left fifth and bilateral sixth cranial nerves. Lumbar puncture showed an elevated opening pressure and a lymphocytic pleocytosis. Lyme IgM and IgG antibodies were positive in the serum and cerebrospinal fluid. The patient was treated with intravenous ceftriaxone for two days empirically followed by doxycycline by mouth for 19 days. Symptoms began improving after 48 hours. The strabismus resolved after two weeks, and the papilledema improved slowly with complete resolution at six months. CONCLUSIONS: Lyme neuroborreliosis can present as isolated intracranial hypertension in the pediatric population; it can be differentiated from idiopathic intracranial hypertension on MRI, and lumbar puncture and can be confirmed with serum antibody testing. Oral doxycycline can be considered for Lyme neuroborreliosis in children.

Orbital Edema Secondary to a Sphenoidal Mass as the Presenting Symptom of High-Risk Precursor B-Cell Acute Lymphoblastic Leukemia.

Introduction: Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy, known to present with ocular manifestations in rare cases. Case Presentation: We describe the case of a 9-year-old previously healthy male who developed a 2-day history of periocular swelling and was found on MRI to have a large sphenoidal mass. Further work up showed involvement of the spinal cord, iliac crests, and kidneys. His initial blood work showed no hematological abnormalities. A bone marrow biopsy taken from the iliac crest demonstrated >90% B lymphoblasts and flow cytometry was positive for CD19. Overall, his investigations were consistent with a diagnosis of precursor B-cell ALL (pre B-ALL). His neuro-ophthalmic exam showed right-sided subtle periocular edema, decreased palpebral fissure height, and proptosis. Posterior exam showed mild nasal elevation of the right optic disc without vessel obscuration and mild tortuosity of the peripheral vessels. He otherwise had no overt signs of afferent or efferent dysfunction despite the proximity of the mass to his optic nerve and globe. Conclusion: This case demonstrates that high-risk pre B-ALL, a childhood cancer not commonly associated with orbital manifestations, can present with orbital edema and normal leukocyte count in an otherwise healthy child.

A Pandemic Innovation: Student-Led Model to Increase Accessibility to Educational and Mentorship Opportunities.

The Canadian Ophthalmology Student Interest Group (COSIG) is the first national medical student-led specialty interest group in Canada. COSIG has run several initiatives aimed at increasing students' opportunities for ophthalmology exposure and learning, including a resident-medical student mentorship program, an annual 6-week introductory course, amongst other events, and webinars.

Risk of ocular adverse events with aromatase inhibitors.

OBJECTIVE: Aromatase inhibitors (AIs) are a class of medications used for adjuvant treatment of breast cancer. Recent case reports suggest that AIs may be associated with various ocular adverse events (AEs). This study evaluates the risk of ocular AEs in patients who take AIs. METHOD: Disproportionality analysis was performed using data from the U.S. Food and Drug Administration's Adverse Events Reporting System database from 2004 to 2022. All cases of vitreomacular traction, macular edema, retinal deposits, retinal artery occlusion, macular hole, retinal hemorrhage, uveitis, retinal tear, retinal detachment, dry eye disease, blepharitis, and optic neuropathy were searched for the 3 AIs anastrozole, letrozole, and exemestane. A search also was performed on trastuzumab as a control. Reported odds ratios (RORs) and corresponding 95% CIs were computed. RESULTS: We identified 322 ocular AEs of interest for the 3 AIs and 55 for trastuzumab. Anastrozole had the most AEs (n = 163) and was found to have strong associations with vitreomacular traction (ROR = 665; 95% CI, 352-1255), macular edema (ROR = 37; 95% CI, 25-54), retinal deposits (ROR = 11; 95% CI, 2-77), and uveitis (ROR = 6; 95% CI, 4-9). Letrozole had strong associations with retinal deposits (ROR = 8, 95% CI, 1-57) and retinal artery occlusion (ROR = 6; 95% CI, 3-11). Exemestane had a strong association with macular holes (ROR = 10; 95% CI, 3-30). CONCLUSION: Disproportionality analysis revealed an increased risk of ocular AEs with each of the AIs. This study calls for clinicians, especially oncologists and ophthalmologists, to be vigilant in patients who are on AI therapy, allowing them to provide prompt interventions to mitigate further ocular morbidities.

Late recurrence of idiopathic Brown's syndrome successfully treated with oral corticosteroids.

INTRODUCTION: Idiopathic Brown's syndrome is a restrictive strabismus of the superior oblique tendon that often presents in pediatric populations and rarely occurs in adults. CASE DESCRIPTION: We present here a case of a 41-year-old man with an idiopathic left Brown's syndrome that recurred after presenting with similar symptoms 14 years prior that was originally treated with oral corticosteroids. This patient had a negative work up for connective tissue disease and only exhibited subtle left trochlear thickening on orbital MRI with contrast. Since he had a good response to oral corticosteroids in the past, this repeat occurrence was treated with oral Prednisone and he promptly responded. His double vision resolved within 2 weeks and he continued to have a normal examination 6 months after presentation. CONCLUSION: We suspect this case was related to a subclinical inflammatory process resulting in the MRI findings and response to steroids. This case demonstrates that idiopathic Brown's syndrome can recur more than a decade later in adults and oral corticosteroids are an effective treatment option even in the absence of an underlying rheumatological condition.

Recent advances and future directions on the use of optical coherence tomography in neuro-ophthalmology.

Optical coherence tomography (OCT) is a noninvasive imaging technique used to qualitatively and quantitatively analyze various layers of the retina. OCT of the retinal nerve fiber layer (RNFL) and ganglion cell-inner plexiform layer (GCIPL) is particularly useful in neuro-ophthalmology for the evaluation of patients with optic neuropathies and retrochiasmal visual pathway disorders. OCT allows for an objective quantification of edema and atrophy of the RNFL and GCIPL, which may be evident before obvious clinical signs and visual dysfunction develop. Enhanced depth imaging OCT allows for visualization of deep structures of the optic nerve and has emerged as the gold standard for the detection of optic disc drusen. In the evaluation of compressive optic neuropathies, OCT RNFL and GCIPL thicknesses have been established as the most important visual prognostic factor. There is increasing evidence that inclusion of OCT as part of the diagnostic criteria for multiple sclerosis (MS) increases its sensitivity. Moreover, OCT of the RNFL and GCIPL may be helpful in the early detection and monitoring the treatment of conditions such as MS and Alzheimer's disease. OCT is an important aspect of the neuro-ophthalmologic assessment and its use is likely to increase moving forward.

Pyelonephritis and Bacteremia Caused by Klebsiella variicola following Renal Transplantation.

Klebsiella variicola (K. variicola) is a Gram-negative organism genetically similar to Klebsiella pneumoniae (K. pneumoniae) that can cause a variety of diseases in humans. Bacteremia due to K. variicola is associated with a higher mortality rate than bacteremia with K. pneumoniae. Here, we describe a 65-year-old woman who developed pyelonephritis 2 months after receiving a renal transplantation following a longstanding history of end-stage renal disease secondary to polycystic kidney disease. Her creatinine on admission was unchanged from her posttransplant baseline, and an abdominal CT scan showed inflammatory changes around the transplanted kidney that were suggestive of an infection rather than allograft rejection. She was initially treated empirically with meropenem given a history of extended-spectrum beta-lactamase- (ESBL-) producing E. coli bacteriuria. After a day of therapy with meropenem, her therapy was streamlined based on culture results to ceftriaxone. She continued to improve, her kidney function remained stable, and she was prescribed oral ciprofloxacin to complete a 14-day total course of antibiotics. This case is the first reported instance of K. variicola bacteremia associated with pyelonephritis in a renal transplant recipient. Hospitalization with acute pyelonephritis within the first year following kidney transplant is common and is associated with increased risk of graft loss and mortality. However, K. variicola is not a commonly known organism to cause this infection. Despite the risk of allograft failure in this circumstance, this patient was successfully treated with a 14-day course of antibiotic therapy.

Effect of COVID-19 on Canadian Medical Student Attitudes toward Ophthalmology Residency Application.

Objective This study aims to survey medical students interested in ophthalmology about how changes in electives and Canadian Residency Matching Service (CaRMS) due to the novel coronavirus disease 2019 (COVID-19) pandemic have affected their attitudes toward applying to ophthalmology residency. Design This is a cross-sectional survey. Participants A total of 32 Canadian medical students interested in ophthalmology responded to the survey. Methods A 32-question survey tool used was developed in consultation with medical students, academic ophthalmologists, and residency program directors. The survey was distributed through e-mail by local ophthalmology interest groups at all of Canada's medical schools. Results Respondents felt that changes in ability to travel for electives significantly decreased their likelihood of applying to ophthalmology residency. Additionally, respondents expressed concerns that lack of travel for electives and in-person CaRMS interviews significantly reduced their chances of successfully matching to ophthalmology. Respondents identified one-on-one video calls with program directors and residents as the initiatives that would best counteract the negative impacts from COVID-19. Increased presence of programs on social media were relatively less valued. Conclusion Canadian medical students interested in ophthalmology have concerns about how changes in electives and the CaRMS match due to COVID-19 will impact their ability to be fairly assessed and successfully match to ophthalmology. Lack of travel for electives and interviews has also resulted in students feeling ill equipped to make informed choices about program selection. However, there remains a sustained interest in ophthalmology among applicants.

Acute Vision Loss as an Ophthalmic Complication of Dental Procedures.

Introduction: Acute vision loss has been previously described as a complication of dental procedures through a variety of mechanisms. The vision loss is typically transient, although permanent loss has been reported. Physicians, including ophthalmologists, typically lack formal education around dental procedures and may be uninformed about the risks to ocular or periocular structures as well as the types of complications that can arise. We aimed to summarize literature describing the various mechanisms by which dental procedures can lead to vision loss in order to equip physicians (primary care, emergency medicine, and ophthalmologists) with a better understanding of the mechanisms by which dental procedures can lead to acute vision loss. Methods: A literature search (1950 to 2020) identified articles discussing acute vision loss as a complication of dental procedures. Results: Dental procedures can result in a variety of ophthalmological conditions through ischemic, infectious, compressive, and anesthetic-related etiologies. Conclusions: While the majority of vision loss is transient and requires little management, there are vision and life-threatening complications that can arise and would require assessment and appropriate treatment.

Pharmacogenomics in Asian Subpopulations and Impacts on Commonly Prescribed Medications.

Asians as a group comprise > 60% the world's population. There is an incredible amount of diversity in Asian and admixed populations that has not been addressed in a pharmacogenetic context. The known pharmacogenetic differences in Asian subgroups generally represent previously known variants that are present at much lower or higher frequencies in Asians compared with other populations. In this review we summarize the main drugs and known genes that appear to have differences in their pharmacogenetic properties in certain Asian populations. Evidence-based guidelines and summary statistics from the US Food and Drug Administration and the Clinical Pharmacogenetics Implementation Consortium were analyzed for ethnic differences in outcomes. Implicated drugs included commonly prescribed drugs such as warfarin, clopidogrel, carbamazepine, and allopurinol. The majority of these associations are due to Asians more commonly being poor metabolizers of cytochrome P450 (CYP) 2C19 and carriers of the human leukocyte antigen (HLA)-B*15:02 allele. The relative risk increase was shown to vary between genes and drugs, but could be > 100-fold higher in Asians. Specifically, there was a 172-fold increased risk of Stevens-Johnson syndrome and toxic epidermal necrolysis with carbamazepine use among HLA-B*15:02 carriers. The effects ranged from relatively benign reactions such as reduced drug efficacy to severe cutaneous skin reactions. These reactions are severe and prevalent enough to warrant pharmacogenetic testing and appropriate changes in dose and medication choice for at-risk populations. Further studies should be done on Asian cohorts to more fully understand pharmacogenetic variants in these populations and to clarify how such differences may influence drug response.

Perspectives About Time Frames in Stem Cell Research for Multiple Sclerosis: "Time Is Brain".

BACKGROUND: Stem cell research has been a focus of inquiry in the field of neurology for nearly 3 decades and has led to much hope for people with multiple sclerosis (MS). Previous studies, however, demonstrate that information about the pace of developments in the stem cell arena is less accessible than are representations of potential benefits. METHODS: To explore the understanding and perspectives of adult patients with MS and MS clinicians about the time frames associated with stem cell research, we conducted semistructured interviews with 20 patients with MS across Canada and 15 clinicians who specialize in MS. Patients who participated did not have any previous stem cell interventions. Interviews were analyzed for recurring themes and individual variations using the constant comparative approach. RESULTS: We found that patients with MS have a limited understanding about the time that it takes for stem cell research to reach the clinic. In parallel, they express a desire to know more than they do about the translational process. Clinicians offer strategies to address patients' questions about the pace of stem cell research and to promote informed hope about experimental interventions. CONCLUSIONS: These results underscore opportunities to promote transparency in clinical discourse about the pace of stem cell research for MS and other progressive neurologic diseases.

Availability, readability, and content of privacy policies and terms of agreements of mental health apps.

OBJECTIVE: To assess the availability, readability, and privacy-related content of the privacy policies and terms of agreement of mental health apps available through popular digital stores. MATERIALS AND METHODS: Popular smartphone app stores were searched using combinations of keywords "track" and "mood" and their synonyms. The first 100 apps from each search were evaluated for inclusion and exclusion criteria. Apps were assessed for availability of a privacy policy (PP) and terms of agreement (ToA) and if available, these documents were evaluated for both content and readability. RESULTS: Most of the apps collected in the sample did not include a PP or ToA. PPs could be accessed for 18% of iOS apps and 4% of Android apps; whereas ToAs were available for 15% of iOS and 3% of Android apps. Many PPs stated that users' information may be shared with third parties (71% iOS, 46% Android). DISCUSSION: Results demonstrate that information collection is occurring with the majority of apps that allow users to track the status of their mental health. Most of the apps collected in the initial sample did not include a PP or ToA despite this being a requirement by the store. The majority of PPs and ToAs that were evaluated are written at a post-secondary reading level and disclose that extensive data collection is occurring. CONCLUSION: Our findings raise concerns about consent, transparency, and data sharing associated with mental health apps and highlight the importance of improved regulation in the mobile app environment.

Pharmacogenomics of Cisplatin-Induced Ototoxicity: Successes, Shortcomings, and Future Avenues of Research.

Cisplatin is a highly effective chemotherapeutic. Unfortunately, its use is limited by cisplatin-induced ototoxicity (CIO). Substantial research has been performed to uncover the genetic variants associated with CIO; however, there has been a lack of consistency in the results that have been reported. This paper aims to provide an overview of the current state of CIO genomics research, delving into the shortcomings of past research, and providing recommendations for future avenues of study.

Treatment effects of the differential first-line antiretroviral regimens among HIV/HBV coinfected patients in southwest China: an observational study.

HIV with HBV co-infection can result in greater HIV-related immunosuppression, morbidity and mortality. Currently, there are few studies to evaluate direct treatment effects on mortality and attrition rates between first-line antiretroviral therapy (ART) based-on tenofovir (TDF) and/or lamivudine (3TC) in a real-world setting. We used Cox proportional hazard models to evaluate direct treatment effects of the first-line ART containing stavudine (d4T), azidothymidine (AZT) and TDF on death and attrition among HIV patients with HBV coinfection. A total of 3912 patients met study eligibility criteria. The overall mortality rate and attrition rate was 2.85 (95% CI: 2.55-3.16) and 8.87 (95% CI: 8.32-9.41) per 100 person-years, respectively. The ART containing TDF had a significantly lower risk of death [adjusted hazard ratio (AHR) = 0.58, 95% CI: 0.44-0.77] when compared to the ART containing d4T, but the risk of death was not significantly different when compared to the ART containing AZT (AHR = 0.91, 95% CI: 0.69-1.20). Patients with HIV/HBV coinfection receiving the ART containing TDF had significantly lower risk rates of attrition compared to those receiving the ART containing d4T (AHR = 0.72, 95% CI: 0.60-0.86) or AZT (AHR = 0.67, 95% CI: 0.58-0.77). Compared with the ART containing d4T, the ART containing AZT was significant and not significant associated with a lower risk of death and attrition, respectively. The ART containing TDF had significant effects on both of death and attrition among HIV patients with HBV coinfection.

Reflections on translation: Views of participants in a multisite Canadian CCSVI clinical trial.

BACKGROUND: We sought to characterize the perspectives of participants in Canada's phase I/II chronic cerebrospinal venous insufficiency (CCSVI) clinical trial prior to and after the disclosure of trial results. METHODS: This was a researcher-administered survey of individuals who participated in Canada's CCSVI trial (Clincialtrials.gov, NCT01864941) about their (1) motivations for participating, (2) understanding of the trial process, and (3) perspectives on the social value of the trial. RESULTS: A total of 63 participants completed the survey. Participants were motivated to participate by altruism (mean score = 4.56 out of 5) and a desire to access the intervention in Canada (mean score = 3.63 out of 5). Many participants expected medical benefits, such as partial disease reversal (mean score = 3.32 out of 5). Participants felt strongly that the crossover trial design promoted fairness (mean score = 4.65 out of 5). Participants' familiarity with the CCSVI controversy increased significantly after the results were revealed (p = 0.0001). Despite negative trial results, participants still felt that the trial was an appropriate use of tax dollars (mean score = 4.68 out of 5). Many (38%) upheld the belief that further CCSVI research is necessary (responses of 4 out of 5 or higher). CONCLUSIONS: There is a strong movement in science today to ensure that research agendas reflect the perspectives of multiple stakeholders, including research participants. While previous work suggests that negative findings adversely affect trust in science, the perspectives of participants in this study demonstrate that good trial design and resilience can prevail over expected tensions.