Faculty Bibliography

IMPORTANCE:People with serious mental illness (SMI), defined as a diagnosis of schizophrenia spectrum disorder, bipolar disorder, or disabling major depressive disorder) die approximately 10 to 25 years earlier than the general population. OBJECTIVE:To develop the first-ever lived experience-led research agenda to address early mortality in people with SMI. EVIDENCE REVIEW:A virtual 2-day roundtable comprising 40 individuals convened on May 24 and May 26, 2022, and used a virtual Delphi method to arrive at expert group consensus. Participants responded to 6 rounds of virtual Delphi discussion via email that prioritized research topics and agreement on recommendations. The roundtable was composed of individuals with lived experience of mental health and/or substance misuse, peer support specialists, recovery coaches, parents and caregivers of people with SMI, researchers and clinician-scientists with and without lived experience, policy makers, and patient-led organizations. Twenty-two of 28 (78.6%) of the authors who provided data represented people with lived experiences. Roundtable members were selected by reviewing the peer-reviewed and gray literature on early mortality and SMI, direct email, and snowball sampling. FINDINGS:The following recommendations are presented in order of priority as identified by the roundtable participants: (1) improve the empirical understanding of the direct and indirect social and biological contributions of trauma on morbidity and early mortality; (2) advance the role of family, extended families, and informal supporters; (3) recognize the importance of co-occurring disorders and early mortality; (4) redefine clinical education to reduce stigma and support clinicians through technological advancements to improve diagnostic accuracy; (5) examine outcomes meaningful to people with an SMI diagnosis, such as loneliness and sense of belonging, and stigma and their complex relationship with early mortality; (6) advance the science of pharmaceuticals, drug discovery, and choice in medication use; (7) use precision medicine to inform treatment; and (8) redefine the terms system literacy and health literacy. CONCLUSIONS AND RELEVANCE:The recommendations of this roundtable are a starting point for changing practice and highlighting lived experience-led research priorities as an option to move the field forward.

The study aimed at widening the clinical and genetic spectrum of ASXL3-related syndrome, a neurodevelopmental disorder, caused by truncating variants in the ASXL3 gene. In this international collaborative study, we have undertaken a detailed clinical and molecular analysis of 45 previously unpublished individuals with ASXL3-related syndrome, as well as a review of all previously published individuals. We have reviewed the rather limited functional characterization of pathogenic variants in ASXL3 and discuss current understanding of the consequences of the different ASXL3 variants. In this comprehensive analysis of ASXL3-related syndrome, we define its natural history and clinical evolution occurring with age. We report familial ASXL3 pathogenic variants, characterize the phenotype in mildly affected individuals and discuss nonpenetrance. We also discuss the role of missense variants in ASXL3. We delineate a variable but consistent phenotype. The most characteristic features are neurodevelopmental delay with consistently limited speech, significant neuro-behavioral issues, hypotonia, and feeding difficulties. Distinctive features include downslanting palpebral fissures, hypertelorism, tubular nose with a prominent nasal bridge, and low-hanging columella. The presented data will inform clinical management of individuals with ASXL3-related syndrome and improve interpretation of new ASXL3 sequence variants.

Background/UNASSIGNED:Hemophagocytic lymphohistiocytosis (HLH) is a rare condition associated with viral infections including HIV. Cases have been reported mainly in advanced HIV/AIDS. This is a rare case that reports HLH associated with human herpes virus-8 (HHV-8) associated multicentric Castleman disease in a stable HIV patient. Case Presentation/UNASSIGNED:A 70-year-old Asian male patient with history of stable HIV on medications with CD 4 cell count above 200 presented with cough and fever and was initially treated for pneumonia as an outpatient. Persisting symptoms prompted presentation to the hospital. The patient was found to have anemia which persisted despite repeated transfusion of packed red cells. A bone marrow biopsy to investigate anemia revealed hemophagocytosis. A CT scan revealed multiple enlarged lymph nodes and hepatosplenomegaly. An excisional lymph node biopsy revealed HHV-8 associated multicentric Castleman disease. The patient deteriorated despite initiation of treatment. Conclusion/UNASSIGNED:HLH can occur at any stage of HIV, rapid diagnosis to identify possible underlying reactive infectious etiology and prompt initiation of treatment is crucial to survival.

Immunoglobulin light chain (AL) amyloidosis is characterized by tissue deposition of amyloid fibers derived from immunoglobulin light chain. AL amyloidosis and multiple myeloma (MM) originate from monoclonal gammopathy of undetermined significance. We wanted to characterize germline susceptibility to AL amyloidosis using a genome-wide association study (GWAS) on 1229 AL amyloidosis patients from Germany, UK and Italy, and 7526 healthy local controls. For comparison with MM, recent GWAS data on 3790 cases were used. For AL amyloidosis, single nucleotide polymorphisms (SNPs) at 10 loci showed evidence of an association at P<10^-5 with homogeneity of results from the 3 sample sets; some of these were previously documented to influence MM risk, including the SNP at the IRF4 binding site. In AL amyloidosis, rs9344 at the splice site of cyclin D1, promoting translocation (11;14), reached the highest significance, P=7.80 × 10^-11; the SNP was only marginally significant in MM. SNP rs79419269 close to gene SMARCD3 involved in chromatin remodeling was also significant (P=5.2 × 10^-8). These data provide evidence for common genetic susceptibility to AL amyloidosis and MM. Cyclin D1 is a more prominent driver in AL amyloidosis than in MM, but the links to aggregation of light chains need to be demonstrated.

Fevers of unknown origin (FUOs) are classified according to the underlying disorder. The 4 main clinical categories of FUOs are infectious, malignant, rheumatic/inflammatory, and miscellaneous disorders. Although malignancy remains the most common cause of FUOs, rheumatic/inflammatory disorders remain important diagnostically and therapeutically. Rheumatic/inflammatory disorders, for example, systemic lupus erythematosus (SLE) presenting as FUO, have become uncommon in recent years because of better serologic diagnostic tests. However, SLE remains a rare but important cause of FUO in adults. SLE may be a difficult FUO diagnosis when a patient presents with fever without joint manifestations as the only symptoms of SLE. During the workup of the patient described in this article, the other causes of pericarditis were ruled out and SLE pericarditis was diagnosed. This is a rare case of an adult FUO with pericarditis as the only manifestation of SLE.