Filial Trauma: The Experience of Adoptive Parents of Children with Complex Behavioral and Relational Problems.

Children adopted from out-of-home care may present symptoms of developmental trauma that affect their functioning. This puts their adoptive parents at risk of experiencing secondary trauma. The purpose of this research was to understand the experience of adoptive parents who self-report symptoms of secondary trauma in relation to their child's symptoms of developmental trauma. Individual semi-structured interviews were conducted, transcribed, and analyzed using Braun and Clarke's (Qualitative Research in Psychology, 3(2), 77-101, 2006) thematic analysis method. Ten adoptive parents were recruited from four community organizations providing support for adoptive parents or parents of children with attachment disorder. All participants reported feeling strong emotions related to secondary trauma, as well as physical and mental health issues that appeared after the child's arrival in the family. Participants reported experiencing aggression from their child, which greatly disturbed the parent-child relationship and led to the child being placed in residential care for half of the families involved in the study. Secondary trauma was insufficient to fully capture the experience of these parents as it failed to account for the suffering and distress linked to their efforts to establish a parent-child relationship. Instead, filial trauma was used to describe this experience. The authors conclude that a better understanding of filial trauma can contribute to improving post-adoption services for parents struggling to fulfill one of the most important roles of their lives: being the parent of their child.

Motivation to participate and attrition factors in a COVID-19 biobank: A qualitative study.

BACKGROUND: The Biobanque québécoise de la COVID-19 (Quebec Biobank for COVID-19, or BQC19) is a provincial initiative that aims to manage the longitudinal collection, storage, and sharing of biological samples and clinical data related to COVID-19. During the study, BQC19 investigators reported a high loss-to-follow-up rate. The current study aimed to explore motivational and attrition factors from the perspective of BQC19 participants and health care and research professionals. METHODS: This was an inductive exploratory qualitative study. Using a theoretical sampling approach, a sample of BQC19 participants and professionals were invited to participate via semi-structured interviews. Topics included motivations to participate; participants' fears, doubts, and barriers to participation; and professionals' experiences with biobanking during the COVID-19 pandemic. RESULTS: Interviews were conducted with BQC19 participants (n = 23) and professionals (n = 17) from 8 clinical data collection sites. Motivations included the contribution to science and society in crisis, self-worth, and interactions with medical professionals. Reasons for attrition included logistical barriers, negative attitudes about public health measures or genomic studies, fear of clinical settings, and a desire to move on from COVID-19. Motivations and barriers seemed to evolve over time and with COVID-19 trends and surges. Certain situations were associated with attrition, such as when patients experienced indirect verbal consent during hospitalization. Barriers related to human and material resources and containment/prevention measures limited the ability of research teams to recruit and retain participants, especially in the ever-evolving context of crisis. CONCLUSION: The pandemic setting impacted participation and attrition, either by influencing participants' motivations and barriers or by affecting research teams' ability to recruit and retain participants. Longitudinal and/or biobanking studies in a public health crisis setting should consider these factors to limit attrition.

Bacterial Biomarkers of the Oropharyngeal and Oral Cavity during SARS-CoV-2 Infection.

(1) Background: Individuals with COVID-19 display different forms of disease severity and the upper respiratory tract microbiome has been suggested to play a crucial role in the development of its symptoms. (2) Methods: The present study analyzed the microbial profiles of the oral cavity and oropharynx of 182 COVID-19 patients compared to 75 unaffected individuals. The samples were obtained from gargle screening samples. 16S rRNA amplicon sequencing was applied to analyze the samples. (3) Results: The present study shows that SARS-CoV-2 infection induced significant differences in bacterial community assemblages, with Prevotella and Veillonella as biomarkers for positive-tested people and Streptococcus and Actinomyces for negative-tested people. It also suggests a state of dysbiosis on the part of the infected individuals due to significant differences in the bacterial community in favor of a microbiome richer in opportunistic pathogens. (4) Conclusions: SARS-CoV-2 infection induces dysbiosis in the upper respiratory tract. The identification of these opportunistic pathogenic biomarkers could be a new screening and prevention tool for people with prior dysbiosis.

Long-Term Consequences of COVID-19 in Predominantly Immunonaive Patients: A Canadian Prospective Population-Based Study.

Background: Lingering symptoms are frequently reported after acute SARS-CoV-2 infection, a condition known as post-COVID-19 condition (PCC). The duration and severity of PCC in immunologically naïve persons remain unclear. Furthermore, the long-term consequences of these chronic symptoms on work and mental health are poorly documented. Objective: To determine the outcome, the risk factors, and the impact on work and mental health associated with post-COVID-19 symptoms. Methods: This prospective population-based study assessed acute COVID-19 symptoms and their evolution for up to nine months following infection. Individuals aged 18 years and older with COVID-19 in three Canadian regions between 1 November 2020 and 31 May 2021 were recruited. Participants completed a questionnaire that was either administered by trained student investigators over the phone or self-administered online. Results: A total of 1349 participants with a mean age of 46.6 ± 16.0 years completed the questionnaire. Participants were mostly unvaccinated at the time of their COVID-19 episode (86.9%). Six hundred and twenty-two participants (48.0%) exhibited one symptom or more, at least three months post-COVID-19. Among participants with PCC, 23.0% to 37.8% experienced fatigue at the time of survey. Moreover, 6.1% expressed psychological distress. Risk factors for PCC and fatigue included female sex (OR = 1.996), higher number of symptoms (OR = 1.292), higher severity of episode (OR = 3.831), and having a mental health condition prior to the COVID-19 episode (OR = 5.155). Conclusions: In this multicenter cohort study, almost half (47%) of the participants reported persistent symptoms >3 months after acute infection. Baseline risk factors for PCC include female sex, number and severity of symptoms during acute infection, and a previous diagnosis of mental health disorder. Having PCC negatively impacted health-related quality of life and these patients were more likely to exhibit psychological distress, as well as fatigue.

Moving towards the implementation of pharmacogenetic testing in Quebec.

Clinical implementation of pharmacogenetics (PGx) into routine care will elevate the current paradigm of treatment decisions. However, while PGx tests are increasingly becoming reliable and affordable, several barriers have limited their widespread usage in Canada. Globally, over ninety successful PGx implementors can serve as models. The purpose of this paper is to outline the PGx implementation barriers documented in Quebec (Canada) to suggest efficient solutions based on existing PGx clinics and propose an adapted clinical implementation model. We conclude that the province of Quebec is ready to implement PGx.

Cannabis use in patients with Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay.

Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset cerebellar ataxia with often presence of peripheral sensorimotor neuropathy and lower limb spasticity. Recently, the presence of pain has been associated with ARSACS in a quarter of the population in relation to spasms and neuropathic pain. However, limited therapeutic options available to patients and the occurrence of persistent symptoms despite treatment with the usual pharmacologic agents have led to exploring cannabis as a potential alternative. The aim of this study was to characterize the profile of cannabis use among patients with ARSACS. Phone interviews were conducted to document current or former cannabis use. Reasons of cannabis use and the characteristics of use were also investigated. Among the 50 study participants, 18% currently used cannabis, 40% reported at least one occurrence of cannabis use and 42% reported having never used cannabis. A greater proportion of patients with regular cannabis use reported chronic pain in comparison to those who never used. Although less frequent than ataxia, spasticity, muscle cramps or muscle spasms, which were independently reported by more than half of the studied sample, chronic pain was notably present in 30% of participants. While our study did not assess the therapeutic effects of cannabis, our results highlight that there is a potential role for cannabis and cannabinoids in the management of multiple ARSACS-associated symptoms and that agents modulating the endocannabinoid system need to be properly investigated.

Family planning decisional needs assessment for recessive hereditary disorders: Insights from carrier couples and professionals.

OBJECTIVE: Carrier couples of recessive diseases face an important decision-making process regarding their familial planning that can become a significant source of discomfort and potential regrets. To date, no study has described the decisional needs of carrier couples of Leigh syndrome French-Canadian type, hereditary tyrosinemia type 1, hereditary motor and sensory neuropathy with or without agenesis of the corpus callosum and autosomal recessive spastic ataxia of Charlevoix-Saguenay undergoing family planning decision-making process. Our study aimed to describe the decisional needs of carrier couples according to the Ottawa Decision Support Framework. METHODS: A qualitative descriptive study was conducted. Qualitative individual and joint couple interviews were performed among 39 carrier individuals and 11 health and social care professionals. RESULTS: Carrier couples' decision-making process is complex, and their decisional needs include, among others, sufficient knowledge about the disease and the reproductive options, personal values and available support. Increased decisional conflict was observed among carriers of diseases associated with low morbidity and mortality. CONCLUSION: Family planning decision-making is an evolutive deliberative process that requires appropriate shared decision-making to insure decisional comfort. PRACTICE IMPLICATIONS: Carrier couples family planning decision-making process needs to be better supported.

The Biobanque québécoise de la COVID-19 (BQC19)-A cohort to prospectively study the clinical and biological determinants of COVID-19 clinical trajectories.

SARS-CoV-2 infection causing the novel coronavirus disease 2019 (COVID-19) has been responsible for more than 2.8 million deaths and nearly 125 million infections worldwide as of March 2021. In March 2020, the World Health Organization determined that the COVID-19 outbreak is a global pandemic. The urgency and magnitude of this pandemic demanded immediate action and coordination between local, regional, national, and international actors. In that mission, researchers require access to high-quality biological materials and data from SARS-CoV-2 infected and uninfected patients, covering the spectrum of disease manifestations. The "Biobanque québécoise de la COVID-19" (BQC19) is a pan-provincial initiative undertaken in Québec, Canada to enable the collection, storage and sharing of samples and data related to the COVID-19 crisis. As a disease-oriented biobank based on high-quality biosamples and clinical data of hospitalized and non-hospitalized SARS-CoV-2 PCR positive and negative individuals. The BQC19 follows a legal and ethical management framework approved by local health authorities. The biosamples include plasma, serum, peripheral blood mononuclear cells and DNA and RNA isolated from whole blood. In addition to the clinical variables, BQC19 will provide in-depth analytical data derived from the biosamples including whole genome and transcriptome sequencing, proteome and metabolome analyses, multiplex measurements of key circulating markers as well as anti-SARS-CoV-2 antibody responses. BQC19 will provide the scientific and medical communities access to data and samples to better understand, manage and ultimately limit, the impact of COVID-19. In this paper we present BQC19, describe the process according to which it is governed and organized, and address opportunities for future research collaborations. BQC19 aims to be a part of a global communal effort addressing the challenges of COVID-19.

A network-informed analysis of SARS-CoV-2 and hemophagocytic lymphohistiocytosis genes' interactions points to Neutrophil extracellular traps as mediators of thrombosis in COVID-19.

Abnormal coagulation and an increased risk of thrombosis are features of severe COVID-19, with parallels proposed with hemophagocytic lymphohistiocytosis (HLH), a life-threating condition associated with hyperinflammation. The presence of HLH was described in severely ill patients during the H1N1 influenza epidemic, presenting with pulmonary vascular thrombosis. We tested the hypothesis that genes causing primary HLH regulate pathways linking pulmonary thromboembolism to the presence of SARS-CoV-2 using novel network-informed computational algorithms. This approach led to the identification of Neutrophils Extracellular Traps (NETs) as plausible mediators of vascular thrombosis in severe COVID-19 in children and adults. Taken together, the network-informed analysis led us to propose the following model: the release of NETs in response to inflammatory signals acting in concert with SARS-CoV-2 damage the endothelium and direct platelet-activation promoting abnormal coagulation leading to serious complications of COVID-19. The underlying hypothesis is that genetic and/or environmental conditions that favor the release of NETs may predispose individuals to thrombotic complications of COVID-19 due to an increase risk of abnormal coagulation. This would be a common pathogenic mechanism in conditions including autoimmune/infectious diseases, hematologic and metabolic disorders.

Characterization of cannabis use by patients with myotonic dystrophy type 1: A pilot study.

The treatment of myotonic dystrophy type 1 (DM1) focuses on reducing symptom burden. However, since medication often fails to produce satisfying symptom relief, some patients seek alternatives, such as cannabis, to help reduce some of these symptoms. The aim of this study was to provide an accurate profile of cannabis use among DM1 patients. Phone interviews were conducted to identify current and former users, and to assess reasons for cannabis use. Characteristics of cannabis use were also investigated. Briefly, among the 72 study participants, 22.2% currently used cannabis and a majority of them (56.9%) reported using it to relieve symptoms associated with DM1. These users, classified as therapeutic users, reported poorer health status (EQ-5D index scores: 0.532±0.230 vs. 0.823±0.208, p = 0.020; EQ-VAS scale 50.56±10.74 vs. 75.57±21.50, p = 0.009) than non-therapeutic users. Finally, differences among sex were also highlighted. While the therapeutic effects of cannabis were not explored in our study, our results support the potential role of cannabis and cannabinoids in the treatment of DM1-associated symptoms which will need to be thoroughly investigated.

Adalimumab, Infliximab, and Vedolizumab in Treatment of Ulcerative Colitis: A Long-Term Retrospective Study in a Tertiary Referral Center.

Background: Biological therapies have changed the landscape of pharmacological management of ulcerative colitis (UC). However, a large proportion of patients do not respond to biologics, lose their response over time, or present adverse drug events. This study aims to assess therapeutic response and treatment persistence to adalimumab, infliximab, and vedolizumab, 3 agents widely used in a tertiary referral center of Saguenay-Lac-Saint-Jean (Quebec, Canada). Methods: We conducted a retrospective population-based study with a thorough review of patients' medical charts. Adults at UC diagnosis, with current or past use of adalimumab, infliximab, or vedolizumab, were included in the study. Clinical data were collected in order to assess response phenotypes and persistence to treatment. Kaplan-Meier curves were performed to assess treatment persistence, and predictors for discontinuation were assessed using Cox regression analyses. Results: A total of 134 patients were included in this study. For the cases exposed to adalimumab, infliximab, and vedolizumab, 56.9%, 62.5%, and 47.5% were responders, respectively. Mean persistence rates (95% CI) were 5.5 (4.3-6.6), 10.1 (8.7-11.5), and 3.6 (2.9-4.2) years for adalimumab, infliximab, and vedolizumab, respectively. Increased persistence rates were observed in biologic-naïve patients treated with infliximab in comparison to those with the previous exposition to 2 biologics, but no such effect was observed for adalimumab or vedolizumab. Overall, 61.9% of cases had adverse drug events and of these, 6 led to treatment discontinuation. Conclusion: This study presents long-term treatment persistence data with adalimumab, infliximab, and vedolizumab, showing that more than half of cases treated with these biologics remained on treatment at least 24 months after initiation.

A Drug-Induced Acute Pancreatitis Retrospective Study.

Background and Aims: Drugs are considered a relatively rare and understudied cause of acute pancreatitis (AP). The lack of convincing and conclusive data on drug-induced AP (DIAP) complicates the diagnosis as well as the identification of the causative drug. The aim of this study is to document causes of DIAP cases that occurred in the Saguenay-Lac-Saint-Jean (SLSJ) population. Methods: We have conducted a retrospective and descriptive population-based study of DIAP cases that occurred between 2006 and 2014 in the six hospitals serving the entire SLSJ population. Cases were selected from the Quebec Ministry of Health hospitalizations registry (MED-ECHO) administrative public database. A medical chart review was performed in an attempt to characterize DIAP hospitalizations and to identify the imputable drugs. Results: During the studied period, 75 cases (30.7% male, 69.3% female) were included totaling 90 hospitalizations for DIAP. Among them, 50 causative drugs were identified and were distributed in 17 different drug classes. Recurrent DIAPs were documented in 13 cases, and among them, 6 cases have experimented a positive rechallenge. Six drugs (5-fluorouracil, atorvastatin, bortezomib, nilotinib, rosuvastatin, and triamcinolone) were associated with the highest degree of evidence. The most common causative drugs of DIAP hospitalization were azathioprine (n = 7), followed by atorvastatin (n = 6), hydrochlorothiazide (n = 5), rosuvastatin (n = 4), and codeine (n = 4). Conclusions: This study has added new evidences about potentially pancreatitis-associated drugs in literature. This is the first study to report definite 5-fluorouracil- and triamcinolone-induced AP. An updated version of the evidence-based literature review is needed to support the clinicians in the identification of the causative drugs.

Gene expression profiles of recurrent acute pancreatitis risk in patients with sustained chylomicronemia.

A fasting triglyceridemia >10 mmol/L is associated with chylomicronemia (CM) and an increased recurrent acute pancreatitis (RAP) risk. The number of pancreatitis episodes varies significantly between patients with CM. The objective of this study was to investigate gene expression profiles of RAP in patients with CM. A total of 47 CM subjects participated in this study. Prior to the analyses, all patients were divided into three groups covering a wide spectrum of RAP: 0 (n = 21), 1-3 (n = 10) or >4 (n = 16) pancreatitis episodes. Gene expression profiles were compared to those of 15 healthy normolipidemic controls. Differential expression moderated T-tests between studied groups were performed using a linear model of the Bioconductor package Limma. The False discovery rate was controlled using the Benjamini-Hochberg procedure. At a p-value <0.01, a false discovery rate of 5% and a >2-fold change expression significance levels, a set of 41 probes have been found differentially expressed in CM subjects with no pancreatitis, 103 in the CM group with 1 to 3 pancreatitis, and 94 in the group with ≥4 pancreatitis compared to healthy controls. Of the identified annotated probes, 14 are shared by all CM groups; 3 are specific to CM with no pancreatitis; 11 are specific to CM with 1 to 3 pancreatitis, and 17 are specific to CM with ≥4 pancreatitis. Most of the annotated biomarkers are involved in inflammatory, immune, lipoprotein kinetics or signalling biological pathways. These results reveal gene expression signatures of RAP in patients with CM.

Dissection of Clinical and Gene Expression Signatures of Familial versus Multifactorial Chylomicronemia.

Familial chylomicronemia syndrome (FCS) is a rare disorder associated with chylomicronemia (CM) and an increased risk of pancreatitis. Most individuals with CM do not have FCS but exhibit multifactorial CM (MCM), which differs from FCS in terms of risk and disease management. This study aimed to investigate clinical and gene expression profiles of FCS and MCM patients. Anthropometrics, clinical, and biochemical variables were analyzed in 57 FCS and 353 MCM patients. Gene expression analyses were performed in a subsample of 19 FCS, 28 MCM, and 15 normolipidemic controls. Receiver operating characteristic (ROC) curve analyses were performed to analyze the capacity of variables to discriminate FCS from MCM. Sustained fasting triglycerides ≥20 mmol/L (>15 mmol/L with eruptive xanthomas), history of pancreatitis, poor response to fibrates, diagnosis of CM at childhood, body mass index <22 kg/m2, and delipidated apolipoprotein B or glycerol levels <0.9 g/L and <0.05 mmol/L, respectively, had an area under the ROC curve ≥0.7. Gene expression analyses identified 142 probes differentially expressed in FCS and 32 in MCM compared with controls. Among them, 13 probes are shared between FCS and MCM; 63 are specific to FCS and 2 to MCM. Most FCS-specific or shared biomarkers are involved in inflammatory, immune, circadian, postprandial metabolism, signaling, docking systems, or receptor-mediated clearance mechanisms. This study reveals differential signatures of FCS and MCM. It opens the door to the identification of key mechanisms of CM expression and potential targets for the development of new treatments.

Pharmacogenetic testing in primary care practice: opinions of physicians, pharmacists and patients.

Aim: Although health authorities have set pharmacogenetic (PGx) markers on labels of hundreds of drugs, the use of PGx in clinical care remains infrequent. The adoption of PGx will depend on the opinions of physicians, pharmacists and patients. Materials & methods: Qualitative focus group interviews were performed with 23 physicians, 11 pharmacists and 30 patients. Results: Majority of the participants showed enthusiasm toward the implementation of PGx in clinics. Lack of knowledge on PGx, roles of healthcare providers, factors in favor and challenges of PGx implementation, ethical and insurance issues, educational and tools needs were the key themes that emerged from the interviews. Conclusion: Several barriers impede the uptake of PGx in clinics, however, opinions of physicians, pharmacists and patients are mostly favorable.

Large-scale deletions of the ABCA1 gene in patients with hypoalphalipoproteinemia.

Copy-number variations (CNVs) have been studied in the context of familial hypercholesterolemia but have not yet been evaluated in patients with extreme levels of HDL cholesterol. We evaluated targeted, next-generation sequencing data from patients with very low levels of HDL cholesterol (i.e., hypoalphalipoproteinemia) with the VarSeq-CNV® caller algorithm to screen for CNVs that disrupted the ABCA1, LCAT, or APOA1 genes. In four individuals, we found three unique deletions in ABCA1: a heterozygous deletion of exon 4, a heterozygous deletion that spanned exons 8 to 31, and a heterozygous deletion of the entire ABCA1 gene. Breakpoints were identified with Sanger sequencing, and the full-gene deletion was confirmed by using exome sequencing and the Affymetrix CytoScan HD array. Previously, large-scale deletions in candidate HDL genes had not been associated with hypoalphalipoproteinemia; our findings indicate that CNVs in ABCA1 may be a previously unappreciated genetic determinant of low levels of HDL cholesterol. By coupling bioinformatic analyses with next-generation sequencing data, we can successfully assess the spectrum of genetic determinants of many dyslipidemias, including hypoalphalipoproteinemia.

Child Maltreatment Among Children With Intellectual Disability in the Canadian Incidence Study.

This study aims to compare, among a representative sample of substantiated child maltreatment cases, the characteristics of those with intellectual disability (ID) from those without ID. Using the 2008 Canadian Incidence Study of Reported Child Abuse and Neglect, 5,797 cases of substantiated maltreatment that involved children aged between 0 and 14 years were analyzed. One in 10 children (11.3%) was identified with ID. Results revealed functional problems to be higher among children with ID and their parents. Moreover, children with ID experienced more severe maltreatment, and were more often referred to ongoing child protection services. These findings suggest that maltreated children with ID are facing additional challenges that must be accounted for in service planning and delivery.

Long-Term Retrospective Analysis of Gene Therapy with Alipogene Tiparvovec and Its Effect on Lipoprotein Lipase Deficiency-Induced Pancreatitis.

Alipogene tiparvovec (Glybera) is a gene therapy product approved in Europe under the "exceptional circumstances" pathway as a treatment for lipoprotein lipase deficiency (LPLD), a rare genetic disease resulting in chylomicronemia and a concomitantly increased risk of acute and recurrent pancreatitis, with potentially lethal outcome. This retrospective study analyzed the frequency and severity of pancreatitis in 19 patients with LPLD up to 6 years after a single treatment with alipogene tiparvovec. An independent adjudication board of three pancreas experts, blinded to patient identification and to pre- or post-gene therapy period, performed a retrospective review of data extracted from the patients' medical records and categorized LPLD-related acute abdominal pain events requiring hospital visits and/or hospitalizations based on the adapted 2012 Atlanta diagnostic criteria for pancreatitis. Both entire disease time period data and data from an equal time period before and after gene therapy were analyzed. Events with available medical record information meeting the Atlanta diagnostic criteria were categorized as definite pancreatitis; events treated as pancreatitis but with variable levels of laboratory and imaging data were categorized as probable pancreatitis or acute abdominal pain events. A reduction of approximately 50% was observed in all three categories of the adjudicated post-gene therapy events. Notably, no severe pancreatitis and only one intensive care unit admission was observed in the post-alipogene tiparvovec period. However, important inter- and intraindividual variations in the pre- and post-gene therapy incidence of events were observed. There was no relationship between the posttreatment incidence of events and the number of LPL gene copies injected, the administration of immunosuppressive regimen or the percent triglyceride decrease achieved at 12 weeks (primary end point in the prospective clinical studies). Although a causal relationship cannot be established and despite the limited number of individuals evaluated, results from this long-term analysis suggest that alipogene tiparvovec was associated with a lower frequency and severity of pancreatitis events, and a consequent overall reduction in health care resource use up to 6 years posttreatment.

Antisense Inhibition of Apolipoprotein C-III in Patients with Hypertriglyceridemia.

BACKGROUND: Apolipoprotein C-III (APOC3) is a key regulator of plasma triglyceride levels. Elevated triglyceride levels are associated with a risk of adverse cardiovascular events and pancreatitis. ISIS 304801 is a second-generation antisense inhibitor of APOC3 synthesis. METHODS: We conducted a randomized, double-blind, placebo-controlled, dose-ranging, phase 2 study to evaluate ISIS 304801 in untreated patients with fasting triglyceride levels between 350 mg per deciliter (4.0 mmol per liter) and 2000 mg per deciliter (22.6 mmol per liter) (ISIS 304801 monotherapy cohort), as well as in patients receiving stable fibrate therapy who had fasting triglyceride levels between 225 mg per deciliter (2.5 mmol per liter) and 2000 mg per deciliter (ISIS 304801-fibrate cohort). Eligible patients were randomly assigned to receive either ISIS 304801, at doses ranging from 100 to 300 mg, or placebo, once weekly for 13 weeks. The primary outcome was the percentage change in APOC3 level from baseline. RESULTS: A total of 57 patients were treated in the ISIS 304801 monotherapy cohort (41 received active agent, and 16 received placebo), and 28 patients were treated in the ISIS 304801-fibrate cohort (20 received active agent, and 8 received placebo). The mean (±SD) baseline triglyceride levels in the two cohorts were 581±291 mg per deciliter (6.6±3.3 mmol per liter) and 376±188 mg per deciliter (4.2±2.1 mmol per liter), respectively. Treatment with ISIS 304801 resulted in dose-dependent and prolonged decreases in plasma APOC3 levels when the drug was administered as a single agent (decreases of 40.0±32.0% in the 100-mg group, 63.8±22.3% in the 200-mg group, and 79.6±9.3% in the 300-mg group, vs. an increase of 4.2±41.7% in the placebo group) and when it was administered as an add-on to fibrates (decreases of 60.2±12.5% in the 200-mg group and 70.9±13.0% in the 300-mg group, vs. a decrease of 2.2±25.2% in the placebo group). Concordant reductions of 31.3 to 70.9% were observed in triglyceride levels. No safety concerns were identified in this short-term study. CONCLUSIONS: We found that treatment with ISIS 304801 was associated with significant lowering of triglyceride levels, among patients with a broad range of baseline levels, through selective antisense inhibition of APOC3 synthesis. (Funded by Isis Pharmaceuticals; ClinicalTrials.gov number, NCT01529424.).