Presumed Melanocytoma-Associated Choroidal Neovascular Membrane with Hemorrhage Successfully Treated with Intravitreal Aflibercept Injections.

A patient presented with melanocytoma and associated choroidal neovascular membrane with hemorrhage involving the macula. The patient was treated with monthly aflibercept (Eylea) injections with significant improvement of best corrected visual acuity. In this report, we explore the development of a choroidal neovascular membrane (CNVM) formation in a patient with melanocytoma and the effect of intravitreal aflibercept (Eylea) on disease course. Case report study used patient data obtained from examination and imaging. The patient was treated with monthly intravitreal aflibercept injections leading to complete resolution of CNVM and hemorrhage, with significant improvement of best corrected visual acuity. Awareness and proper monitoring for the sequelae of melanocytoma are important for early detection and prevention of visually threatening outcomes. In cases of melanocytoma-associated CNVM formation with large subretinal hemorrhage, intravitreal aflibercept can be an effective tool for inducing CNVM regression and allowing improvement of visual acuity.

Association Between the Pulmonary Artery Pulsatility Index and Prognosis in Pulmonary Arterial Hypertension: A Multicentre Study.

Background: Risk stratification is fundamental in the management of pulmonary arterial hypertension (PAH). Pulmonary artery pulsatility index (PAPi), defined as pulmonary arterial pulse pressure divided by right atrial pressure (RAP), is a hemodynamic index shown to predict acute right ventricular (RV) dysfunction in several settings. Our objective was to test the prognostic utility of PAPi in a diverse multicentre cohort of patients with PAH. Methods: A multicentre retrospective cohort study of consecutive adult patients with a new diagnosis of PAH on right heart catheterization between January 2016 and December 2020 was undertaken across 4 major centres in Canada. Hemodynamic data, clinical data, and outcomes were collected. The association of PAPi and other hemodynamic variables with mortality was assessed by receiver-operating characteristic curves and Cox proportional hazards modeling. Results: We identified 590 patients with a mean age of 61.4 ± 15.5 years, with 66.3% being female. A low PAPi (defined as < 5.3) was associated with higher mortality at 1 year: 10.2% vs 5.2% (P = 0.02). In a multivariable model including age, sex, body mass index, and functional class, a low PAPi was associated with mortality at 1 year (area under the curveof 0.64 (95% confidence interval 0.55-0.74). However, high RAP (> 8 mm Hg) was similarly predictive of mortality, with an area under the curve of 0.65. Conclusion: PAPi was associated with mortality in a large incident PAH cohort. However, the discriminative value of PAPi was not higher than that of RAP alone.

Contexte: La stratification des risques est fondamentale dans la prise en charge de l'hypertension artérielle pulmonaire (HTAP). L'indice de pulsatilité des artères pulmonaires (iPAP), défini comme la pression différentielle dans les artères pulmonaires divisée par la pression auriculaire droite (PAD), est un indice hémodynamique qui s'est révélé prédictif d'une dysfonction ventriculaire droite (VD) aiguë dans plusieurs situations. Notre objectif était d'évaluer l'utilité pronostique de l'iPAP dans une cohorte multicentrique diversifiée de patients atteints d'HTAP. Méthodologie: Une étude de cohorte multicentrique rétrospective de patients adultes consécutifs atteints d'une HTAP nouvellement diagnostiquée par cathétérisme cardiaque droit entre janvier 2016 et décembre 2020 a été effectuée dans quatre grands centres au Canada. Les données hémodynamiques, les données cliniques et les résultats ont été recueillis. La corrélation de l'iPAP et d'autres va-riables hémodynamiques avec la mortalité a été évaluée par les courbes caractéristiques opérationnelles du receveur et des modèles à risques proportionnels de Cox. Résultats: Nous avons recensé 590 patients dont l'âge moyen était de 61,4 ± 15,5 ans; la proportion de femmes était de 66,3 %. Un faible iPAP (défini comme une valeur < 5,3) a été associé à une hausse de la mortalité à 1 an : 10,2 % contre 5,2 % (p= 0,02). Dans un modèle multivarié comprenant l'âge, le sexe, l'indice de masse corporelle et la classe fonctionnelle, un faible iPAP a été associé à la mortalité à 1 an (aire sous la courbe de 0,64 [intervalle de confiance à 95 %; de 0,55 à 0,74]). Cependant, une PAD élevée (> 8 mmHg) a aussi été un facteur prédictif de mortalité, l'aire sous la courbe étant de 0,65. Conclusions: L'iPAP a été associé à la mortalité dans une vaste cohorte de patients atteints d'une HTAP. Toutefois, la valeur discriminante de l'iPAP n'a pas été supérieure à celle de la PAD seule.

"R1 Nightmares": a resident-led on-call medical emergency simulation course for junior residents.

Implication Statement On-call medical emergencies can be a source of anxiety for junior medical residents. Senior resident teachers are well-positioned to teach a safe approach to managing on-call emergencies, and simulation-based training has educational and patient safety advantages. We describe the implementation of a resident-facilitated, on-call emergency simulation course for first-year residents. The course was low-cost, time-efficient, increased residents' self-rated comfort with acutely deteriorating patients and was highly recommended by participants. The "R1 Nightmares" course could be adapted for other residency programs and institutions.

Énoncé des implications de la rechercheLes urgences durant la garde peuvent être une source d'anxiété pour les résidents juniors. Les résidents seniors se trouvent en situation privilégiée pour enseigner une approche sûre de la gestion des urgences sur la garde. De plus, la formation basée sur la simulation présente des avantages sur le plan pédagogique et sur le plan de la sécurité des patients. Nous décrivons la mise en œuvre d'un cours de simulation d'urgences survenant durant le service de garde destiné aux résidents de première année et animé par leurs collègues séniors. Nécessitant peu de temps et de ressources financières, le cours a permis aux résidents d'améliorer leur niveau de confort auprès des patients dont l'état se détériore rapidement et il a été fortement recommandé par les participants. Le cours «Cauchemars de R1¼ peut être adapté à d'autres programmes de résidence et à d'autres établissements.

Mortality trends in pulmonary arterial hypertension in Canada: a temporal analysis of survival per ESC/ERS guideline era.

BACKGROUND: The evolution in pulmonary arterial hypertension (PAH) management has been summarised in three iterations of the European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines. No study has assessed whether changes in management, as reflected in the changing guidelines, has translated to improved long-term survival in PAH. METHODS: We performed a mixed retrospective/prospective analysis of treatment-naïve, incident PAH patients (n=392) diagnosed at three major centres in Canada from 2009 to 2021. Patients were divided into two groups based on their diagnosis date and in accordance with the 2009 and 2015 ESC/ERS guideline iterations. Overall survival was assessed based on date of diagnosis and initial treatment strategy (i.e. monotherapy versus combination therapy). RESULTS: There was a shift towards more aggressive upfront management with combination therapy in Canada after the publication of the 2015 ESC/ERS guidelines (10.4% and 30.8% in patients from 2009 to 2015 and 36.0% and 57.4% in patients diagnosed after 2015 for baseline and 2-year follow-up, respectively). A key factor associated with combination therapy after 2015 was higher pulmonary vascular resistance (p=0.009). The 1-, 3- and 5-year survival rates in Canada were 89.2%, 75.6% and 56.0%, respectively. Despite changes in management, there was no improvement in long-term survival before and after publication of the 2015 ESC/ERS guidelines (p=0.53). CONCLUSIONS: There was an increase in the use of initial and sequential combination therapy in Canada after publication of the 2015 ESC/ERS guidelines, which was not associated with improved long-term survival. These data highlight the continued difficulties of managing this aggressive pulmonary disease in an era without a cure.

Management of Pulmonary Hypertension Due to Chronic Lung Disease.

Pulmonary hypertension (PH) is a known complication of chronic parenchymal lung diseases, including chronic obstructive lung disease, interstitial lung diseases, and more rare parenchymal lung diseases. Together, these diseases encompass two of the five clinical classifications of PH: group 3 (chronic lung disease [CLD] and/or hypoxia) and group 5 (unclear and/or multifactorial mechanisms). The principal management strategy in PH associated with CLD is optimization of the underlying lung disease. There has been increasing interest in therapies that treat pulmonary arterial hypertension (group 1, PAH), and although some studies have explored the use of these oral PAH-targeted therapies to treat PH associated with CLD, there is currently no evidence to support their routine use; in fact, some studies suggest harm. Inhaled therapies that target the pulmonary vasculature may avoid certain problems observed with oral PAH therapies. Recent studies suggest a promising role for inhaled PAH therapies in group 3 PH, but this requires further study. The objective of this article is to review the current treatment strategies for group 3 and group 5 PH.

Stones, bones, groans, thrones, and psychiatric overtones: Systemic associations of sclerochoroidal calcification.

Sclerochoroidal calcification (SCC) is a frequent masquerader of choroidal melanoma with important systemic associations such as hyperparathyroidism and parathyroid adenoma. Herein, we describe a case of a 67-year-old male who presented with an amelanotic choroidal lesion in the right eye (OD) and a history of kidney stones. Ultrasonography showed the lesion to be flat and calcified OD. Incidentally, a subclinical calcified plaque was also found in the fellow eye. Optical coherence tomography showed an elevated suprachoroidal mass in a table mountain configuration OD and flat configuration left eye, consistent with type 4 and type 1 SCC. The patient was referred for metabolic testing to rule out the underlying electrolyte imbalance and was found to be normal.

Clinical Features Differentiating Benign From Malignant Conjunctival Tumors in Children.

IMPORTANCE: Conjunctival tumors in children are usually benign and rarely malignant. OBJECTIVE: To evaluate clinical features of conjunctival tumors in children by comparing benign tumors with their malignant counterparts. DESIGN, SETTING, AND PARTICIPANTS: This retrospective case series reviewed 806 cases of conjunctival tumor in children (aged <21 years) who were evaluated at a tertiary referral center between November 1, 1975, and July 1, 2015. This study included 262 children who were part of a published review. MAIN OUTCOMES AND MEASURES: Features of benign and malignant tumors were compared. Data were collected on patient demographics, tumor features, and specific diagnoses to determine findings related to each tumor. RESULTS: Among the 806 patients with conjunctival tumor, the top 5 diagnoses included nevus (492 [61%]), benign reactive lymphoid hyperplasia (BRLH) (38 [5%]), nodular conjunctivitis (31 [4%]), dermoid (30 [4%]), and primary acquired melanosis (27 [3%]). Overall, conjunctival tumors were benign (779 [97%]) or malignant (27 [3%]), including melanoma (18 [2.2%]) and lymphoma (9 [1.1%]). The mean age at detection was 11 years for benign tumors and 14 years for malignant tumors (P = .005), with mean difference of 3 years (95% CI, 1.2-4.6). The relative frequency of any malignancy (per all conjunctival tumors) by age bracket (0-5 years, >5-10 years, >10-15 years, and >15-<21 years) was 1%, 2%, 3%, and 7%, respectively. A comparison between nevus and melanoma found differences with melanoma in the 10 to 15 years age bracket (29% vs 61%; difference of 32% [95% CI, 10%-55%]; P = .006), mean tumor thickness (1.1 mm vs 1.5 mm; difference of 0.4 mm [95% CI, -0.29 mm to 1.12 mm]; P = .04), tumor base of 10 mm or greater (relative risk [RR] = 4.92; 95% CI, 1.73-13.97; P = .003), tumor hemorrhage (RR = 25.30; 95% CI, 11.91-53.78; P < .001), and lack of intrinsic cysts (RR = 5.06; 95% CI, 1.84-13.98; P = .002). A comparison between BRLH and lymphoma revealed lymphoma with a larger base (RR = 5.16; 95% CI, 1.19- 22.19; P = .002) and diffuse location (RR = 16.50; 95% CI, 4.31-63.22; P < .001) and inferior (RR = 12.38; 95% CI, 2.88-53.16; P < .001) or superior vs nasal (RR = 8.25; 95% CI, 1.56-43.51; P = .01). The small cohort of malignant lesions precluded determining if these features were independent of one another. CONCLUSIONS AND RELEVANCE: These data, from an ocular tertiary referral center, suggest that conjunctival tumors in children are nearly always benign. The few malignant tumors included melanoma and lymphoma. Melanoma, compared with nevus, was associated with older children (aged >10-15 years) with larger tumor, hemorrhage, and lack of cyst. Lymphoma, compared with BRLH, was associated with larger size and diffuse involvement.

Conjunctival Tumors in 5002 Cases. Comparative Analysis of Benign Versus Malignant Counterparts. The 2016 James D. Allen Lecture.

PURPOSE: To evaluate frequency of conjunctival tumors in all ages and compare benign vs malignant counterparts. DESIGN: Retrospective series. METHODS: setting: Tertiary referral center. STUDY POPULATION: Total of 5002 patients. OBSERVATION: Clinical features. MAIN OUTCOME MEASURE: Differentiation of benign from malignant counterparts. RESULTS: The tumor was benign (52%), premalignant (18%), or malignant (30%). Malignant tumors included melanoma (12%), squamous cell carcinoma (SCC) (9%), lymphoma (7%), and others. Comparison of primary acquired melanosis vs melanoma revealed melanoma with greater median patient age (54 vs 61 years, P < .0001), male sex (35% vs 49%, P < .0001), location in fornix (2% vs 6%, P = .0016) and tarsus (1% vs 4%, P = .0018), larger median basal diameter (6 vs 8 mm, P < .0001) and thickness (<1 vs 1 mm, P < .0001), and intralesional cysts (0% vs 7%, P < .0001), feeder vessels (10% vs 48%, P < .0001), intrinsic vessels (4% vs 33%, P < .0001), and hemorrhage (<1% vs 3%, P = .0001). Comparison of conjunctival intraepithelial neoplasia (CIN) vs SCC revealed SCC with greater diffuse involvement (1% vs 8%, P < .0001) and larger median basal diameter (7 vs 8 mm, P < .0001) and thickness (1 mm vs 2 mm, P < .0001). Comparison of benign reactive lymphoid hyperplasia vs lymphoma revealed lymphoma with greater median patient age (50 vs 61 years, P < .0001), fornix location (32% vs 54%, P < .0001), larger median basal diameter (10 vs 20 mm, P < .0001), and less involvement of nasal region (50% vs 23%, P < .0001). CONCLUSION: In an ocular oncology practice, conjunctival tumors are benign (52%), premalignant (18%), or malignant (30%). Malignant tumors tend to occur in older patients and demonstrate greater basal diameter and thickness, compared with benign counterparts.

Latent Tuberculosis in Pregnancy: A Systematic Review.

BACKGROUND: In countries with low tuberculosis (TB) incidence, immigrants from higher incidence countries represent the major pool of individuals with latent TB infection (LTBI). The antenatal period represents an opportunity for immigrant women to access the medical system, and hence for potential screening and treatment of LTBI. However, such screening and treatment during pregnancy remains controversial. OBJECTIVES: In order to further understand the prevalence, natural history, screening and management of LTBI in pregnancy, we conducted a systematic literature review addressing the screening and treatment of LTBI, in pregnant women without known HIV infection. METHODS: A systematic review of 4 databases (Embase, Embase Classic, Medline, Cochrane Library) covering articles published from January 1st 1980 to April 30th 2014. Articles in English, French or Spanish with relevant information on prevalence, natural history, screening tools, screening strategies and treatment of LTBI during pregnancy were eligible for inclusion. Articles were excluded if (1) Full text was not available (2) they were case series or case studies (3) they focused exclusively on prevalence, diagnosis and treatment of active TB (4) the study population was exclusively HIV-infected. RESULTS: Of 4,193 titles initially identified, 208 abstracts were eligible for review. Of these, 30 articles qualified for full text review and 22 were retained: 3 cohort studies, 2 case-control studies, and 17 cross-sectional studies. In the USA, the estimated prevalence of LTBI ranged from 14 to 48% in women tested, and tuberculin skin test (TST) positivity was associated with ethnicity. One study suggested that incidence of active TB was significantly increased during the 180 days postpartum (Incidence rate ratio, 1.95 (95% CI 1.24-3.07). There was a high level of adherence with both skin testing (between 90-100%) and chest radiography (93-100%.). In three studies from low incidence settings, concordance between TST and an interferon-gamma release assay was 77, 88 and 91% with kappa values ranging from 0.26 to 0.45. In low incidence settings, an IGRA may be more specific and less sensitive than TST, and results do not appear to be altered by pregnancy. The proportion of women who attended follow-up visits after positive tuberculin tests varied from 14 to 69%, while 5 to 42% of those who attended follow-up visits completed a minimum of 6 months of isoniazid treatment. One study raised the possibility of an association of pregnancy/post-partum state with INH hepatitis (risk ratio 2,5, 95% CI 0.8-8.2) and fatal hepatotoxicity (rate ratio 4.0, 95% CI 0.2-258). One study deemed INH safe during breastfeeding based on peak concentrations in plasma and breast milk after INH administration. CONCLUSION: Pregnancy is an opportunity to screen for LTBI. Interferon-gamma release assays are likely comparable to tuberculin skin tests and may be used during pregnancy. Efforts should be made to improve adherence with follow-up and treatment post-partum. Further data are needed with respect to safety and feasibility of antepartum INH therapy, and with respect to alternative treatment regimens.

Xpert®MTB/RIF for the Diagnosis of Tuberculosis in a Remote Arctic Setting: Impact on Cost and Time to Treatment Initiation.

BACKGROUND: Tuberculosis (TB) remains a significant health problem in the Canadian Arctic. Substantial health system delays in TB diagnosis can occur, in part due to the lack of capacity for onsite microbiologic testing. A study recently evaluated the yield and impact of a rapid automated PCR test (Xpert®MTB/RIF) for the diagnosis of TB in Iqaluit (Nunavut). We conducted an economic analysis to evaluate the expected cost relative to the expected reduction in time to treatment initiation, with the addition of Xpert®MTB/RIF to the current diagnostic and treatment algorithms used in this setting. METHODS: A decision analysis model compared current microbiologic testing to a scenario where Xpert®MTB/RIF was added to the current diagnostic algorithm for active TB, and incorporated costs and clinical endpoints from the Iqaluit study. Several sensitivity analyses that considered alternative use were also considered. We estimated days to TB diagnosis and treatment initiation, health system costs, and the incremental cost per treatment day gained for each individual evaluated for possible TB. RESULTS: With the addition of Xpert®MTB/RIF, costs increased while days to TB treatment initiation were reduced. The incremental cost per treatment day gained (per individual investigated for TB) was $164 (95% uncertainty range $85, $452). In a sensitivity analysis that considered hospital discharge after a single negative Xpert®MTB/RIF, the Xpert®MTB/RIF scenario was cost saving. INTERPRETATION: Adding Xpert®MTB/RIF to the current diagnostic algorithm for TB in Nunavut appears to reduce time to diagnosis and treatment at reasonable cost. It may be especially well suited to overcome some of the other logistical barriers that are unique to this and other remote communities.

Tuberculosis in pregnancy: an estimate of the global burden of disease.

BACKGROUND: The estimated number of maternal deaths in 2013 worldwide was 289 000, a 45% reduction from 1990. Non-obstetric causes such as infectious diseases including tuberculosis now account for 28% of maternal deaths. In 2013, 3·3 million cases of tuberculosis were estimated to occur in women globally. During pregnancy, tuberculosis is associated with poor outcomes, including increased mortality in both the neonate and the pregnant woman. The aim of our study was to estimate the burden of tuberculosis disease among pregnant women, and to describe how maternal care services could be used as a platform to improve case detection. METHODS: We used publicly accessible country-level estimates of the total population, distribution of the total population by age and sex, crude birth rate, estimated prevalence of active tuberculosis, and case notification data by age and sex to estimate the number of pregnant women with active tuberculosis for 217 countries. We then used indicators of health system access and tuberculosis diagnostic test performance obtained from published literature to determine how many of these cases could ultimately be detected. FINDINGS: We estimated that 216 500 (95% uncertainty range 192 100-247 000) active tuberculosis cases existed in pregnant women globally in 2011. The greatest burdens were in the WHO African region with 89 400 cases and the WHO South East Asian region with 67 500 cases in pregnant women. Chest radiography or Xpert RIF/MTB, delivered through maternal care services, were estimated to detect as many as 114 100 and 120 300 tuberculosis cases, respectively.

Quantifying the importance of pMHC valency, total pMHC dose and frequency on nanoparticle therapeutic efficacy.

Nanoparticles (NPs) coated with ß-cell-specific peptide major histocompatibility complex (pMHC) class I molecules can effectively restore normoglycemia in spontaneously diabetic nonobese diabetic mice. They do so by expanding pools of cognate memory autoreactive regulatory CD8+ T cells that arise from naive low-avidity T-cell precursors to therapeutic levels. Here we develop our previously constructed mathematical model to explore the effects of compound design parameters (NP dose and pMHC valency) on therapeutic efficacy with the underlying hypothesis that the functional correlates of the therapeutic response (expansion of autoregulatory T cells and deletion of autoantigen-loaded antigen-presenting cells by these T cells) are biphasic. We show, using bifurcation analysis, that the model exhibits a 'resonance'-like behavior for a given range of NP dose in which bistability between the healthy state (possessing zero level of effector T-cell population) and autoimmune state (possessing elevated level of the same population) disappears. A heterogeneous population of model mice subjected to several treatment protocols under these new conditions is conducted to quantify both the average percentage of autoregulatory T cells in responsive and nonresponsive model mice, and the average valency-dependent minimal optimal dose needed for effective therapy. Our results reveal that a moderate increase (≥1.6-fold) in the NP-dependent expansion rate of autoregulatory T-cell population leads to a significant increase in the efficacy and the area corresponding to the effective treatment regimen, provided that NP dose ≥8 µg. We expect the model developed here to generalize to other autoimmune diseases and serve as a computational tool to understand and optimize pMHC-NP-based therapies.