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Background Covert cerebrovascular disease (CCD) has been shown to be associated with dementia in population‐based studies with magnetic resonance imaging (MRI) screening, but dementia risk associated with incidentally discovered CCD is not known. Methods and Results Individuals aged ≥50 years enrolled in the Kaiser Permanente Southern California health system receiving head computed tomography (CT) or MRI for nonstroke indications from 2009 to 2019, without prior ischemic stroke/transient ischemic attack, dementia/Alzheimer disease, or visit reason/scan indication suggestive of cognitive decline or stroke were included. Natural language processing identified incidentally discovered covert brain infarction (id‐CBI) and white matter disease (id‐WMD) on the neuroimage report; white matter disease was characterized as mild, moderate, severe, or undetermined. We estimated risk of dementia associated with id‐CBI and id‐WMD. Among 241 050 qualified individuals, natural language processing identified 69 931 (29.0%) with id‐WMD and 11 328 (4.7%) with id‐CBI. Dementia incidence rates (per 1000 person‐years) were 23.5 (95% CI, 22.9–24.0) for patients with id‐WMD, 29.4 (95% CI, 27.9–31.0) with id‐CBI, and 6.0 (95% CI, 5.8–6.2) without id‐CCD. The association of id‐WMD with future dementia was stronger in younger (aged <70 years) versus older (aged ≥70 years) patients and for CT‐ versus MRI‐discovered lesions. For patients with versus without id‐WMD on CT, the adjusted HR was 2.87 (95% CI, 2.58–3.19) for younger and 1.87 (95% CI, 1.79–1.95) for older patients. For patients with versus without id‐WMD on MRI, the adjusted HR for dementia risk was 2.28 (95% CI, 1.99–2.62) for younger and 1.48 (95% CI, 1.32–1.66) for older patients. The adjusted HR for id‐CBI was 2.02 (95% CI, 1.70–2.41) for younger and 1.22 (95% CI, 1.15–1.30) for older patients for either modality. Dementia risk was strongly correlated with id‐WMD severity; adjusted HRs compared with patients who were negative for id‐WMD by MRI ranged from 1.41 (95% CI, 1.25–1.60) for those with mild disease on MRI to 4.11 (95% CI, 3.58–4.72) for those with severe disease on CT. Conclusions Incidentally discovered CCD is common and associated with a high risk of dementia, representing an opportunity for prevention. The association is strengthened when discovered at younger age, by increasing id‐WMD severity, and when id‐WMD is detected by CT scan rather than MRI.

AbstractBackgroundGenetic risk in common variants have been identified for Progressive Supranuclear Palsy (PSP), but common variants only account for a portion of disease heritability. A proportion of the remaining disease heritability is likely contributed by rare variants identifiable via sequencing. Leveraging whole‐genome sequencing of 1719 PSP cases and 2940 controls from the Alzheimer’s Disease Sequencing Project, we detected single nucleotide variants (SNVs), insertion/deletions (INDELs), and copy number variants (CNVs). Note that all samples are non‐Hispanic whites with identity by descent (IBD) >0.25, and no outlier is >6 standard deviation in the principal component analysis. We conducted association analysis for variants, genes and gene sets to identify rare genetic risk for PSP.MethodAfter quality control (variants and genotypes notated PASS by the calling algorithms), we detected 85,228,234 rare SNVs/INDELs and 163,987 rare CNVs (minor allele frequency (MAF) < 1%). For rare SNVs/INDELs, the Sequence Kernel Association Test Optimized was performed to identify rare genetic PSP risk from protein truncating variants (PTV) and damaging missense variants (MAF<0.01%) in both protein coding genes and gene sets that were previously associated with PSP based on protein co‐expression networks. For rare CNVs, a permutation‐based association test implemented in Plink was performed to identify CNVs associated with PSP.ResultCombining protein truncating variants (PTV) and damaging missense variants, we identified one genome‐wide significant gene, FBXO38 (FDR = 0.0003, OR = 1.78). We also found enrichment of PTVs and damaging missense variants in genes comprising the C2 module, a neuronal module previously identified in post mortem PSP brain (FDR = 0.0016). For CNV analysis, there were 17 significant deletions and 2 significant duplications that were associated with PSP (Padjust < 0.05). The deletion (18:58488230‐58488489) in ALPK2, which has been identified as an Alzheimer’s Disease risk gene, was the only CNV that conferred a higher‐risk for PSP. Particularly, one deletion (17:46009357‐46009595) was in linkage disequilibrium with MAPT H2 haplotype which has been associated various neurodegenerative diseases including PSP.ConclusionWe identified several new genes and a protein co‐expression network in which risk variants were associated with PSP. These genes and pathways provide potential candidate drug targets for future investigation.

Abstract POEMS syndrome is a rare paraneoplastic syndrome and therapies are directed against plasma cells that produce the proteins that cause this syndrome. Novel therapies are widely used in multiple myeloma aiming for plasma cell eradication. However, data on their use in POEMS syndrome are lacking. In this case series, we provide the Mayo Clinic experience in treating 16 patients with relapsed POEMS syndrome with novel agents (daratumumab, carfilzomib, pomalidomide, and elotuzumab). The patients were treated with a doublet including dexamethasone (N = 5) (31%) or in various combinations with other agents: DRd (N = 6), DC(V)d (N = 3), KRd (N = 3), KPd (N = 1), DP(V)d (N = 5), and EloRd (N = 1). The outcomes with novel agent therapies were favorable. Overall, twelve patients treated with daratumumab-based therapies (86%) and five patients treated with carfilzomib-based therapies (83%) responded to therapy. Among patients treated with daratumumab based therapies (N = 14), 9 patients achieved CR/VGPRH, 7 patients achieved CRV, and 5 patients achieved CRP. Among patients treated with carfilzomib-based therapies (N = 6), 3 patients achieved CR/VGPRH, and one achieved PRH. At a median follow-up of 38 months since starting of the novel agent (IQR 24–57), 15 of the patients (93%) are still alive, and the median TTNT was not reached. None of the patients discontinued therapy due to adverse events and no deaths occurred on therapy. Novel therapies were safe with 7 events of hospitalization due to pneumonia (4 in daratumumab-based therapies and 3 on carfilzomib-based therapies), and 4 patients were hospitalized due to volume overload. Three patients experienced infusion-related reactions (IRR) to the first dose of IV daratumumab. The response rate to novel agents was high, and the responses were deep. Novel agent therapies were safe, and no death case occurred on therapy. Future studies are needed to clarify the optimal sequence of novel agents and the best combination.

Thyroid eye disease (TED) remains challenging for clinicians to evaluate and manage. Novel therapies have recently emerged, and their specific roles are still being determined. Most patients with TED develop eye manifestations while being treated for hyperthyroidism and under the care of endocrinologists. Endocrinologists, therefore, have a key role in diagnosis, initial management, and selection of patients who require referral to specialist care. Given that the need for guidance to endocrinologists charged with meeting the needs of patients with TED transcends national borders, and to maximize an international exchange of knowledge and practices, the American Thyroid Association and European Thyroid Association joined forces to produce this consensus statement.

The COVID-19 pandemic has significantly impacted the production, distribution, and demand of essential laboratory supplies worldwide. In 2021, severe shortages in required laboratory supplies such as blood collection tubes, butterfly needles, and blood gas syringes became a critical issue across Canada. Many hospitals or institutions had to instruct physicians and patients to limit laboratory testing where possible and, in some cases, required emergency shipments of tubes from alternative vendors or nearby hospitals. Laboratory testing is ubiquitous in managing patients. It is used for screening, diagnosis, and monitoring purposes. With limited blood collection tubes, consideration for restricting non-urgent testing is needed to conserve supply and protect acute care departments that manage critically ill patients. In addition, laboratories across Canada have experienced significant staffing shortages, resulting in an even greater need for appropriate laboratory utilization. Consequently, the Canadian Society of Clinical Chemists (CSCC) and the Canadian Association of Medical Biochemists (CAMB) curated utilization recommendations for both hospital and primary care settings in collaboration with Choosing Wisely Canada (CWC). These recommendations were specifically selected from those previously published by Choosing Wisely Canada (CWC), with impact statements and rationales added to conserve at-risk laboratory resources. Supply chain disruptions of clinical laboratory resources are expected to continue throughout 2022, indicating that now, more than ever, a focus on appropriate laboratory utilization is essential.

Thyroid eye disease (TED) remains challenging for clinicians to evaluate and manage. Novel therapies have recently emerged, and their specific roles are still being determined. Most patients with TED develop eye manifestations while being treated for hyperthyroidism and under the care of endocrinologists. Endocrinologists, therefore, have a key role in diagnosis, initial management, and selection of patients who require referral to specialist care. Given that the need for guidance to endocrinologists charged with meeting the needs of patients with TED transcends national borders, and to maximize an international exchange of knowledge and practices, the American Thyroid Association and European Thyroid Association joined forces to produce this Consensus Statement.