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Canada ratified the United Nations Convention on the Law of the Sea (UNCLOS) in 2003. With that ratification is an obligation to submit data and information to the U.N. pertaining to the limits of the country’s extended continental shelf (ECS); the portion of the juridical continental shelf that extends beyond 200 nautical miles. A team of Canadian scientists, managers, and legal experts that included representation from three Federal Departments (Natural Resources Canada, Fisheries and Oceans Canada, and Global Affairs Canada) with additional support from other departments, spent 13 years compiling and acquiring data to provide the scientific evidence to support delineation of Canada’s seaward most maritime limit. The submission has the potential to provide Canada with 2.4 million km2 of additional submarine landmass in the Atlantic and the Arctic oceans over which Canada exercises sovereign rights for the purpose of exploring and exploiting its natural resources. Specific information such as the tectonic framework of the continental margin, the geomorphology of the margin and in particular the continental slope, the geologic nature of adjoined ridges, rises, and plateaux, and sediment thickness within adjacent basins are examples of fundamental pieces of geoscientific information needed to substantiate Canada’s outermost maritime limits. This paper highlights a number of segments of Canada’s continental margins to showcase this scientific evidence and how it is applied in the UNCLOS context. In doing so, the paper demonstrates the geologic complexity of Canada’s margins as illustrated in scientific publications that have resulted from these new data collections, while at the same time presenting new scientific evidence and interpretations. This collection of data and information provides a wealth of new knowledge in Canada’s offshore regions. The massive data compilation in the Atlantic led to conception of continental margins, in a source-to-sink scenario, as having an equilibrium base level or graded form, comparable to river systems. Departures from this shape relate to the interplay of sedimentary processes and in particular to those processes that do not fit the source-to-sink paradigm. For example, a significant part of the Atlantic margin is shown to be heavily influenced by along-slope geostrophic currents that generated massive contourite drift deposits. These deposits reflect lateral transport of sediment that had a significant impact on the morphology of the margin. The role of mass transport processes in shaping continental margins is also highlighted, and in particular the collapses of entire segments of the margin were observed. The prominent role mass failure processes play in delivering sediment to the adjacent abyssal plain is also critical in the ECS context. These observations challenge the entrenched notion of a continental margin comprising a shelf, slope, and rise and in particular the concept of the “continental rise”. Prior to 2006, regions of the Arctic Ocean seaward of the Canadian landmass had fewer than 5000 km of seismic reflection data. The massive efforts of Arctic coastal States to map their margins for ECS purposes have led to a leap in technological advances to acquire data in ice-covered seas and have led to a wealth of new geoscientific knowledge. Perhaps foremost amongst this knowledge is demonstration that Canada Basin is indeed a fully developed ocean basin, albeit significantly infilled with sediment. Based on this knowledge and identification of related structures, new realistic tectonic scenarios for opening of the Amerasia Basin are proposed that include a significant component of transform or strike-slip motions. With seismic velocity and rock sample information, the continental nature of Alpha and Mendeleev ridges has been substantiated. Even bathymetric data were lacking in the Arctic and new editions of seafloor maps now support grids of 500 m spacing; although some regions remain sparse. Once thought to be relatively stagnant, sedimentary processes such as found in many ocean basins were discovered in the Arctic Ocean. Evidence of geostrophic currents, sediment mass failures, and deep-sea turbidity current channels were found to be ubiquitous, even in the deepest parts of the Arctic’s basins.

Immune-mediated neuropathies such as chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN) produce significant disability and often require maintenance treatment. There is a paucity of epidemiological data on these conditions in Australia.We undertook a prevalence study of CIDP and MMN in North Queensland and Tasmania, coinciding with a national census. Diagnoses were classified against the diagnostic criteria of the European Federation of Neurological Societies/Peripheral Nerve Society. Case ascertainment was undertaken via multiple methods, including survey of local neurologists across public and private clinics, search of neurophysiology, neurology and hospital databases, search of admitted hospital database collections using ICD codes and through immunoglobulin therapy prescription lists.The crude prevalence of CIDP was 5.00 per 100,000 (95% confidence interval [CI] 3.79-6.62) and the crude prevalence of MMN was 1.33 per 100,000 (95% CI 0.78-2.27). Prevalence was also investigated using National Blood Authority numbers of cases prescribed immunoglobulin therapy, indicating a CIDP prevalence of 5.72 per 100,000 (95% CI 4.41-7.43) and MMN prevalence of 1.94 per 100,000 (95% CI 1.24-3.03). There was no significant difference between these numbers and those calculated through access of patient records locally. There was no significant difference in prevalence between Tasmania and North Queensland for any category.This study updates the prevalence of CIDP and MMN in Australia. Understanding the distribution of CIDP and MMN patients and their need for treatment is essential for future resource planning and to enable monitoring and coordination of therapies such as immunoglobulin.

you are agreeing to our Cookie Policy | Continue JAMA Network HomeJAMA Neurology This Issue Views 2,357 Citations 0 60 Full Text Share Comment Original Investigation May 15, 2023 Comparative Effectiveness of Autologous Hematopoietic Stem Cell Transplant vs Fingolimod, Natalizumab, and Ocrelizumab in Highly Active Relapsing-Remitting Multiple Sclerosis Tomas Kalincik, MD, PhD1,2; Sifat Sharmin, PhD1,2; Izanne Roos, MBChB, PhD1,2; Mark S. Freedman, MD3; Harold Atkins, MD4; Joachim Burman, MD, PhD5; Jennifer Massey, MBBS, PhD6,7; Ian Sutton, MBBS, PhD6,8; Barbara Withers, MD, PhD7,9; Richard Macdonell, MD, PhD10,11; Andrew Grigg, MD, PhD11,12; Øivind Torkildsen, MD, PhD13; Lars Bo, MD, PhD13; Anne Kristine Lehmann, MD, PhD14; Eva Kubala Havrdova, MD, PhD15; Eva Krasulova, MD, PhD15; Marek Trněný, MD, PhD16; Tomas Kozak, MD, PhD17; Anneke van der Walt, MBBS, PhD18,19; Helmut Butzkueven, MBBS, PhD18,19; Pamela McCombe, MBBS20,21; Olga Skibina, MBBS18,22,23; Jeannette Lechner-Scott, MD, PhD24,25; Barbara Willekens, MD, PhD26,27; Elisabetta Cartechini, MD28; Serkan Ozakbas, MD29; Raed Alroughani, MD30; Jens Kuhle, MD, PhD31; Francesco Patti, MD32,33; Pierre Duquette, MD34; Alessandra Lugaresi, MD, PhD35,36; Samia J. Khoury, MD, PhD37; Mark Slee, MD, PhD38; Recai Turkoglu, MD39; Suzanne Hodgkinson, MD40; Nevin John, MD, PhD41,42; Davide Maimone, MD43; Maria Jose Sa, MD44; Vincent van Pesch, MD, PhD45,46; Oliver Gerlach, MD, PhD47,48; Guy Laureys, MD49; Liesbeth Van Hijfte, MD49; Rana Karabudak, MD50; Daniele Spitaleri, MD51; Tunde Csepany, MD, PhD52; Riadh Gouider, MD53,54; Tamara Castillo-Triviño, MD55; Bruce Taylor, MD, PhD56,57; Basil Sharrack, MD, PhD58; John A. Snowden, MD, PhD59; and the MSBase Study Group Collaborators; and the MSBase Study Group Authors Author Affiliations JAMA Neurol. 2023;80(7):702-713. doi:10.1001/jamaneurol.2023.1184 editorial comment iconEditorial Comment Key Points Question What is the comparative effectiveness of autologous hematopoietic stem cell transplant (AHSCT) vs individual most potent disease-modifying therapies for relapsing-remitting multiple sclerosis (MS), such as natalizumab or ocrelizumab? Findings In this observational comparative effectiveness study of 4915 individuals using a composite cohort from specialized MS centers and the MSBase international registry, the effectiveness of AHSCT was compared with 1 medium-efficacy and 2 high-efficacy disease-modifying therapies (fingolimod, natalizumab, and ocrelizumab) in patients with relapsing-remitting MS, high frequency of relapses, and moderate disability. Over 5 years, AHSCT was associated with substantially lower relapse rate than fingolimod and marginally lower relapse rate than natalizumab and was also associated with a higher rate of recovery from disability compared with fingolimod and natalizumab, but no evidence of difference in clinical outcomes between AHSCT and ocrelizumab was found at 3-year follow-up. Meaning The results indicate that in relapsing-remitting MS, the clinical effectiveness of AHSCT is considerably superior to fingolimod and marginally superior to natalizumab. Abstract Importance Autologous hematopoietic stem cell transplant (AHSCT) is available for treatment of highly active multiple sclerosis (MS). Objective To compare the effectiveness of AHSCT vs fingolimod, natalizumab, and ocrelizumab in relapsing-remitting MS by emulating pairwise trials. Design, Setting, and Participants This comparative treatment effectiveness study included 6 specialist MS centers with AHSCT programs and international MSBase registry between 2006 and 2021. The study included patients with relapsing-remitting MS treated with AHSCT, fingolimod, natalizumab, or ocrelizumab with 2 or more years study follow-up including 2 or more disability assessments. Patients were matched on a propensity score derived from clinical and demographic characteristics. Exposure AHSCT vs fingolimod, natalizumab, or ocrelizumab. Main outcomes Pairwise-censored groups were compared on annualized relapse rates (ARR) and freedom from relapses and 6-month confirmed Expanded Disability Status Scale (EDSS) score worsening and improvement. Results Of 4915 individuals, 167 were treated with AHSCT; 2558, fingolimod; 1490, natalizumab; and 700, ocrelizumab. The prematch AHSCT cohort was younger and with greater disability than the fingolimod, natalizumab, and ocrelizumab cohorts; the matched groups were closely aligned. The proportion of women ranged from 65% to 70%, and the mean (SD) age ranged from 35.3 (9.4) to 37.1 (10.6) years. The mean (SD) disease duration ranged from 7.9 (5.6) to 8.7 (5.4) years, EDSS score ranged from 3.5 (1.6) to 3.9 (1.9), and frequency of relapses ranged from 0.77 (0.94) to 0.86 (0.89) in the preceding year. Compared with the fingolimod group (769 [30.0%]), AHSCT (144 [86.2%]) was associated with fewer relapses (ARR: mean [SD], 0.09 [0.30] vs 0.20 [0.44]), similar risk of disability worsening (hazard ratio [HR], 1.70; 95% CI, 0.91-3.17), and higher chance of disability improvement (HR, 2.70; 95% CI, 1.71-4.26) over 5 years. Compared with natalizumab (730 [49.0%]), AHSCT (146 [87.4%]) was associated with marginally lower ARR (mean [SD], 0.08 [0.31] vs 0.10 [0.34]), similar risk of disability worsening (HR, 1.06; 95% CI, 0.54-2.09), and higher chance of disability improvement (HR, 2.68; 95% CI, 1.72-4.18) over 5 years. AHSCT (110 [65.9%]) and ocrelizumab (343 [49.0%]) were associated with similar ARR (mean [SD], 0.09 [0.34] vs 0.06 [0.32]), disability worsening (HR, 1.77; 95% CI, 0.61-5.08), and disability improvement (HR, 1.37; 95% CI, 0.66-2.82) over 3 years. AHSCT-related mortality occurred in 1 of 159 patients (0.6%). Conclusion In this study, the association of AHSCT with preventing relapses and facilitating recovery from disability was considerably superior to fingolimod and marginally superior to natalizumab. This study did not find evidence for difference in the effectiveness of AHSCT and ocrelizumab over a shorter available follow-up time.

Background Immigrants' healthcare needs can be a considerable challenge, as their risk profile can differ from the native population, and they may experience barriers to accessing health services in recipient countries. Immigration is projected to increase further due to conflicts and climate changes, and awareness on immigrants' health status is therefore warranted. Atrial fibrillation (AF) is the most common sustained arrhythmia with an estimated prevalence of approximately 2%. However, there is a paucity of data on AF epidemiology among immigrants. Purpose The aim of this study is to examine incidence of AF hospital diagnoses according to country of origin and to study if there is a difference in risk between immigrants and Danish born individuals. Methods The study period included 1st of January 1998 to 31st of December 2017 and the population consisted of all Danish citizens aged 45 or older. We included individuals as they turned 45 during the study period. Individuals who had been diagnosed with AF were excluded. Data was obtained from the Danish National Patient Registry and the Civil Registration System. Country of origin was based on the ten most represented counties in the population. Immigrants were defined as people born outside Denmark with none of the parents being both Danish citizens and born in Denmark. AF was defined as a hospital diagnosis according to international Classification of Diseases (ICD) version 8 and 10. Poisson regression were used to compute relative risk (RR) and associated 95% confidence intervals (CI). RRs were adjusted for sex, age, socioeconomic status, visits to general practitioner and comorbidity. Results The study population consist of 3,596,234 Danish-Born and 215,401 immigrants. A total of 334,636 had an incident AF diagnosis during the study period. Compared to Danish-born individuals, migrants from the Nordic countries had a higher adjusted RR of being diagnosed with AF: Norway 1.21 [95% CI: 1.05; 1.40], Sweden 1.16 [95% CI: 0.99; 1.35] and Germany 1.17 [95% CI: 1.06; 1.28]. In contrast, lower adjusted RRs were observed for individuals from Poland (0.82 [95% CI: 0.67; 1.01]), UK (0.89 [95% CI: 0.73; 1.08]), and the US (0.95 [95% CI: 0.72; 1.25]), respectively, and in particular for individuals from the non-Western countries: Turkey (0.49 [95% CI: 0.40; 0.59], Iran (0.48 [95% CI: 0.36; 0.65]), Iraq (0.32 [95% CI: 0.22; 0.45] and Bosnia-Herzegovina (0.63 [95% CI: 0.49; 0.79]). Conclusion Substantial variation in the incidence rate of incident AF hospital diagnoses according to country of origin. Further studies are warranted in order to clarify to what extent these differences reflets true differences in AF incidence or ethnic inequalities in the detection of AF in the health care system. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Karen Elise Jensen Foundation

PURPOSE: Overlapping clinical features of cutaneous leishmaniasis (CL) with ulcers caused by fungi and mycobacteria necessitate confirmatory diagnostic testing. We evaluated a handheld battery-operated device for detection of CL and common fungal and mycobacterial causes of ulcers. METHODS: We validated Palm PCR™ for detection of common ulcerative skin pathogens using ATCC(®) reference and clinical strains of Leishmania, mycobacteria, and fungi in the lab and field. Amplified products were Sanger sequenced. Performance characteristics were calculated using conventional PCR as a reference standard. RESULTS: Palm PCR™ detected 100% of ATCC(®) strains of Leishmania, fungi, and mycobacteria, with sensitivity and specificity of 90% and 91.7%, respectively. In the field, the sensitivity for detection of Leishmania in patients with suspected CL was 100%. In 61% of CL patients, co-colonization with genera such as Malassezia, Aspergillus, Candida, and Cladosporium was detected. In 50% of CL patients with an inflammatory (secondarily infected) phenotype, detected fungal species had known associations with human cutaneous disease. CONCLUSIONS: Palm PCR™ performs comparably to conventional PCR for detection of Leishmania, fungi, and mycobacteria. This work has implications for the diagnostic approach to tropical ulcers, and has the potential to improve field detection of ulcerative pathogens in resource constrained areas

Background Standard dapsone and clofazimine-containing multidrug therapy (MDT) for leprosy is limited by drug tolerability, which poses treatment adherence barriers. Although ofloxacin-based regimens are promising alternatives, current efficacy and safety data are limited, particularly outside of endemic areas. We evaluated treatment outcomes in patients with leprosy receiving ofloxacin-containing MDT (OMDT) at our center. Methods We performed a retrospective chart review of patients treated for leprosy at our center over an 8-year period (2011-2019). Primary outcomes evaluated were clinical cure rate, occurrence of leprosy reactions, antibiotic-related adverse events, and treatment adherence. Analyses were descriptive; however, data were stratified by age, sex, spectrum of disease, region of origin, and treatment regimen, and odds ratios were reported to assess associations with adverse outcomes. Results Over the enrolment period, 26 patients were treated with OMDT ( n = 19 multibacillary, n = 7 paucibacillary), and none were treated with clofazimine-based standard MDT. At the time of analysis, 23 patients (88%) had completed their course of treatment, and all were clinically cured, while 3 (12%) were still on treatment. Eighteen patients (69%) experienced either ENL ( n = 7, 27%), type 1 reactions ( n = 7, 27%), or both ( n = 4, 15%). No patients stopped ofloxacin due to adverse drug effects, and there were no cases of allergic hypersensitivity, tendinopathy or rupture, or C. difficile colitis. Conclusions We demonstrate a high cure rate and tolerability of OMDT in this small case series over an 8-year period, suggesting its viability as an alternative to standard clofazimine-containing MDT.

Marine geological and geophysical data from Alpha Ridge in the Arctic Ocean are sparse because of thick perennial sea-ice cover, which prevents access by most surface vessels. Rare seismic data in this area, acquired largely from drifting ice-camps, had shown the hemipelagic drape that covers most of the ridge is highly disrupted within a large (>90 000 km2) south central region. Here, evidence of pronounced seafloor erosion and debris flows infilling seafloor lows was previously interpreted to be the result of a possible bolide impact. In recent years, several icebreaker expeditions have successfully acquired multibeam bathymetry and sub-bottom profiler data in the western segment of this region. Analysis of these data reveals a complex seafloor morphology characterized by ridges and troughs, angular blocks and escarpments as well as seismic facies characterized by hyperbolic seafloor reflections, and convoluted to incoherent and transparent sub-bottom reflectivity. These features are interpreted as evidence of sediment mass movement with varying degrees of lateral transport deformation. At least two episodes of failure are interpreted based on the presence of both buried and surficial mass-transport features. As multiple events are interpreted, seismicity is the most plausible trigger mechanism rather than bolide impact.

Single-nucleotide polymorphisms at several loci have been correlated with Plasmodium falciparum drug resistance. We examined the prevalence of resistance markers in P. falciparum from imported malaria cases in Canada during 3 time periods, 2008-2009, 2013-2014, and 2017-2018. We evaluated single-nucleotide polymorphisms at atpase6 (pfATPase6), pfcrt (chloroquine resistance transporter), cytb (cytochrome b), dhfr (dihydrofolate reductase), dhps (dihydropteroate synthetase), mdr1 (multidrug resistance protein) and mdr1 copy number, and kelch13 (kelch protein gene on chromosome 13). Over time, we observed increasing mutant genotypes for dhfr S108N and dhps A613T and decreasing mutant genotypes for mdr1 N86Y, D1246Y, pfcrt K76T, and pfcrt 74-75; we identified no kelch13 mutations. We observed fewer mutations indicative of chloroquine resistance over time, which may reflect reduced chloroquine pressure in specimens from travelers to Africa. Mutations conferring proguanil resistance increased over time. Minor genotypes confirm the heterogeneous nature of infection and may affect treatment success.

Introduction: Leishmaniasis is a neglected tropical disease that manifests as three major disease phenotypes: cutaneous, mucocutaneous, and visceral. In this preliminary study, we quantified virulence factor (VF) RNA transcript expression in Leishmania species, stratified by geographic origin and propensity for specific disease phenotypes. Methods: Cultured promastigotes of 19 Leishmania clinical and ATCC isolates were extracted for total cellular RNA, cDNA was reverse transcribed, and qPCR assays were performed to quantify VF RNA transcript expression for hsp23, hsp70, hsp83, hsp100, mpi, cpb, and gp63. Results: Comparison of visceralizing species (Leishmania donovani, Leishmania chagasi, and Leishmania infantum) versus non-visceralizing species [Leishmania (Viannia) spp., Leishmania tropica, Leishmania major, Leishmania mexicana, and Leishmania amazonensis] revealed a significantly greater pooled transcript expression for visceralizing species (p = 0.0032). Similarly, Old World species demonstrated significantly higher VF RNA transcript expression than New World species (p = 0.0015). On a per-gene basis, species with a propensity to visceralize ubiquitously expressed higher levels of gp63 (p = 0.005), cpb (p = 0.0032), mpi (p = 0.0032), hsp23 (p = 0.0039), hsp70 (p = 0.0032), hsp83 (p = 0.0032), and hsp100 (p = 0.0032). Conclusion: Here, we provide quantitative, preliminary evidence of elevated VF RNA transcript expression driven largely by the visceralizing causative species of Leishmania. This work highlights the extensive heterogeneity in pathogenicity mechanisms between Leishmania species, which may partly underpin the fatal progression of visceral leishmaniasis.

American Tegumentary Leishmaniasis (ATL) is an endemic and neglected disease of South America. Here, mucosal leishmaniasis (ML) disproportionately affects up to 20% of subjects with current or previous localised cutaneous leishmaniasis (LCL). Preclinical and clinical reports have implicated the Leishmania RNA virus-1 (LRV1) as a possible determinant of progression to ML and other severe manifestations such as extensive cutaneous and mucosal disease and treatment failure and relapse. However, these associations were not consistently found in other observational studies and are exclusively based on cross-sectional designs. In the present study, 56 subjects with confirmed ATL were assessed and followed out for 24-months post-treatment. Lesion biopsy specimens were processed for molecular detection and quantification of Leishmania parasites, species identification, and LRV1 detection. Among individuals presenting LRV1 positive lesions, 40% harboured metastatic phenotypes; comparatively 58.1% of patients with LRV1 negative lesions harboured metastatic phenotypes (p = 0.299). We found treatment failure (p = 0.575) and frequency of severe metastatic phenotypes (p = 0.667) to be similarly independent of the LRV1. Parasite loads did not differ according to the LRV1 status (p = 0.330), nor did Leishmanin skin induration size (p = 0.907) or histopathologic patterns (p = 0.780). This study did not find clinical, parasitological, or immunological evidence supporting the hypothesis that LRV1 is a significant determinant of the pathobiology of ATL.

Introduction: Due to lower intensity of infection and greater intervals from last exposure, parasitologic detection methods for schistosomiasis are poorly sensitive in non-endemic areas, challenging accurate diagnosis. Methods: We evaluated parasitologic versus indirect detection methods for schistosomiasis. We included specimens submitted for Schistosoma serology, and stool for ova and parasite microscopy. Three real-time PCR assays targeting Schistosoma mansoni and S. haematobium were performed. Primary outcome measures were sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), where both microscopy and serology were the composite reference standard against serum PCR. Results: Of 8168 serum specimens submitted for Schistosoma serology, 638 (7.8%) were reactive and 6705 (82.1%) were non-reactive. Of 156,771 stool specimens submitted for ova and parasite testing, 46 (0.03%) were positive for eggs of S. mansoni. Four (0.5%) urine specimens were positive for eggs of S. haematobium. Combined serum PCRs targeting S. mansoni had a sensitivity and specificity of 27.8% (95% CI = 18.3–39.1%) and 100% (95% CI = 83.9–100%), respectively, with PPV of 100% (95% CI = 100%) and NPV of 26.9% (95% CI = 24.3–29.7%). The one serum sample positive for S. haematobium was also detectable by our S. haematobium PCR. No cross-reactivity was observed for all three PCR assays. Conclusions: Although serology is highly sensitive, parasitologic tests signify active infection, but are limited by low population-level sensitivity, particularly in non-endemic settings. Although serum PCR offered no performance advantage over stool microscopy, its role in diagnostic parasitology should be pursued due to its high-throughput and operator-independent nature.

Dengue virus (DENV) is a mosquito-borne single-stranded RNA virus of the Flaviviridae family with four serotypes (DENV1, DENV2, DENV3, and DENV4) circulating many tropical and subtropical regions of the world. Endemic in more than 100 countries, DENV results in over 400 million cases annually, a subset presenting with severe or life-threatening illnesses such as dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). While no specific treatments outside of supportive management exist, vaccines are an area of major research with two vaccines, Dengvaxia® (CYD-TDV) and Denvax® (TAK003), recently licensed for clinical use. CYD-TDV is highly efficacious in children 9 years or older who have had prior DENV infection due to the high risk of severe disease in seronegative children aged 2–5 years. Meanwhile, TAK003 has shown efficacy at 97.7% and 73.7% against, DENV2 and DENV1, respectively, in phase 3 clinical trials across Latin America and Asia in healthy children aged 4–16 with virologically confirmed dengue. Other vaccines including TV003 and TV005 continue to be developed across the world, with the hopes of entering clinical trials in the near future. We discuss the current state of vaccine development against dengue, with a focus on CYD-TDV and TAK003 as promising novel vaccines to target this neglected tropical disease (NTD).

Strongyloides colitis is a gastrointestinal manifestation of the parasitic infection, Strongyloides stercoralis, which may be misdiagnosed and treated as ulcerative colitis (UC) in patients presenting in non-endemic regions. Treatment of Strongyloides colitis as UC can lead to a lethal hyperinfection syndrome. Therefore, prior to commencing immunosuppressive treatment of UC, it is essential to use diagnostic markers to differentiate the two etiologies. In this case series, we discuss two migrant patients who were previously diagnosed with UC and treated accordingly who presented to our clinic for further investigation of suspected parasitic infection.

Susac syndrome (SuS) is an inflammatory condition of the brain, eye and ear. Diagnosis can be challenging, and misdiagnosis is common.This is a retrospective review of the medical records of 32 adult patients from an Australasian cohort of SuS patients.An alternative diagnosis prior to SuS was made in 30 patients (94%) with seven patients receiving two or more diagnoses. The median time to diagnosis of SuS was 3 months (range 0.5-100 months). The commonest misdiagnoses were migraine in 10 patients (31%), cerebral vasculitis in six (19%), multiple sclerosis in five (16%) and stroke in five (16%). Twenty-two patients were treated for alternative diagnoses, 10 of whom had further clinical manifestations prior to SuS diagnosis. At presentation seven patients (22%) met criteria for definite SuS, 19 (59%) for probable SuS and six (19%) for possible SuS. Six patients (19%) presented with brain-eye-ear involvement, 14 with brain-ear (44%), six with brain-eye (19%) and six (19%) with only brain involvement. In patients with the complete triad of symptoms the median delay to diagnosis was 3 months (range 1-9 months) compared to 5.25 months (range 0.5-100 months) for patients with encephalopathy and ocular symptoms at presentation.Susac syndrome patients are frequently misdiagnosed at initial presentation, despite many having symptoms or radiological features that are red flags for the diagnosis. Delayed diagnosis can lead to patient morbidity. The varied ways in which SuS can present, and clinician failure to consider or recognize SuS, appear to be the main factors leading to misdiagnosis.

Cerebral amyloid angiopathy with related inflammation (CAA-RI) is an uncommon inflammatory subtype of CAA, with a variety of presentations that can mimic other focal and diffuse neurological disorders. We present a 63-year-old man with recurrent stereotyped focal neurological symptoms, who was initially diagnosed as capsular warning syndrome and treated with antithrombotic therapy. Atypical imaging led to further investigation including a cerebral biopsy, which confirmed CAA-RI; he improved clinically and radiologically with immunosuppression. This case highlights how CAA-RI is often under-recognised and that patients risk receiving inappropriate anticoagulation and delay in starting immunosuppression.

Point-of-care dengue diagnostics are unavailable in most settings; thus, diagnosis is clinical until more definitive microbiological testing — such as serology — is resulted. Thrombocytopenia and lymphopenia are common hallmarks of dengue fever; however, neutropenia is a prominent, yet less frequently reported trend. We aimed to identify hematological patterns that can assist frontline clinicians with diagnostic certainty of dengue. Dengue patients presenting to our unit via the Emergency Department were compared to those presenting with other febrile illness (OFI) diagnoses. Patient demographics, day of illness, and neutrophil, lymphocyte, and platelet counts from days 1 to 14 of illness were collected, where available. Analyses were stratified by day of illness. Eighteen patients were included in the dengue group and 151 in the OFI group. The frequency of thrombocytopenia, neutropenia, and lymphopenia was each significantly greater in the dengue cohort than in the OFI group (p

This chapter describes the types of pathogens, geographic distribution, sources and routes of transmission, clinical presentations, and management of water-associated infections. It analyzes the pathogens in water that infect susceptible humans through skin and mucous membranes via inhalation of aerosols, aspiration, and ingestion. Clinical manifestations of water-associated infections range from superficial skin lesions to fatal, systemic infections. The chapter analyzes the survival of many water-associated pathogens that is influenced by climate, season, other environmental conditions, and the level of sanitation. The risk of infection by waterborne pathogens depends on the duration and type of exposure, concentration density of organisms in water, and host immunity.

The Zika virus outbreak in the Americas prompted enhanced global surveillance due to the recognition of adverse neurological outcomes, including Guillain-Barre Syndrome, a novel but devastating congenital syndrome. Symptomatic Zika virus infection is clinically indistinguishable from other arboviral infections of the Americas such as chikungunya, dengue, and the more recently emerging Mayaro virus. We conducted laboratory surveillance for such arboviruses in ill returned travelers to the Americas between November 2015 and May 2016 by examining whole blood, malaria-negative specimens with noted travel history to the Americas by real-time and end-point PCR for the following targets: chikungunya (CHIKV), flaviviruses (Pan-Flavi), dengue virus types 1–4 (DEN1, DEN2, DEN3, DEN4), and Zika virus (ZIKV). End-point PCR was performed to detect Mayaro virus (MAYV). 1294 malaria-negative specimens were evaluated for compatible travel history. Of 224 enrolled specimens, 124 (55%) were from returned travelers to the Caribbean, while 66 (29.5%) were from Central America, and 34 (15.2%) from South America. Arboviral pathogens detected included: dengue (n = 3, 1.3%), Zika virus (n = 2, 0.9%), and unspecified flavivirus (n = 2, 0.9%). No cases of chikungunya or Mayaro were detected in the cohort. Common arboviruses circulating in the Americas were detected in over 3% of whole-blood malaria-free specimens from ill returned travelers, supporting the notion that during this time period, Zika virus was as commonly imported as dengue from this geographic region. Surveillance for other flaviviruses and alphaviruses including Mayaro virus is warranted to detect sentinel events, and inform priorities for diagnostic testing capacity.

Leprosy is a neglected tropical disease (NTD) that continues to burden low- and middle-income countries (LMICs), despite being eliminated as a public health concern by the World Health Organization (WHO) in 2000. The causative agents, Mycobacterium leprae and Mycobacterium lepromatosis, affect nearly 200,000 individuals globally each year, with over 19,000 new cases detected in the Americas in 2020 alone. Canada has experienced an increasing incidence of leprosy, due to rising levels of travel and migration from endemic areas, reaching over 37,000 individuals with leprosy by the end of 2020. Patients experience a spectrum of signs and symptoms including hypopigmented cutaneous macules alongside peripheral neuropathy including peripheral neuropathic pain (PNP) and disabling sensory neuropathies. Despite the development of effective and curative therapeutics via multidrug therapy (MDT), many barriers to treatment adherence and effective immunological control of the pathogen challenge the care of patients with leprosy. Socioeconomic barriers, such as disability-related social stigma and often undiagnosed nutritional deficiencies, have resulted in heightened disease severity. PNP therapeutics are associated with significant side effects and remain ineffective as the majority of individuals will not experience a greater than 30% reduction of symptoms. Nutrient supplementation is known to be instrumental in reducing host oxidative stress, strengthening the immune system and mitigating comorbidities. Likewise, dietary lifestyle interventions known to be physiologically beneficial have recently emerged as powerful tools conferring neuroprotective effects, potentially mitigating PNP severity. However, a significant knowledge gap concerning the effect of adequate nutrition on host immunological control of leprosy and PNP severity exists. Further evaluation of this relationship will provide key insight into the pathogenesis of leprosy, strengthening the current body of literature.

Leishmaniasis is a neglected tropical disease that manifests as three major disease phenotypes: cutaneous, mucocutaneous, and visceral. In this preliminary study, we quantified virulence factor (VF) RNA transcript expression inCultured promastigotes of 19Comparison of visceralizing species (Leishmania donovani, Leishmania chagasi, and Leishmania infantum) versus non-visceralizing species [Leishmania (Viannia) spp., Leishmania tropica, Leishmania major, Leishmania mexicana, and Leishmania amazonensis] revealed a significantly greater pooled transcript expression for visceralizing species (p = 0.0032). Similarly, Old World species demonstrated significantly higher VF RNA transcript expression than New World species (p = 0.0015). On a per-gene basis, species with a propensity to visceralize ubiquitously expressed higher levels of gp63 (p = 0.005), cpb (p = 0.0032), mpi (p = 0.0032), hsp23 (p = 0.0039), hsp70 (p = 0.0032), hsp83 (p = 0.0032), and hsp100 (p = 0.0032).Here, we provide quantitative, preliminary evidence of elevated VF RNA transcript expression driven largely by the visceralizing causative species of

Background and objectives We describe the third documented case of autochthonous human babesiosis in Canada and the second in a Canadian blood donor. Materials and methods Multiple laboratory investigations were carried out on the donor and the immunocompromised recipient of an associated, potentially infectious red blood cell product. Results The donor had not travelled except for outdoor exposure in south-eastern Manitoba, followed by illness and hospital admission. The donor had a notable parasitaemia, positive for Babesia microti using whole blood nucleic acid testing (NAT). The recipient was negative for B. microti by both serology and NAT. Conclusion There was no evidence of transfusion-transmitted babesiosis.

Introduction Neuropathic extremity pain is reported in 26% (95% CI 7-53%) of patients with multiple sclerosis (MS),1 causing significant morbidity. Evidence for pharmaceutical management is limited and medications may cause prominent adverse effects. Spinal cord stimulation (SCS) is an effective treatment for central neuropathic pain and has demonstrated efficacy in MS.2–4 Limitations to use include lack of awareness, expense and the consequent inability to perform MRI for MS surveillance.4 Methods We report four patients from a regional MS clinic with refractory neuropathic pain referred for SCS. Quality of life scores using the multiple sclerosis impact scale (MSIS-29) and medications requirements prior to SCS and at most recent review were assessed. Results Four female patients, aged 48 to 55, were referred for SPS. All patients had a positive response to trial stimulation and proceeded to SCS implantation. Mean MSIS-29 score was 101/145 (range 91–121) prior to SCS and 54.5/145 (range 40-83) at most recent review. Three patients were able to reduce or cease analgesic medications. There was no associated operative morbidity. Conclusions Three of the 4 patients in this series with refractory neuropathic pain experienced significant improvement in quality of life, measured by MSIS-29, after SCS implantation and were able to reduce or discontinue analgesic medications. SCS is a potentially effective treatment for refractory neuropathic pain in MS however is under-utilised for this indication. These 4 individuals, identified from a regional MS service, represent the only MS patients referred to this tertiary pain centre in recent year for consideration of SCS. References Foley PL, Vesterinen HM, Laird BJ, Sena ES, Colvin LA, Chandran S, et al. Prevalence and natural history of pain in adults with multiple sclerosis: systematic review and meta-analysis. Pain 2013;154(5):632–42. Kumar K, Nath R, Wyant GM. Treatment of chronic pain by epidural spinal cord stimulation: a 10-year experience. Journal of Neurosurgery 1991;75(3):402. Provenzano DA, Williams JR, Jarzabek G, DeRiggi LA, Scott TF. Treatment of neuropathic pain and functional limitations associated with multiple sclerosis using an MRI-compatible spinal cord stimulator: a case report with two year follow-up and literature review. Neuromodulation: Technology at the Neural Interface 2016;19(4):406–13. Abboud H, Hill E, Siddiqui J, Serra A, Walter B. Neuromodulation in multiple sclerosis. Multiple Sclerosis Journal 2017;23(13):1663–76.

The humanised recombinant monoclonal antibody natalizumab (Tysabri), is a selective antagonist of the α4 subunit of the leukocyte adhesion molecule integrin, VLA-3. Blockade of VLA-3 leads to inhibition of immune cell transmigration into target organs, notably the intestinal lining and central nervous system.1,2 Natalizumab is approved to treat relapsing-remitting Multiple Sclerosis (RRMS) in the US and Europe, and Crohn’s Disease in the US. Following approval in 2004, natalizumab was withdrawn in 2005 due to 3 reported cases of progressive multifocal leukoencephalopathy (PML). In 2006, it re-entered the market with additional monitoring requirements.

Purpose: To report a series of cases demonstrating the resolution of Acanthamoeba keratitis (AK) with adjunctive use of oral miltefosine.Methods: Retrospective case series.Results: The first case was a 27-year-old female who presented with severe pain and photophobia. The diagnosis of AK was made with confocal microscopy, which revealed a significant burden of stromal cysts. After approximately 2 weeks of adjunctive oral miltefosine therapy, there was a severe inflammatory response within the cornea followed by quick resolution of the AK. The second case was a 31-year-old male in whom the diagnosis of AK was confirmed by culture and polymerase chain reaction. Adjunctive oral miltefosine was started 3 months after presentation, leading to a quick resolution.Conclusions: Oral miltefosine may have cysticidal properties and should be considered as adjunctive therapy for the treatment of AK, particularly in cases with a significant burden of cysts or in cases recalcitrant to other treatments.

Type 1 reactions, characterized by increasing lesion erythema, pain, and nerve damage, commonly complicate leprosy. Dapsone hypersensitivity syndrome (DHS) is a potentially fatal reaction occurring 6-8 weeks into dapsone therapy. We present a case of intercurrent Type 1 reaction and DHS in a multibacillary leprosy patient recently started on multidrug treatment.

Schistosoma mansoni (Sm) infection has been linked with an increased risk of HIV acquisition in women. Therefore, defining the mechanism(s) by which Sm alters HIV susceptibility might lead to new HIV prevention strategies. Here, we analyze the impact of standard Sm therapy in HIV-uninfected Sm+ Ugandan adult women on genital HIV susceptibility and mucosal and systemic immunology. Schistosomiasis treatment induces a profound reduction of HIV entry into cervical and blood CD4+ T cells that is sustained for up to two months, despite transient systemic and mucosal immune activation and elevated genital IL-1α levels. Genital IFN-α2a levels are also elevated post-treatment, and IFN-α2a blocks HIV entry into primary CD4+ T cells ex vivo. Transcriptomic analysis of blood mononuclear cells post-Sm treatment shows IFN-I pathway up-regulation and partial reversal of Sm-dysregulated interferon signaling. These findings indicate that Sm therapy may reduce HIV susceptibility for women with Sm infection, potentially through de-repression of IFN-I pathways., Schistosoma mansoniinfection has been linked with an increased risk of HIV acquisition in women. Here, the authors show that standard S. mansoniinfection treatment causes a reduction of HIV entry into cervical and blood CD4+ T cells, which is sustained for up to two months and is associated with de-repression of IFN-I signaling.

Overlapping clinical features of cutaneous leishmaniasis (CL) with ulcers caused by fungi and mycobacteria necessitate confirmatory diagnostic testing. We evaluated a handheld battery-operated device for detection of CL and common fungal and mycobacterial causes of ulcers.We validated Palm PCR™ for detection of common ulcerative skin pathogens using ATCCPalm PCR™ detected 100% of ATCCPalm PCR™ performs comparably to conventional PCR for detection of Leishmania, fungi, and mycobacteria. This work has implications for the diagnostic approach to tropical ulcers, and has the potential to improve field detection of ulcerative pathogens in resource constrained areas.

Purpose To describe a case of diffuse unilateral subacute neuroretinitis (DUSN), a rare condition that causes progressive vision loss following infection by a nematode using enface vitreous imaging. Observations We present the clinical findings of a 37-year-old female, clinically diagnosed with DUSN after a non-invasive multimodal imaging approach that included MultiColor scanning laser imaging and enface vitreous OCT, which revealed the nematode body and lacunae created by worm migration, respectively. Conclusion and importance To our knowledge, this is the first reported case of lacunae visualized using enface vitreous optical coherence tomography (OCT), potentially marking the migration path of the nematode.

Background As rates of international travel increase, more individuals are at risk of travel-acquired infections (TAIs). We aimed to review all microbiologically confirmed cases of malaria, dengue, chikungunya, and enteric fever (Salmonella enterica serovar Typhi/Paratyphi) in Ontario, Canada between 2008-2020 to identify high-resolution geographical clusters that could be targeted for pre-travel prevention. Methods Retrospective cohort study of over 174,000 unique tests for the four above TAIs from Public Health Ontario Laboratories. Test-level data were processed to calculate annual case counts and crude population-standardized incidence ratios (SIRs) at the forward sortation area (FSA) level. Moran’s I statistic was used to test for global spatial autocorrelation. Smoothed SIRs and 95% posterior credible intervals (CIs) were estimated using a spatial Bayesian hierarchical model, which accounts for statistical instability and uncertainty in small-area incidence. Posterior CIs were used to identify high- and low-risk areas, which were described using sociodemographic data from the 2016 Census. Finally, a second model was used to estimate the association between drivetime to the nearest travel clinic and risk of TAI within high-risk areas. Results There were 5962 cases of the four TAIs across Ontario over the study period. Smoothed FSA-level SIRs are shown in Figure 1a, with an inset for the Greater Toronto Area (GTA) in 1b. There was spatial clustering of TAIs (Moran’s I=0.61, p< 2.2e-16). Identified high- and low-risk areas are shown in panels c and d. Compared to low-risk areas, high-risk areas were significantly more likely to have higher proportions of immigrants (p< 0.0001), lower household after-tax income (p=0.04), more university education (p< 0.0001), and were less knowledgeable of English/French (p< 0.0001). In the high-risk GTA, each minute increase in drivetime to the closest travel clinic was associated with a 4% reduction in TAI risk (95% CI 2 - 6%). Bayesian hierarchical model (BHM) smoothed standardized incidence ratios (SIRs) for travel-acquired infections (TAIs) and estimated risk levels (a and c) with insets for the Greater Toronto Area (b and d). High-risk areas are defined as those with smoothed SIR 95% CIs greater than 2, and low-risk areas with smoothed SIR 95% CIs less than 0.25. Conclusion Urban neighbourhoods in the GTA had elevated risks of becoming ill with TAIs. However, geographic proximity to a travel clinic was not associated with an area-level risk reduction in TAI, suggesting other barriers to seeking and adhering to pre-travel advice. Disclosures Isaac Bogoch, MD, MSc, BlueDot (Consultant)National Hockey League Players' Association (Consultant) Andrea Boggild, MSc MD DTMH FRCPC, Nothing to disclose Shaun Morris, MD, MPH, DTM&H, FRCPC, FAAP, GSK (Speaker's Bureau)Pfizer (Advisor or Review Panel member)Pfizer (Grant/Research Support)

Background Cryptosporidiosis is a gastrointestinal disease with global distribution. It has been a reportable disease in Canada since 2000; however, routine molecular surveillance is not conducted. Therefore, sources of contamination are unknown. The aim of this project was to identify species and subtypes of Cryptosporidium in clinical cases from Ontario, the largest province in Canada, representing one third of the Canadian population, in order to understand transmission patterns. Methods A total of 169 frozen, banked, unpreserved stool specimens that were microscopy positive for Cryptosporidium over the period 2008–2017 were characterized using molecular tools. A subset of the 169 specimens were replicate samples from individual cases. DNA was extracted directly from the stool and nested PCR followed by Sanger sequencing was conducted targeting the small subunit ribosomal RNA (SSU) and glycoprotein 60 (gp60) genes. Results Molecular typing data and limited demographic data were obtained for 129 cases of cryptosporidiosis. Of these cases, 91 (70.5 %) were due to Cryptosporidium parvum and 24 (18.6%) were due to Cryptosporidium hominis. Mixed infections of C. parvum and C. hominis occurred in four (3.1%) cases. Five other species observed were Cryptosporidium ubiquitum (n = 5), Cryptosporidium felis (n = 2), Cryptosporidium meleagridis (n = 1), Cryptosporidium cuniculus (n = 1) and Cryptosporidium muris (n = 1). Subtyping the gp60 gene revealed 5 allelic families and 17 subtypes of C. hominis and 3 allelic families and 17 subtypes of C. parvum. The most frequent subtype of C. hominis was IbA10G2 (22.3%) and of C. parvum was IIaA15G2R1 (62.4%). Conclusions The majority of isolates in this study were C. parvum, supporting the notion that zoonotic transmission is the main route of cryptosporidiosis transmission in Ontario. Nonetheless, the observation of C. hominis in about a quarter of cases suggests that anthroponotic transmission is also an important contributor to cryptosporidiosis pathogenesis in Ontario. Graphical Abstract

The prognosis and treatment of New World tegumentary leishmaniasis is dependent on the infecting species, yet such species identification in the Leishmania Viannia subgenus poses a diagnostic challenge. Currently, speciation relies on standard molecular techniques such as restriction fragment length polymorphism (RFLP) analysis, and Sanger sequencing (SS). Whole-genome sequencing (WGS) is a robust and increasingly cost-efficient tool that may improve Leishmania species identification. We evaluated WGS versus standard RFLP-SS for species identification in three reference and five clinical strains of Leishmania Viannia spp. Internal transcribed spacer1 (its1), cysteine proteinase b (cpb), and heat shock protein 70 (hsp70) polymerase chain reaction-restriction fragment length polymorphism (RFLP) was performed, followed by SS of the its2, cpb, hsp70, and mannose phosphate isomerase (mpi) loci. After de novo assembly, sequences were mapped, and homology compared with both reference strains and reference genomes on National Center for Biotechnology Information. All American Type Culture Collection strains were confirmed to be single-species of L. V. braziliensis, L. V. guyanensis, or L. V. panamensis by WGS. Conversely, RFLP-SS was able to definitively identify one of three isolates to the species level. Clinical samples were identified as either single-species (N = 3), mixed (N = 1), or hybrid (N = 1) infections by WGS, while standard molecular diagnosis required multi-target composite analysis for identification due to loci-dependent results by RFLP-SS. We have corroborated the utility of WGS as a diagnostic tool to speciate members of the L. Viannia subgenus and to discriminate between mixed and hybrid infections. WGS is a potentially useful complement to multistaged RFLP-SS for species identification in Leishmania infections.

While impact investments place value on positive impact alongside financial returns, how those attributes are prioritized within investment decision-making varies drastically. How investors manage these trade-offs is an active area of practitioner interest. There is a gap in financial tools that directly tie financial returns to the observed impact of investee businesses to manage these trade-offs. This limits professional impact investors’ ability to efficiently manage impact and financial goals. This chapter examines the growing number of innovative, debt-based transactions that are explicitly tying investor returns to the observed impact of investee businesses. A particular focus is the direct linking of returns between asset managers and investee businesses. While there are examples of explicitly linking impact and returns in transactions on both large and small scales, strong theoretical similarities exist among these tools. They all involve internalizing previously externalized factors. The use of impact-linked debt instruments is viewed here as providing impact investing practitioners more and better options to manage the trade-offs between risk, return, and impact. Opportunities and challenges for the replication and adoption of these tools are discussed, with a particular emphasis on related challenges in impact data gathering and management. These tools are expected to become more commonplace as impact measurement tools and practices mature.

Coccidioidomycosis incidence has been increasing recently in endemic regions. The disease can manifest with variable pulmonary and cutaneous presentations, challenging the clinical diagnosis. Our case highlights the differential diagnosis that must be considered for presentations of erythema nodosum and cavitating lung lesions and the importance of synthesizing the entire patient history—including travel history—for construction of appropriate diagnostic and treatment plans.

Acanthamoeba spp. are the causative pathogens of several infections, including amoebic keratitis (AK), a vision-threatening infection. Acanthamoebae from corneal specimens of patients with AK harbor bacterial endosymbionts, which may increase virulence. We sought to understand the spectrum of bacterial endosymbionts present in clinical isolates of Acanthamoeba spp. identified in our reference parasitology laboratory. Isolates of Acanthamoeba spp. obtained from our biobank of anonymized corneal scrapings were screened for potential endosymbionts by PCR using primer pairs detecting bacteria belonging to orders Chlamydiales, Rickettsiales, or Legionellales and pan16S primers. Three primer pairs specific to the 18s rRNA gene of Acanthamoeba spp. were used for the amplification of Acanthamoeba DNA used for sequencing. Sanger sequencing of all PCR products was performed, followed by BLAST analysis for species identification. We screened 26 clinical isolates of Acanthamoeba spp. for potential endosymbionts. Five isolates (19%) were found to contain bacterial DNA belonging to Legionellales. Three (11%) contained members of the Rickettsiales and Pseudomonas genticulata was detected in a Rickettsia-positive sample. One strain (4%) contained Neochlamydia hartmannellae, a member of the Chlamydiales order. Bacterial endosymbionts are prevalent in clinical strains of Acanthamoeba causing AK isolated from corneal scrapings. The demonstration of these organisms in clinical Acanthamoeba isolates supports a potential exploration of anti-endosymbiont therapeutics as an adjuvant therapy in the treatment of AK.

SummaryBackgroundThere are currently no effective treatments for outpatients with coronavirus disease 2019 (COVID-19). Interferon-lambda-1 is a Type III interferon involved in the innate antiviral response with activity against respiratory pathogens.MethodsIn this double-blind, placebo-controlled trial, outpatients with laboratory-confirmed COVID-19 were randomized to a single subcutaneous injection of peginterferon-lambda 180μg or placebo within 7 days of symptom onset or first positive swab if asymptomatic. The primary endpoint was proportion negative for SARS-CoV-2 RNA on Day 7 post-injection.FindingsThere were 30 patients per arm, with median baseline SARS-CoV-2 viral load of 6.71 (IQR 1.3-8.0) log copies/mL. The decline in SARS-CoV-2 RNA was greater in those treated with peginterferon-lambda than placebo (p=0.04). On Day 7, 24 participants (80%) in the peginterferon-lambda group had an undetectable viral load compared to 19 (63%) in the placebo arm (p=0.15). After controlling for baseline viral load, peginterferon lambda treatment resulted in a 4.12-fold (95CI 1.15-16.7, p=0.029) higher likelihood of viral clearance by Day 7. Of those with baseline viral load above 10E6 copies/mL, 15/19 (79%) in the peginterferon-lambda group were undetectable on Day 7 compared to 6/16 (38%) in the placebo group (p=0.012). Adverse events were similar between groups with only mild reversible transaminase elevations more frequently observed in the peginterferon-lambda group.InterpretationPeginterferon-lambda accelerated viral decline in outpatients with COVID-19 resulting in a greater proportion with viral clearance by Day 7, particularly in those with high baseline viral load. Peginterferon-lambda may have potential to prevent clinical deterioration and shorten duration of viral shedding.(NCT04354259)FundingThis study was supported by the Toronto COVID-19 Action Initiative, University of Toronto and the Ontario First COVID-19 Rapid Research Fund. Medication was supplied by Eiger BioPharma.Research in ContextTreatment trials for COVID-19 have largely focused on hospitalized patients and no treatments are approved for people with mild to moderate disease in the outpatient setting. A number of studies in ambulatory populations have been registered but no controlled studies in the outpatient setting have been reported to date (Pubmed Search October 20, 2020, COVID-19 treatment; controlled trials). Uncontrolled case series of hydroxychloroquine with or without azithromycin have been reported with mixed results but no clear signal of efficacy and some concerns raised about cardiac toxicity. Treamtent in the outpatient setting has potential to prevent infected individuals from deteriorating and perhaps more importantly, may shorten the duration of viral shedding, reducing the risk of transmission and the duration required for self-isolation, with significant public health and societal impact.Added value of this studyThis is the first study to show an antiviral effect in outpatients with COVID-19. After controlling for baseline viral load, those treated with peginterferon-lambda had a 4.12-fold (95%CI 1.15-16.7, p=0.029) higher odds of viral clearance by Day 7 compared to those who received placebo. The viral load decline was faster with pegterferon-lambda and the effect was most pronounced in those with high viral loads. In individuals with a baseline viral load of 10E6 copies/mL or higher, 15/19 (79%) in the peginterferon-lambda arm cleared by Day 7 compared to 6/16 (38%) (p=0.012) in the placebo arm (OR 6.25, 95%CI 1.49-31.1, p=0.012), translating to a median time to viral clearance of 7 days (95%CI 6.2-7.8 days) with peginterferon-lambda compared to 10 days (95%CI 7.8-12.2 days) with placebo (p=0.038). Those with low viral loads (Implications of all available evidenceThere is no currently approved therapy for outpatients with COVID-19. This study showed that peginterferon-lambda accelerated viral clearance, particularly in those with high baseline viral loads, highlighting the importance of quantitative viral load testing in the evaluation of antiviral agents for COVID-19. Treatment early in the course of disease may prevent clinical deterioration and shorenting of the duration of viral shedding may have important public health impact by limiting transmission and reducing the duration required for self-isolation. Additional trials of peginterferon-lambda and other antiviral strategies in the outpatient setting are required.

Summary Background To date, only monoclonal antibodies have been shown to be effective for outpatients with COVID-19. Interferon lambda-1 is a type III interferon involved in innate antiviral responses with activity against respiratory pathogens. We aimed to investigate the safety and efficacy of peginterferon lambda in the treatment of outpatients with mild-to-moderate COVID-19. Methods In this double-blind, placebo-controlled trial, outpatients with laboratory-confirmed COVID-19 were randomly assigned to a single subcutaneous injection of peginterferon lambda 180 μg or placebo within 7 days of symptom onset or first positive swab if asymptomatic. Participants were randomly assigned (1:1) using a computer-generated randomisation list created with a randomisation schedule in blocks of four. At the time of administration, study nurses received a sealed opaque envelope with the treatment allocation number. The primary endpoint was the proportion of patients who were negative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA on day 7 after the injection, analysed by a χ2 test following an intention-to-treat principle. Prespecified analysis of the primary endpoint, adjusted for baseline viral load, using bivariate logistic regression was done. The trial is now complete. This trial is registered with ClinicalTrials.gov, NCT04354259. Findings Between May 18, and Sept 4, 2020, we recruited 30 patients per group. The decline in SARS-CoV-2 RNA was greater in those treated with peginterferon lambda than placebo from day 3 onwards, with a difference of 2·42 log copies per mL at day 7 (p=0·0041). By day 7, 24 (80%) participants in the peginterferon lambda group had an undetectable viral load, compared with 19 (63%) in the placebo group (p=0·15). After controlling for baseline viral load, patients in the peginterferon lambda group were more likely to have undetectable virus by day 7 than were those in the placebo group (odds ratio [OR] 4·12 [95% CI 1·15–16·73; p=0·029). Of those with baseline viral load above 106 copies per mL, 15 (79%) of 19 patients in the peginterferon lambda group had undetectable virus on day 7, compared with six (38%) of 16 in the placebo group (OR 6·25 [95% CI 1·49–31·06]; p=0·012). Peginterferon lambda was well tolerated, and adverse events were similar between groups with mild and transient aminotransferase, concentration increases more frequently observed in the peginterferon lambda group. Two individuals met the threshold of grade 3 increase, one in each group, and no other grade 3 or 4 laboratory adverse events were reported. Interpretation Peginterferon lambda accelerated viral decline in outpatients with COVID-19, increasing the proportion of patients with viral clearance by day 7, particularly in those with high baseline viral load. Peginterferon lambda has potential to prevent clinical deterioration and shorten duration of viral shedding. Funding The Toronto COVID-19 Action Initiative, University of Toronto, and the Ontario First COVID-19 Rapid Research Fund, Toronto General & Western Hospital Foundation.

Neuromyelitis optica spectrum disorders (NMOSD) and multiple sclerosis (MS) show overlap in their clinical features. We performed an analysis of relapses with the aim of determining differences between the two conditions. Cases of NMOSD and age- and sex-matched MS controls were collected from across Australia and New Zealand. Demographic and clinical information, including relapse histories, were recorded using a standard questionnaire. There were 75 cases of NMOSD and 101 MS controls. There were 328 relapses in the NMOSD cases and 375 in MS controls. Spinal cord and optic neuritis attacks were the most common relapses in both NMOSD and MS. Optic neuritis (p < 0.001) and area postrema relapses (P = 0.002) were more common in NMOSD and other brainstem attacks were more common in MS (p < 0.001). Prior to age 30 years, attacks of optic neuritis were more common in NMOSD than transverse myelitis. After 30 this pattern was reversed. Relapses in NMOSD were more likely to be treated with acute immunotherapies and were less likely to recover completely. Analysis by month of relapse in NMOSD showed a trend toward reduced risk of relapse in February to April compared to a peak in November to January (P = 0.065). Optic neuritis and transverse myelitis are the most common types of relapse in NMOSD and MS. Optic neuritis tends to occur more frequently in NMOSD prior to the age of 30, with transverse myelitis being more common thereafter. Relapses in NMOSD were more severe. A seasonal bias for relapses in spring-summer may exist in NMOSD.

Background: With the increasing interest in the importance and potential benefits of vitamin D, there has been a significant rise in unnecessary vitamin D testing. The aim of the project was to reduce unnecessary repeat vitamin D testing at Women’s College Hospital by 50% by May 30th 2020. Methods: The Model for Improvement framework was used in the design of the quality improvement project to reduce unnecessary repeat vitamin D testing. Problem characterization was conducted to design the intervention to address root causes and iterative Plan-do-Study-Act cycles were used to develop an intervention that incorporated a best practice advisory (BPA). The primary outcome measure was unnecessary vitamin D testing. Unnecessary repeat testing was defined as: repeat 25-hydroxyvitamin D testing within 3 months or repeat 25-hydroxyvitamin D testing after a normal result (>75 mmol/L) in the preceding 12 months. Secondary outcomes which included BPAs generated, as well as the number of BPAs that resulted in no test being ordered were tracked. Paper-based orders were also tracked as a balancing measure. Results: It was identified that 12.7% of vitamin D testing (n= 289/2276) between July 2017 and July 2018 was related to unnecessary repeat testing. Following our cause and effect analysis and problem characterization, it was noted that providers ordered repeat vitamin D testing due to being unaware of prior normal results, as well as due to a knowledge gap of current testing recommendations. If the 25-hydroxyvitamin D order was identified as unnecessary at the time of order entry, a BPA was generated at the point of care. The BPA was implemented on February 4th, 2019. As of August 31st, 2019 based on the analysis of the number of BPAs generated and the number of tests not ordered as a result, there has been a 26% reduction in the number of inappropriate repeat vitamin D orders. Conclusions: Based on the preliminary data, a best practice advisory alert for vitamin D testing can be an appropriate QI intervention to reduce unnecessary vitamin D testing. Ongoing data analysis will be conducted to assess the long-term impact and sustainability of this intervention. Next steps include consideration of implementation of force function to reduce inappropriate repeat vitamin D testing.

Background Gestational helminth infections are correlated to adverse outcomes including maternal anemia; as such, treatment is recommended. However, little published high-quality data exist around the efficacy, safety, and tolerability of anti-helminthics in pregnancy. We therefore conducted a systematic review and synthesized the available data on maternal outcomes following gestational treatment of intestinal nematodes to help guide clinical decision-making. Methods Five electronic databases were searched for studies reporting the efficacy, safety, or tolerability of anti-helminthic drugs for gestational treatment of intestinal nematodes. Studies were systematically screened, followed by data extraction. Trial quality was assessed using the GRADE approach. We conducted a narrative synthesis followed by meta-analyses using random-effects models as appropriate. Data were summarized using qualitative and quantitative measures for specific parasitic infections as well as efficacy and safety of anti-parasitic agents. Outcomes of interest included: maternal anemia, minor adverse outcomes, pregnancy loss, pre-mature delivery, prevalence of infection, and cure rate. Results 23 studies were included. Gestational treatment with albendazole had cure rates up to 90% for hookworm and Ascaris, but only 50% for Trichuris. Mebendazole had an overall cure rate of ≤70% for Ascaris, hookworm, and Trichuris. Pooled relative risk reduction of hookworm prevalence at delivery with albendazole compared to placebo was 90% (95%CI 0.09-0.15, n=2, I2=0%). Rate of pregnancy loss and hemoglobin concentration did not differ between albendazole or mebendazole versus placebo, and rates of pre-term delivery were similar in albendazole-treated pregnant women versus controls. Ivermectin demonstrated a cure rate of 29% for hookworm and 56% for Trichuris in pregnant women. No serious adverse events were attributable to any drug studied. Conclusions With increased international travel and migration of vulnerable populations, practitioners will encounter nematode infections in pregnant patients. Our analysis supports that albendazole in pregnancy has high cure rates for STHs and is safe for the mother.

Intoxication syndromes may be travel acquired, and are related to intentional or accidental inhalational or percutaneous exposures or ingestions. Due to their myriad clinical presentations, initial differential diagnosis of such intoxications in returned travelers is broad, and typically requires detailed history and laboratory investigations to disentangle. We herein use a case-based clinical problem solving approach to illumination of a mercury intoxication syndrome, which presented in a 48-year-old VFR traveler to Guyana. Common clinical presentations, differential diagnoses, laboratory investigations, and therapeutic interventions are discussed.

Introduction: While monophasic and relapsing forms of myelin oligodendrocyte glycoprotein antibody associated disorders (MOGAD) are increasingly diagnosed world-wide, consensus on management is yet to be developed. Objective: To survey the current global clinical practice of clinicians treating MOGAD. Method: Neurologists worldwide with expertise in treating MOGAD participated in an online survey (February–April 2019). Results: Fifty-two responses were received (response rate 60.5%) from 86 invited experts, comprising adult (78.8%, 41/52) and paediatric (21.2%, 11/52) neurologists in 22 countries. All treat acute attacks with high dose corticosteroids. If recovery is incomplete, 71.2% (37/52) proceed next to plasma exchange (PE). 45.5% (5/11) of paediatric neurologists use IV immunoglobulin (IVIg) in preference to PE. Following an acute attack, 55.8% (29/52) of respondents typically continue corticosteroids for ≥ 3 months; though less commonly when treating children. After an index event, 60% (31/51) usually start steroid-sparing maintenance therapy (MT); after ≥ 2 attacks 92.3% (48/52) would start MT. Repeat MOG antibody status is used by 52.9% (27/51) to help decide on MT initiation. Commonly used first line MTs in adults are azathioprine (30.8%, 16/52), mycophenolate mofetil (25.0%, 13/52) and rituximab (17.3%, 9/52). In children, IVIg is the preferred first line MT (54.5%; 6/11). Treatment response is monitored by MRI (53.8%; 28/52), optical coherence tomography (23.1%; 12/52) and MOG antibody titres (36.5%; 19/52). Regardless of monitoring results, 25.0% (13/52) would not stop MT. Conclusion: Current treatment of MOGAD is highly variable, indicating a need for consensus-based treatment guidelines, while awaiting definitive clinical trials.

Background: There are currently no effective treatments for outpatients with coronavirus disease. 2019 (COVID-19). Interferon-lambda-1 is a Type III interferon involved in the innate antiviral response with activity against respiratory pathogens. Methods: In this double-blind, placebo-controlled trial, outpatients with laboratory-confirmed COVID-19 were randomized to a single subcutaneous injection of peginterferon-lambda 180μg or placebo within 7 days of symptom onset or first positive swab if asymptomatic. The primary endpoint was proportion negative for SARS-CoV-2 RNA on Day 7 post-injection. Results: There were 30 patients per arm, with median baseline SARS-CoV-2 viral load of 6.71 (IQR 1.3-8.0) log copies/mL. The decline in SARS-CoV-2 RNA was greater in those treated with peginterferon-lambda than placebo (p=0.04). On Day 7, 24 participants (80%) in the peginterferon-lambda group had an undetectable viral load compared to 19 (63%) in the placebo arm (p=0.15). After controlling for baseline viral load, peginterferon-lambda treatment resulted in a 4.12-fold (95CI 1.15-16.7, p=0.029) higher likelihood of viral clearance by Day 7. Of those with baseline viral load above 10E6 copies/mL, 15/19 (79%) in the peginterferon-lambda group were undetectable on Day 7 compared to 6/16 (38%) in the placebo group (p=0.012). Adverse events were similar between groups with only mild reversible transaminase elevations more frequently observed in the peginterferon-lambda group. Conclusion: Peginterferon-lambda accelerated viral decline in outpatients with COVID-19 resulting in a greater proportion with viral clearance by Day 7, particularly in those with high baseline viral load. Peginterferon-lambda may have potential to prevent clinical deterioration and shorten duration of viral shedding. Trial Registration: NCT04354259 Funding Statement: This study was supported by the Toronto COVID-19 Action Initiative, University of Toronto and the Ontario First COVID-19 Rapid Research Fund. Medication was supplied by Eiger BioPharma. Declaration of Interests: JJF reports research support unrelated to this work from Eiger BioPharmaceuticals. BC has received research support unrelated to this work from Nubiyota LLC and Sanofi. IC and CH are employees of Eiger BioPharmaceuticals. JSG is a board member and founder of Eiger BioPharmaceuticals, Inc., in which he has an equity interest, and is an inventor on a patent application for the use of interferon lambda to treat coronavirus infections. All other authors have nothing to declare. Ethics Approval Statement: The Research Ethics Boards of all participating institutions approved the study, which was conducted under a Clinical Trial Application approved by Health Canada.