Anti-HMGCR myopathy: Diversity of clinical presentations in a national cohort in New Zealand.

AIMS: We describe the varied clinical presentations, barriers in diagnosis and outcomes of anti-HMGCR myopathy in a large national cohort. METHODS: Adults found positive for serum anti-HMGCR autoantibodies via line blot or enzyme-immunoassay followed by immunoprecipitation were included in the study. RESULTS: Of 75 patients identified, the records of 72 (96 %) described weakness as the presenting symptom. The records of 65 gave a reliable description of proximal weakness. In 22/65 (33.8 %) the weakness was described as predominantly or solely lower limb weakness. Forty-five of 75 (60 %) presented with a subacute onset (duration of symptoms >4 weeks -≤6 months), whilst 22/75 (29.3 %) presented with a more indolent chronic onset (duration of symptoms >6 months). Eighteen of 75 (24 %) suffered falls and 2/75 (2.7 %) had "general decline". In three patients no weakness was described: two presented with myalgia and one with a skin rash characterized as Jessner lymphocytic skin rash. Median creatine kinase at presentation was 7337 U/L (range 1050-25,500). Muscle biopsy was performed in 38 (50.7 %). Associated malignancy was infrequent. Four patients recovered without immunosuppression. Five-year and 10-year survival was 92.7 % (95 % CI 80.6-97.4 %), and 82.5 % (95 % CI 61.2-92.8 %) respectively. CONCLUSION: Recurrent falls, a long prodrome and dominant lower limb proximal weakness were common in this anti-HMGCR myopathy cohort. These features overlap with frailty syndrome and sporadic inclusion body myositis emphasizing the importance of considering anti-HMGCR myopathy in that clinical context. A minority of patients recover after statin withdrawal alone.

The autoimmune rheumatological presentation of Common Variable Immunodeficiency Disorders with an overview of genetic testing.

Primary immunodeficiency Disorders (PIDS) are rare, mostly monogenetic conditions which can present to a number of specialties. Although infections predominate in most PIDs, some individuals can manifest autoimmune or inflammatory sequelae as their initial clinical presentation. Identifying patients with PIDs can be challenging, as some can present later in life. This is often seen in patients with Common Variable Immunodeficiency Disorders (CVID), where symptoms can begin in the sixth or even seventh decades of life. Some patients with PIDs including CVID can initially present to rheumatologists with autoimmune musculoskeletal manifestations. It is imperative for these patients to be identified promptly as immunosuppression could lead to life-threatening opportunistic infections in these immunocompromised individuals. These risks could be mitigated by prior treatment with subcutaneous or intravenous (SCIG/IVIG) immunoglobulin replacement or prophylactic antibiotics. Importantly, many of these disorders have an underlying genetic defect. Individualized treatments may be available for the specific mutation, which may obviate or mitigate the need for hazardous broad-spectrum immunosuppression. Identification of the genetic defect has profound implications not only for the patient but also for affected family members, who may be at risk of symptomatic disease following an environmental trigger such as a viral infection. Finally, there may be clinical clues to the underlying PID, such as recurrent infections, the early presentation of severe or multiple autoimmune disorders, as well as a relevant family history. Early referral to a clinical immunologist will facilitate appropriate diagnostic evaluation and institution of treatment such as SCIG/IVIG immunoglobulin replacement. This review comprises three sections; an overview of PIDs, focusing on CVID, secondly genetic testing of PIDs and finally the clinical presentation of these disorders to rheumatologists.

Development of a Culinary Medicine Curriculum to Support Nutrition Knowledge for Gastroenterology Fellows and Faculty.

Gastroenterologists encounter many nutrition-related disorders in their practice, yet the nutritional needs of patients with chronic gastrointestinal (GI) and liver disease are largely unaddressed by treating physicians, due to suboptimal nutrition education. To address this gap, we developed and piloted a culinary medicine course for a GI fellowship training program. The objective of this study is to describe the development, implementation, and acceptability of the course. A registered dietitian, a chef instructor, and a gastroenterology clinical professor trained in culinary medicine developed the four-class tailored curriculum and delivered the classes remotely. Each class had a theme related to commonly encountered GI disorders and included hands-on meal preparation, a nutrition lecture, and a patient case study discussion. Post-course feedback surveys were disseminated. Twenty-three GI physicians enrolled in the course and the attendance rates in classes 1-4 were 83%, 65%, 61%, and 48%, respectively. Among 15 completed feedback surveys, 80% reported that the class contents were either moderately or extremely useful and all endorsed the curriculum for other gastroenterologists. Future studies of culinary medicine programs tailored to medical specialties should identify strategies to maintain engagement and assess the impact on nutrition knowledge, competencies, and translation of these new skills to clinical practice.

CRISPR-Cas9 In Vivo Gene Editing of KLKB1 for Hereditary Angioedema.

BACKGROUND: Hereditary angioedema is a rare genetic disease that leads to severe and unpredictable swelling attacks. NTLA-2002 is an in vivo gene-editing therapy based on clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9. NTLA-2002 targets the gene encoding kallikrein B1 (KLKB1), with the goal of lifelong control of angioedema attacks after a single dose. METHODS: In this phase 1 dose-escalation portion of a combined phase 1-2 trial of NTLA-2002 in adults with hereditary angioedema, we administered NTLA-2002 at a single dose of 25 mg, 50 mg, or 75 mg. The primary end points were the safety and side-effect profile of NTLA-2002 therapy. Secondary and exploratory end points included pharmacokinetics, pharmacodynamics, and clinical efficacy determined on the basis of investigator-confirmed angioedema attacks. RESULTS: Three patients received 25 mg of NTLA-2002, four received 50 mg, and three received 75 mg. At all dose levels, the most common adverse events were infusion-related reactions and fatigue. No dose-limiting toxic effects, serious adverse events, grade 3 or higher adverse events, or clinically important laboratory findings were observed after the administration of NTLA-2002. Dose-dependent reductions in the total plasma kallikrein protein level were observed between baseline and the latest assessment, with a mean percentage change of -67% in the 25-mg group, -84% in the 50-mg group, and -95% in the 75-mg group. The mean percentage change in the number of angioedema attacks per month between baseline and weeks 1 through 16 (primary observation period) was -91% in the 25-mg group, -97% in the 50-mg group, and -80% in the 75-mg group. Among all the patients, the mean percentage change in the number of angioedema attacks per month from baseline through the latest assessment was -95%. CONCLUSIONS: In this small study, a single dose of NTLA-2002 led to robust, dose-dependent, and durable reductions in total plasma kallikrein levels, and no severe adverse events were observed. In exploratory analyses, reductions in the number of angioedema attacks per month were observed at all dose levels. (Funded by Intellia Therapeutics; ClinicalTrials.gov number, NCT05120830.).

Genotypes distribution of human papillomavirus in cervical samples of Ecuadorian women / Distribuição dos genótipos de papilomavírus humano em amostras de colo do útero de mulheres equatorianas

ABSTRACT: Introduction: Human papillomavirus (HPV) is considered a necessary causative agent for developing oropharyngeal, anal and cervical cancer. Among women in Ecuadorian population, cervical cancer ranks as the second most common gynecological cancer. Not many studies about HPV burden have been published in Ecuador, and genotypes distribution has not been established yet. The little data available suggest the presence of other genotypes different than 16 and 18. Objectives: In the present study, we attempt to estimate the prevalence of HPV 16, HPV 18 and other 35 genotypes among Ecuadorian women undergoing cervical cancer screening. The overall prevalence of HPV infection was also estimated. Methods: Routine cervical samples were analyzed using Linear Array(r) HPV Genotyping test (Roche). Results: A total of 1,581 cervical samples obtained from Ecuadorian women undergoing cervical cancer screening were included in this study. HPV DNA was detected in 689 cervical samples (43.58%). Of these samples, 604 (38.20%) were positive for a single HPV genotype, while another 85 (5.37%) samples were positive for multiple HPV types. Genotype 16 (5.50%) resulted in the most frequently detected type in both single and multiple infections. HPV 33 (4.55%) and HPV 11 (3.80%) occupied the second and the third place in frequency among all detected genotypes. Conclusions: Viral genotypes different from HPV 16 and HPV 18 are frequently detected among Ecuadorian women. The overall prevalence of HPV resulted higher than the one reported in other South American countries with a greater burden in the second and third decades of life.

RESUMO: Introdução: O papilomavírus humano (HPV) é considerado agente causador necessário para o desenvolvimento de câncer da orofaringe, do colo do útero e anal. Na população feminina do Equador, o câncer de colo do útero é o segundo câncer ginecológico mais comum. No Equador, o número de estudos publicados sobre o HPV é pequeno, e a distribuição de genótipos ainda não foi estabelecida. Os dados limitados sugerem a presença de outros genótipos diferentes dos tipos 16 e 18. Objetivos: No presente estudo, foi estimada a prevalência de HPV 16, HPV 18 e outros 35 genótipos entre as mulheres equatorianas submetidas ao exame de rastreamento para câncer do colo do útero. Métodos: Amostras cervicais de rotina foram analisadas pelo (método) Linear Array(r) VPH (Roche). Resultados: Foram incluídas neste estudo 1.581 amostras cervicais de mulheres equatorianas. O HPV foi detectado em 689 (43,58%) amostras cervicais. Destas, 604 (38,20%) foram positivas para somente um genótipo de HPV, enquanto 85 (5.37%) amostras foram positivas para vários tipos. O genótipo 16 (5,50%) foi a variante mais frequentemente detectada nos casos com infecção única ou múltipla. HPV 33 (4,55%) e HPV 11 (3,80%) ficaram, respectivamente, em segundo e terceiro lugar em frequência entre todos os genótipos detectados. Conclusões: Outros genótipos virais de alto risco diferentes do que HPV 16 e HPV 18 são frequentemente detectados entre as mulheres equatorianas. A prevalência global de infecção cervical pelo HPV foi maior do que a observada em outros países da América do Sul.