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Background: Increasing evidence suggests that TAR DNA-binding protein 43 (TDP-43) pathology in Alzheimer’s disease (AD), or AD-TDP, can be diffuse or limbic-predominant. Understanding whether diffuse AD-TDP has genetic, clinical, and pathological features that differ from limbic AD-TDP could have clinical and research implications. Objective: To better characterize the clinical and pathologic features of diffuse AD-TDP and differentiate it from limbic AD-TDP. Methods: 363 participants from the Mayo Clinic Study of Aging, Alzheimer’s Disease Research Center, and Neurodegenerative Research Group with autopsy confirmed AD and TDP-43 pathology were included. All underwent genetic, clinical, neuropsychologic, and neuropathologic evaluations. AD-TDP pathology distribution was assessed using the Josephs 6-stage scale. Stages 1–3 were classified as limbic, those 4–6 as diffuse. Multivariable logistic regression was used to identify clinicopathologic features that independently predicted diffuse pathology. Results: The cohort was 61% female and old at onset (median: 76 years [IQR:70–82]) and death (median: 88 years [IQR:82–92]). Fifty-four percent were limbic and 46% diffuse. Clinically, ∼10–20% increases in odds of being diffuse associated with 5-year increments in age at onset (p = 0.04), 1-year longer disease duration (p = 0.02), and higher Neuropsychiatric Inventory scores p = 0.03), while 15-s longer Trailmaking Test-B times (p = 0.02) and higher Block Design Test scores (p = 0.02) independently decreased the odds by 10–15%. There was evidence for association of APOE ɛ4 allele with limbic AD-TDP and of TMEM106B rs3173615C allele with diffuse AD-TDP. Pathologically, widespread amyloid-β plaques (Thal phases: 3–5) decreased the odds of diffuse TDP-43 pathology by 80–90%, while hippocampal sclerosis increased it sixfold (p

ObjectivesTo determine the incidence of osteoarthrits (OA) in patients with atopic disease compared with matched non-exposed patients.MethodsWe conducted a retrospective cohort study with propensity score matching using claims data from Optum’s de-identified Clinformatics Data Mart (CDM) (January 2003 to June 2019) and electronic health record data from the Stanford Research Repository (STARR) (January 2010 to December 2020). We included adult patients without pre-existing OA or inflammatory arthritis who were exposed to atopic disease or who were non-exposed. The primary outcome was the development of incident OA.ResultsIn Optum CDM, we identified 117 346 exposed patients with asthma or atopic dermatitis (mean age 52 years; 60% female) and 1 247 196 non-exposed patients (mean age 50 years; 48% female). After propensity score matching (n=1 09 899 per group), OA incidence was higher in patients with asthma or atopic dermatitis (26.9 per 1000 person-years) compared with non-exposed patients (19.1 per 1000 person-years), with an adjusted odds ratio (aOR) of 1.58 (95% CI 1.55 to 1.62) for developing OA. This effect was even more pronounced in patients with both asthma and atopic dermatitis compared with non-exposed patients (aOR=2.15; 95% CI 1.93 to 2.39) and in patients with asthma compared with patients with chronic obstructive pulmonary disease (aOR=1.83; 95% CI 1.73 to 1.95). We replicated our results in an independent dataset (STARR), which provided the added richness of body mass index data. The aOR of developing OA in patients with asthma or atopic dermatitis versus non-exposed patients in STARR was 1.42 (95% CI 1.36 to 1.48).ConclusionsThis study demonstrates an increased incidence of OA in patients with atopic disease. Future interventional studies may consider targeting allergic pathways for the prevention or treatment of OA.

Sporadic, adult-onset cerebellar ataxia is a disease with multiple etiologies. In addition to cortical cerebellar atrophy (CCA), which is often used for the pathological diagnosis, other terms such as idiopathic late-onset cerebellar ataxia (ILOCA) and sporadic adult-onset ataxia of unknown etiology (SAOA) have been used to refer to this disorder. These names describe key features of the disease, including degeneration limited to the cerebellar cortex (with or without secondary involvement of inferior olivary nuclei), a slowly progressive ataxia, and absence of a clear etiology, such as multiple system atrophy, as well as paraneoplastic, autoimmune, infectious and inherited ataxias. In this Point of View article, we describe two patients with sporadic, adult-onset ataxia with rapidly progressive disease course in addition to extracerebellar symptoms resembling prion disease, including the reevaluation of one patient who was previously reported. Pathological findings are mostly consistent with CCA, but also have degenerative changes in the thalamus. Whole genome sequencing in two patients with rapidly progressive CCA did not reveal any pathogenic variants associated with cerebellar ataxia. Although the underlying etiology behind rapidly progressive CCA is unknown, we suggest that the unique combination of clinical and pathological features of CAA with a short disease course defines a new disease entity, rapidly progressive cerebellar cortical and thalamic degeneration. This viewpoint article draws attention to this rare sporadic cerebellar ataxia with the hope that highlighting clinical and pathologic findings in a typical case will lead to improved recognition and research.

Posterior cortical atrophy (PCA) and logopenic progressive aphasia (LPA) are clinical syndromes that commonly have underlying Alzheimer’s disease (AD), although non-AD pathologies have also been reported. PET imaging allows for identification of beta-amyloid (Aβ) and tau in AD, so we aimed to assess these in a large cohort to identify patients that do not have evidence for biomarker-defined AD. Eight-one patients, 47 PCA and 34 LPA, underwent extensive neurological and neuropsychological testing, [(11)C] Pittsburgh compound B, [(18)F] flortaucipir and [(18)F] fluorodeoxyglucose PETs. Global Aβ and tau-PET standardized uptake value ratios (SUVRs) were plotted for all patients and outliers, and patients with abnormally low SUVRs compared to the biomarker-classic cohort were identified. Six (7.4%) biomarker-outlier cases were identified, and three patterns were observed: i) negative/borderline Aβ-PET and striking widespread tau-PET uptake (two LPA); ii) negative/borderline Aβ-PET and low tau-PET uptake (three PCA) and iii) elevated Aβ-PET uptake but mild focal tau-PET uptake (one LPA). Among the unusual patients in group ii, two patients showed no abnormal tau uptake suggesting non-AD pathology, with one developing features of corticobasal syndrome and the other dementia with Lewy bodies. The remaining patient showed very mild focal tau uptake. This study demonstrates that a small minority (~8%) of PCA and LPA patients do not show the typical striking patterns of Aβ and tau PET uptake, with only 2% showing absence of both proteins. These findings will help inform the use of molecular PET in clinical treatment trials that include patients with atypical phenotypes of AD.

BackgroundPick’s disease (PiD) is a rare and predominantly sporadic form of frontotemporal dementia that is classified as a primary tauopathy. PiD is pathologically defined by argyrophilic inclusion Pick bodies and ballooned neurons in the frontal and temporal brain lobes. PiD is characterised by the presence of Pick bodies which are formed from aggregated, hyperphosphorylated, 3-repeat tau proteins, encoded by theMAPTgene. TheMAPTH2 haplotype has consistently been associated with a decreased disease risk of the 4-repeat tauopathies of progressive supranuclear palsy and corticobasal degeneration, however its role in susceptibility to PiD is unclear. The primary aim of this study was to evaluate the association betweenMAPTH2 and risk of PiD.MethodsWe established the Pick’s disease International Consortium (PIC) and collected 338 (60.7% male) pathologically confirmed PiD brains from 39 sites worldwide. 1,312 neurologically healthy clinical controls were recruited from Mayo Clinic Jacksonville, FL (N=881) or Rochester, MN (N=431). For the primary analysis, subjects were directly genotyped forMAPTH1-H2 haplotype-defining variant rs8070723. In secondary analysis, we genotyped and constructed the six-variantMAPTH1 subhaplotypes (rs1467967, rs242557, rs3785883, rs2471738, rs8070723, and rs7521).FindingsOur primary analysis found that theMAPTH2 haplotype was associated with increased risk of PiD (OR: 1.35, 95% CI: 1.12-1.64 P=0.002). In secondary analysis involving H1 subhaplotypes, a protective association with PiD was observed for the H1f haplotype (0.0% vs. 1.2%, P=0.049), with a similar trend noted for H1b (OR: 0.76, 95% CI: 0.58-1.00, P=0.051). The 4-repeat tauopathy risk haplotypeMAPTH1c was not associated with PiD susceptibility (OR: 0.93, 95% CI: 0.70-1.25, P=0.65).InterpretationThe PIC represents the first opportunity to perform relatively large-scale studies to enhance our understanding of the pathobiology of PiD. This study demonstrates that in contrast to its protective role in 4R tauopathies, theMAPTH2 haplotype is associated with an increased risk of PiD. This finding is critical in directing isoform-related therapeutics for tauopathies.FundingSee funding section

Objective: Mechanistic target of rapamycin (mTOR) inhibitors are effective in animal models of granulomatous disease, but their benefit in sarcoidosis patients is unknown. We evaluated the incidence of sarcoidosis in patients treated with mTOR inhibitors versus calcineurin inhibitors. Methods: This was a cohort study using the Optum Clinformatics® Data Mart (CDM) Database (2003–2019), IBM® MarketScan® Research Database (2006–2016), and Danish health and administrative registries (1996–2018). Patients aged ≥18 years with ≥1 year continuous enrollment before and after kidney, liver, heart, or lung transplant treated with an mTOR inhibitor or calcineurin inhibitor were included. Patients diagnosed with sarcoidosis before, or up to 90 days after, transplant were excluded. The incidence of sarcoidosis by treatment group was calculated. Results: In the Optum CDM/IBM MarketScan cohort, 1,898 patients were treated with an mTOR inhibitor (mean age 49 years; 34% female) and 9,894 patients were treated with a calcineurin inhibitor (mean age 50 years; 37% female). The mean follow-up in the mTOR inhibitor group was 1.1 years, with no incident sarcoidosis diagnosed. In the calcineurin inhibitor group, the mean follow-up was 2.2 years, with 12 incident sarcoidosis cases diagnosed. In the Danish cohort, 230 patients were treated with an mTOR inhibitor (mean age 49; 45% female), with no incident sarcoidosis diagnosed. There were 3,411 patients treated with a calcineurin inhibitor (mean age 45; 40% female), with 10 incident cases of sarcoidosis diagnosed. Conclusions: This study indicates a potential protective effect of mTOR inhibitor treatment compared with calcineurin inhibitor treatment against the development of sarcoidosis.

ObjectiveSerum IgG4 concentrations are used to evaluate a diagnosis of IgG4-related disease (IgG4-RD), but the positive predictive value (PPV) of a very high IgG4 level is uncertain. This study evaluated the PPV of a very high IgG4 concentration for diagnosing IgG4-RD.MethodsThe data warehouses of 2 large academic healthcare systems were queried for IgG4 concentration test results. Cases with serum IgG4 concentrations > 5× the upper limit of normal (ULN) were included. Cases of IgG4-RD were determined using the American College of Rheumatology/European Alliance of Associations for Rheumatology (ACR/EULAR) classification criteria. The PPV for IgG4-RD of an IgG4 concentration > 5× ULN was estimated. Other conditions associated with very high IgG4 concentrations and specific features of IgG4-RD cases were characterized.ResultsIgG4 concentrations were available in 32,206 cases. Of these, 3039 (9.4%) had elevated IgG4 concentrations, and a final cohort of 191 (0.6%) cases had IgG4 concentrations > 5× ULN (median age 66 yrs, 72% male). The PPV of an IgG4 concentration > 5× ULN for a diagnosis of IgG4-RD was 75.4% (95% CI 68.7-81.3). In the remaining cases, elevated IgG4 concentrations were observed among patients with malignancies, autoimmune diseases, and infections.ConclusionThe majority of cases with serum IgG4 concentrations > 5× ULN in this study had IgG4-RD. These data support the high weight placed on very high serum IgG4 concentrations in the ACR/EULAR classification criteria. However, 25% of cases with very high IgG4 concentrations had an alternative diagnosis, underscoring the importance of considering the broad differential of etiologies associated with an elevated IgG4 concentration when evaluating a patient.

Objectives: Sarcoidosis may have an infectious trigger, including Mycobacterium spp. The Bacille Calmette-Guérin (BCG) vaccine provides partial protection against tuberculosis and induces trained immunity. We examined the incidence rate (IR) of sarcoidosis in Danish individuals born during high BCG vaccine uptake (born before 1976) compared with individuals born during low BCG vaccine uptake (born in or after 1976). Methods: We performed a quasi-randomized registry-based incidence study using data from the Danish Civil Registration System and the Danish National Patient Registry between 1995 and 2016. We included individuals aged 25–35 years old and born between 1970 and 1981. Using Poisson regression models, we calculated the incidence rate ratio (IRR) of sarcoidosis in individuals born during low BCG vaccine uptake versus high BCG vaccine uptake, adjusting for age and calendar year (separately for men and women). Results: The IR of sarcoidosis was increased for individuals born during low BCG vaccine uptake compared with individuals born during high BCG vaccine uptake, which was largely attributed to men. The IRR of sarcoidosis for men born during low BCG vaccine uptake versus high BCG vaccine uptake was 1.22 (95% confidence interval [CI] 1.02–1.45). In women, the IRR was 1.08 (95% CI 0.88–1.31). Conclusion: In this quasi-experimental study that minimizes confounding, the time period with high BCG vaccine uptake was associated with a lower incidence rate of sarcoidosis in men, with a similar effect seen in women that did not reach significance. Our findings support a potential protective effect of BCG vaccination against the development of sarcoidosis. Future interventional studies for high-risk individuals could be considered.

This study assessed the impact of individual social risk factor variables and social determinants of health (SDOH) measures on hospital readmission rates and penalties used in the Centers for Medicare and Medicaid Services (CMS) Hospital Readmissions Reduction Program (HRRP). Using 2012-16 hospital discharge data from New York City, we projected HRRP penalties by augmenting CMS's readmission model for heart attack, heart failure, and pneumonia with SDOH scores constructed at each of four geographic levels and a measure of individual-level social risk. Including additional SDOH scores in the model, especially those constructed with the most granular geographic data, along with social risk factor variables substantially affects projected penalties for hospitals treating the highest proportion of patients with high SDOH scores. Improved performance occurred even after we included peer-group stratification in the HRRP model pursuant to the 21st Century Cures Act. Small improvements in model accuracy were associated with substantial shifts in projected performance. Our results suggest that CMS's continued omission of relevant patient and geographic data from the HRRP readmission model misallocates penalties attributable to SDOH and social risk factor effects to hospitals with the largest share of high-risk patients.

Background The prevalence of burnout and depressive symptoms is high among physician trainees. Research Question What is the burden of burnout and depressive symptoms among fellows training in pulmonary and critical care medicine (PCCM) and what are associated individual fellow, program, and institutional characteristics? Study Design and Methods We conducted a cross-sectional electronic survey of fellows enrolled in pulmonary, PCCM, and critical care medicine training programs in the United States to assess burnout and depressive symptoms. Burnout symptoms were measured using the Maslach Burnout Index two-item measure. The two-item Primary Care Evaluation of Mental Disorders Procedure was used to screen for depressive symptoms. For each of the two outcomes (burnout and depressive symptoms), we constructed three multivariate logistic regression models to assess individual fellow characteristics, program structure, and institutional polices associated with either burnout or depressive symptoms. Results Five hundred two of the 976 fellows who received the survey completed it—including both outcome measures—giving a response rate of 51%. Fifty percent of fellows showed positive results for either burnout or depressive symptoms, with 41% showing positive results for depressive symptoms, 32% showing positive results for burnout, and 23% showing positive results for both. Reporting a coverage system in the case of personal illness or emergency (adjusted OR [aOR], 0.44; 95% CI, 0.26-0.73) and access to mental health services (aOR, 0.14; 95% CI, 0.04-0.47) were associated with lower odds of burnout. Financial concern was associated with higher odds of depressive symptoms (aOR, 1.13; 95% CI, 1.05-1.22). Working more than 70 hours in an average clinical week and the burdens of electronic health record (EHR) documentation were associated with a higher odds of both burnout and depressive symptoms. Interpretation Given the high prevalence of burnout and depressive symptoms among fellows training in PCCM, an urgent need exists to identify solutions that address this public health crisis. Strategies such as providing an easily accessible coverage system, access to mental health resources, reducing EHR burden, addressing work hours, and addressing financial concerns among trainees may help to reduce burnout or depressive symptoms and should be studied further by the graduate medical education community.

We present a 58-year-old left hand-dominant woman with right glenohumeral osteoarthritis and anterior instability in the setting of a congenital residual limb at the level of the mid-humerus. She had persistent pain and dysfunction despite trying conservative treatments and elected for a stemless or "canal-sparing" hemiarthroplasty with anterior capsular reconstruction. At the 2-year follow-up, there was significant improvement in her pain, motion, and function without signs of radiographic loosening.A stemless humeral implant is a versatile component that can be used in the face of humeral dysplasia, such as this patient with a congenital residual limb.

ImportanceMetformin may have a protective association against developing osteoarthritis (OA), but robust epidemiological data are lacking.ObjectiveTo determine the risk of OA and joint replacement in individuals with type 2 diabetes treated with metformin compared with a sulfonylurea.Design, Setting, and ParticipantsThis retrospective cohort study used claims data from the Optum deidentified Clinformatics Data Mart Database between December 2003 and December 2019. Participants included individuals aged 40 years or older with at least 1 year of continuous enrollment and type 2 diabetes. Individuals with type 1 diabetes or a prior diagnosis of OA, inflammatory arthritis, or joint replacement were excluded. Time-conditional propensity score matching was conducted using age, sex, race, Charlson comorbidity score, and treatment duration to create a prevalent new-user cohort. Data were analyzed from April to December 2021.ExposuresTreatment with metformin or a sulfonylurea.Main Outcomes and MeasuresThe outcomes of interest were incident OA and joint replacement. Cox proportional hazard models were used to calculate adjusted hazard ratios (aHRs) of incident OA and joint replacement. In a sensitivity analysis, individuals only ever treated with metformin were compared with individuals only ever treated with a sulfonylurea, allowing for longer-term follow up of the outcome (even after stopping the medication of interest).ResultsAfter time-conditional propensity score matching, the metformin and control groups each included 20 937 individuals (mean [SD] age 62.0 [11.5] years; 24 379 [58.2%] males). In the adjusted analysis, the risk of developing OA was reduced by 24% for individuals treated with metformin compared with a sulfonylurea (aHR, 0.76; 95% CI, 0.68-0.85; P P = .34). In the sensitivity analysis, the risk of developing OA remained lower in individuals treated with metformin compared with a sulfonylurea (aHR, 0.77; 95% CI, 0.65-0.90; P P = .89).Conclusions and RelevanceIn this cohort study of individuals with diabetes, metformin treatment was associated with a significant reduction in the risk of developing OA compared with sulfonylurea treatment. These results further support preclinical and observational data that suggest metformin may have a protective association against the development of OA; future interventional studies with metformin for the treatment or prevention of OA should be considered.

ImportanceCurrent data are lacking regarding the risk of biologic and targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD) use on the development of interstitial lung disease (ILD) in patients with rheumatoid arthritis (RA).ObjectiveTo determine the risk of developing ILD in patients with RA undergoing treatment with different b/tsDMARDs.Design, Setting, and ParticipantsRetrospective cohort study using claims data from the Optum Clinformatics Data Mart between December 2003 and December 2019. Adult patients with RA, 1 year or more of continuous enrollment, treatment with a b/tsDMARD of interest, and without preexisting ILD were included. Data were analyzed from October 2021 to April 2022.ExposuresNew administration of adalimumab, abatacept, rituximab, tocilizumab, or tofacitinib.Main Outcomes and MeasuresCrude incidence rates (IRs) for the development of ILD were calculated. The risk of ILD across different b/tsDMARDs was compared using Cox-regression models. A sensitivity analysis using a prevalent new-user cohort design compared patients treated with tofacitinib and adalimumab.ResultsA total of 28 559 patients with RA (mean [SD] age 55.6 [13.7] years; 22 158 female [78%]) were treated with adalimumab (13 326 patients), abatacept (5676 patients), rituximab (5444 patients), tocilizumab (2548 patients), or tofacitinib (1565 patients). Crude IRs per 1000 person-years for ILD were 3.43 (95% CI 2.85-4.09) for adalimumab, 4.46 (95% CI 3.44-5.70) for abatacept, 6.15 (95% CI 4.76-7.84) for rituximab, 5.05 (95% CI 3.47-7.12) for tocilizumab, and 1.47 (95% CI 0.54-3.27) for tofacitinib. After multiple adjustments, compared with patients treated with adalimumab, patients treated with tofacitinib had a lower risk of ILD (adjusted hazard ratio [aHR] 0.31; 95% CI, 0.12-0.78; P = .009). In a prevalent new-user cohort analysis, patients treated with tofacitinib had 68% reduced risk of ILD compared with adalimumab (aHR 0.32; 95% CI 0.13-0.82; P Conclusions and RelevanceIn this retrospective cohort of patients with RA, patients treated with tofacitinib had the lowest incidence of ILD compared with patients treated with all bDMARDs evaluated, and patients treated with tofacitinib had a reduced risk of ILD compared with patients treated with adalimumab after adjusting for important covariates. Additional prospective studies are needed to better understand the role tofacitinib may play in preventing ILD in patients with RA. These results, while significant, should be interpreted with caution given the fairly small sample size of the tofacitinib group.

To accelerate the use of outcome measures in rheumatology, we developed and evaluated a natural language processing (NLP) pipeline for extracting these measures from free-text outpatient rheumatology notes within the American College of Rheumatology's Rheumatology Informatics System for Effectiveness (RISE) registry.We included all patients in RISE (2015-2018). The NLP pipeline extracted scores corresponding to 8 measures of rheumatoid arthritis (RA) disease activity (DA) and functional status (FS) documented in outpatient rheumatology notes. Score extraction performance was evaluated by chart review, and we assessed agreement with scores documented in structured data. We conducted an external validation of our NLP pipeline using data from rheumatology notes from an academic medical center that is not included in the RISE registry.We processed over 34 million notes from 854,628 patients, 158 practices, and 24 electronic health record (EHR) systems from RISE. Manual chart review revealed a sensitivity, positive predictive value (PPV), and F1 score of 95%, 87%, and 91%, respectively. Substantial agreement was observed between scores extracted from RISE notes and scores derived from structured data (κ = 0.43-0.68 among DA and 0.86-0.98 among FS measures). In the external validation, we found a sensitivity, PPV, and F1 score of 92%, 69%, and 79%, respectively.We developed an NLP pipeline to extract RA outcome measures from a national registry of notes from multiple EHR systems and found it to have good internal and external validity. This pipeline can facilitate measurement of clinical- and patient-reported outcomes for use in research and quality measurement.

Frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) is a complex heterogeneous neurodegenerative disorder for which mechanisms are poorly understood. To explore transcriptional changes underlying FTLD-TDP, we performed RNA-sequencing on 66 genetically unexplained FTLD-TDP patients, 24 FTLD-TDP patients with GRN mutations and 24 control participants. Using principal component analysis, hierarchical clustering, differential expression and coexpression network analyses, we showed that GRN mutation carriers and FTLD-TDP-A patients without a known mutation shared a common transcriptional signature that is independent of GRN loss-of-function. After combining both groups, differential expression as compared to the control group and coexpression analyses revealed alteration of processes related to immune response, synaptic transmission, RNA metabolism, angiogenesis and vesicle-mediated transport. Deconvolution of the data highlighted strong cellular alterations that were similar in FTLD-TDP-A and GRN mutation carriers with NSF as a potentially important player in both groups. We propose several potentially druggable pathways such as the GABAergic, GDNF and sphingolipid pathways. Our findings underline new disease mechanisms and strongly suggest that affected pathways in GRN mutation carriers extend beyond GRN and contribute to genetically unexplained forms of FTLD-TDP-A.

AimsAccumulating evidence suggests that patients with frontotemporal lobar degeneration (FTLD) can have pathologic accumulation of multiple proteins, including tau and TDP-43. This study aimed to determine the frequency and characteristics of concurrent tau pathology in FTLD with TDP-43 pathology (FTLD-TDP).MethodsThe study included 146 autopsy-confirmed cases of FTLD-TDP and 55 cases of FTLD-TDP with motor neuron disease (FTLD-MND). Sections from the basal forebrain were screened for tau pathology with phospho-tau immunohistochemistry. For cases with tau pathology on the screening section, additional brain sections were studied to establish a diagnosis. Genetic analysis of C9ORF72, GRN, and MAPT was performed on select cases.ResultsAmong 201 cases, we found 72 cases (36%) with primary age-related tauopathy (PART), 85 (42%) with aging-related tau astrogliopathy (ARTAG), 45 (22%) with argyrophilic grain disease (AGD), and 2 cases (1%) with corticobasal degeneration (CBD). Patients with ARTAG or AGD were significantly older than those without these comorbidities. One of the patients with FTLD-TDP and CBD had C9ORF72 mutation and relatively mild tau pathology, consistent with incidental CBD.ConclusionThe coexistence of TDP-43 and tau pathologies was relatively common, particularly PART and ARTAG. Although rare, individual patients with FTLD can have multiple concurrent proteinopathies. The absence of TDP-43-positive astrocytic plaques may suggest that CBD and FTLD-TDP were independent disease processes in the two patients with both tau and TDP-43 pathologies. It remains to be determined if mixed cases represent a unique disease process or two concurrent disease processes in an individual.

BackgroundThe majority of patients with SARS-CoV-2 infection are diagnosed and managed as outpatients; however, little is known about the burden of pulmonary disease in this setting. Lung ultrasound (LUS) is a convenient tool for detection of COVID-19 pneumonia. Identifying SARS-CoV-2 infected outpatients with pulmonary disease may be important for early risk stratification.ObjectivesTo investigate the prevalence, natural history and clinical significance of pulmonary disease in outpatients with SARS-CoV-2.MethodsSARS-CoV-2 PCR positive outpatients (CV(+)) were assessed with LUS to identify the presence of interstitial pneumonia. Studies were considered positive based on the presence of B-lines, pleural irregularity and consolidations. A subset of patients underwent longitudinal examinations. Correlations between LUS findings and patient symptoms, demographics, comorbidities and clinical outcomes over 8 weeks were evaluated.Results102 CV(+) patients underwent LUS with 42 (41%) demonstrating pulmonary involvement. Baseline LUS severity scores correlated with shortness of breath on multivariate analysis. Of the CV(+) patients followed longitudinally, a majority showed improvement or resolution in LUS findings after 1–2 weeks. Only one patient in the CV(+) cohort was briefly hospitalised, and no patient died or required mechanical ventilation.ConclusionWe found a high prevalence of LUS findings in outpatients with SARS-CoV-2 infection. Given the pervasiveness of pulmonary disease across a broad spectrum of LUS severity scores and lack of adverse outcomes, our findings suggest that LUS may not be a useful as a risk stratification tool in SARS-CoV-2 in the general outpatient population.

PURPOSE The authors examined the "hub-and-spoke" health care system in the United States for patients transferred from one hospital ("spoke") to a major teaching hospital ("hub") and assessed the financial and clinical impact of this system on major teaching hospitals. METHOD The authors surveyed Council of Teaching Hospitals and Health Systems members to collect detailed financial and clinical data from fiscal year 2015 for transfer cases and nontransfer cases (cases directly admitted to the teaching hospital). Data included computed margins (the difference between revenue received and direct and indirect facility costs as estimated by the hospitals) as well as case severity, average length of stay (ALOS), time of admission, surgical or medical status, and other situational variables for All Patient Refined Diagnosis Related Groups (APR-DRGs). The authors used an ordinary least-squares regression model with fixed effects to analyze the data. RESULTS Twenty-six hospitals provided data. The average difference between transfer and nontransfer cases was a 2.18 day longer ALOS and a $1,716 lower computed margin, for a case in the same APR-DRG and hospital (P < .001 for both outcomes). Transfer cases had a 19% higher case severity of illness rating and were disproportionately represented among complex APR-DRGs. Transfer patients were 14% more likely to be Medicaid beneficiaries. CONCLUSIONS Compared with nontransfer cases, transfer cases at major teaching hospitals were more complex and resulted in greater resource utilization, affecting the financial margins on which teaching hospitals rely to support their multipart mission.

Managing patients with rheumatic disease during the COVID-19 pandemic has posed a unique challenge. Immunosuppressed patients are at an increased risk for developing severe COVID-19 and may not derive full protection from the vaccine (1-5). Thus, it is paramount we develop strategies whereby rheumatic disease patients can be protected from the pandemic virus and its variants.

In 2018, Medicare implemented a successor to its Bundled Payments for Care Improvement (BPCI) program, BPCI Advanced, with stricter participation rules and new financial incentives to reduce spending.Using claims-based episode data from thirteen participants, we compared spending and utilization in the first fifteen months of the new program (October 2018 to December 2019) to hospital- and episode-specific target prices, with a deep dive into clinical correlates for the most commonly-selected clinical episodes, sepsis and congestive heart failure.Twelve out of thirteen participants in a collaborative of teaching hospitals achieved shared savings for both Medicare and their own institution. Aggregate hospital shared savings were 5.8% of benchmark prices across 6,131 patients in 16 clinical episodes (p0.001), appreciably higher than the reference savings rates reported after the first period of Medicare's predecessor BPCI program. Differences in shared savings across hospitals for sepsis and congestive heart failure correlated with reductions in patients' use of post-acute care, including reductions in skilled nursing facility, readmission, and home health rates. Evidence is presented showing reductions in patient utilization for cost-intensive post-acute settings accompanied increases in the proportion of patients exclusively utilizing non-institutional care after discharge from an anchor stay or procedure.These findings provide an example of the fulfillment of a core promise of bundled payments to uncover new opportunities for reduced spending.Non-random cohort of hospitals.

This study assessed the impact of individual social risk factor variables and social determinants of health (SDOH) measures on hospital readmission rates and penalties used in the Centers for Medicare and Medicaid Services (CMS) Hospital Readmissions Reduction Program (HRRP). Using 2012-16 hospital discharge data from New York City, we projected HRRP penalties by augmenting CMS's readmission model for heart attack, heart failure, and pneumonia with SDOH scores constructed at each of four geographic levels and a measure of individual-level social risk. Including additional SDOH scores in the model, especially those constructed with the most granular geographic data, along with social risk factor variables substantially affects projected penalties for hospitals treating the highest proportion of patients with high SDOH scores. Improved performance occurred even after we included peer-group stratification in the HRRP model pursuant to the 21st Century Cures Act. Small improvements in model accuracy were associated with substantial shifts in projected performance. Our results suggest that CMS's continued omission of relevant patient and geographic data from the HRRP readmission model misallocates penalties attributable to SDOH and social risk factor effects to hospitals with the largest share of high-risk patients.

Background Vagus nerve stimulation delivered with an implanted device has been shown to improve rheumatoid arthritis severity. We aimed to investigate the safety and efficacy of non-invasive stimulation of the auricular branch of the vagus nerve for the treatment of patients with moderately to severely active rheumatoid arthritis. Methods This prospective, multicentre, open-label, single-arm proof-of-concept study enrolled patients aged 18-80 years with active rheumatoid arthritis who had an inadequate response to conventional synthetic disease-modifying antirheumatic drugs (DMARDs) and up to one biological DMARD. Biological DMARDs were stopped at least 4 weeks before enrolment and concomitant use was not allowed during the study. All eligible participants were assigned to use a non-invasive, wearable vagus nerve stimulation device for up to 30 min per day, which delivered pulses of 20 kHz. Follow-up visits occurred at week 1, week 2, week 4, week 8, and week 12 after the baseline visit. The primary endpoint was the mean change in Disease Activity Score of 28 joints with C-reactive protein (DAS28-CRP) at week 12 compared with baseline. Secondary endpoints included the mean change in the Health Assessment Questionnaire-Disability Index (HAQ-DI), the proportion of patients with a minimal clinically important difference of 0 center dot 22 on HAQ-DI, the proportion achieving American College of Rheumatology (ACR) 20, ACR50, and ACR70 response, and safety analysis. This study is registered with ClinicalTrials.gov (NCT04116866). Findings Of 35 patients screened for eligibility, 30 (86%) were enrolled at six centres in Spain between Dec 27, 2018, and Oct 24, 2019, of whom 27 (90%) completed the week 12 visit. The mean change in DAS28-CRP at 12 weeks was -1 & middot;4 (95% CI -1 & middot;9 to -0 & middot;9; p

Background IgG4-related disease (IgG4-RD) is a fibroinflammatory condition involving loss of B-cell tolerance and production of autoantibodies. However, the relevant targets and role of these aberrant humoral immune responses are not defined. Objective Our aim was to identify novel autoantibodies and autoantigen targets that promote pathogenic responses in IgG4-RD. Methods We sequenced plasmablast antibody repertoires in patients with IgG4-RD. Representative mAbs were expressed and their specificities characterized by using cytokine microarrays. The role of anti–IL-1 receptor antagonist (IL-1RA) autoantibodies was investigated by using in vitro assays. Results We identified strong reactivity against human IL-1RA by using a clonally expanded plasmablast-derived mAb from a patient with IgG4-RD. Plasma from patients with IgG4-RD exhibited elevated levels of reactivity against IL-1RA compared with plasma from the controls and neutralized IL-1RA activity, resulting in inflammatory and fibrotic mediator production in vitro. IL-1RA was detected in lesional tissues from patients with IgG4-RD. Patients with anti–IL-1RA autoantibodies of the IgG4 subclass had greater numbers of organs affected than did those without anti–IL-1RA autoantibodies. Peptide analyses identified IL-1RA epitopes targeted by anti–IL-1RA antibodies at sites near the IL-1RA/IL-1R interface. Serum from patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) also had elevated levels of anti–IL-1RA autoantibodies compared with those of the controls. Conclusion A subset of patients with IgG4-RD have anti–IL-1RA autoantibodies, which promote proinflammatory and profibrotic meditator production via IL-1RA neutralization. These findings support a novel immunologic mechanism underlying the pathogenesis of IgG4-RD. Anti–IL-1RA autoantibodies are also present in a subset of patients with SLE and RA, suggesting a potential common pathway in multiple autoimmune diseases.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by B cell dysregulation and breaks in tolerance that lead to the production of pathogenic autoantibodies. We performed single-cell RNA sequencing of B cells from healthy donors and individuals with SLE which revealed upregulated CD52 expression in SLE patients. We further demonstrate that SLE patients exhibit significantly increased levels of B cell surface CD52 expression and plasma soluble CD52, and levels of soluble CD52 positively correlate with measures of lupus disease activity. Using CD52-deficient JeKo-1 cells, we show that cells lacking surface CD52 expression are hyperresponsive to B cell receptor (BCR) signaling, suggesting an inhibitory role for the surface-bound protein. In healthy donor B cells, antigen-specific BCR-activation initiated CD52 cleavage in a phospholipase C dependent manner, significantly reducing cell surface levels. Experiments with recombinant CD52-Fc showed that soluble CD52 inhibits BCR signaling in a manner partially-dependent on Siglec-10. Moreover, incubation of unstimulated B cells with CD52-Fc resulted in the reduction of surface immunoglobulin and CXCR5. Prolonged incubation of B cells with CD52 resulted in the expansion of IgD+IgMlo anergic B cells. In summary, our findings suggest that CD52 functions as a homeostatic protein on B cells, by inhibiting responses to BCR signaling. Further, our data demonstrate that CD52 is cleaved from the B cell surface upon antigen engagement, and can suppress B cell function in an autocrine and paracrine manner. We propose that increased expression of CD52 by B cells in SLE represents a homeostatic mechanism to suppress B cell hyperactivity.

Background: CMS recently decided to produce private “healthcare disparities reports” that include dual eligibility (DE) as the sole stratifying variable used to assess pneumonia readmission disparities. Research design: We measure the relationship between DE status and readmissions, both with and without conceptually relevant social risk factors, including air pollution, severe housing problems, and food insecurity, using data from county- and hospital-level readmission rates, DE status, and social risk factors. Results: At the county level, the relationship between DE status and readmissions is partially confounded by at least three social risk factors. DE populations vary widely across hospitals, creating unequal between-hospital comparisons. Conclusions: Because of differences in the DE population, between-hospital comparisons could be misleading using a methodology that stratifies by DE only. We suggest viable alternatives to sole-factor stratification to properly account for social risk factors and better isolate quality differences that might yield readmission rate inequities. Implications: CMS's healthcare disparities reports provided to hospitals are limited by relying exclusively on DE proportion as the measure of social risk, undercutting the power of quality measurement and its related incentives to close or minimize healthcare inequities.

RESEARCH OBJECTIVE: To inform how the measurement of community‐level social determinants of health (SDOH) at different levels of geography may affect the specification of the relationship between SDOH and hospital readmissions, as well as limitations and misclassifications that may occur at each level. STUDY DESIGN: Using a unique inpatient data set from New York State, including a subset of New York City residents and their geographic location geocoded to a block group, census tract, the NYC‐specific Neighborhood Tabulation Area (NTA), and Public Use Microdata Area (PUMA), we compare models predicting all‐cause unplanned hospital readmission rates within 30 days after inpatient discharge for three common conditions (acute myocardial infarction or AMI, heart failure or HF, and pneumonia or PN) using SDOH composite scores from variables collected at each geographic level with the baseline readmission model used by the Centers for Medicare & Medicaid Services (CMS). These models are compared on goodness of fit, statistical significance of the variables added to the baseline model, and the impact on hospitals treating high‐risk patients. SDOH data included geographic‐level variables for education, income, housing, English‐speaking, housing value, and employment. POPULATION STUDIED: All‐age and all‐payer residents of New York City that had an inpatient admission to a hospital in New York State for AMI (n = 17 994), HF (n = 53 998), or PN (n = 69 539) between January 1, 2013 and November 30, 2016. PRINCIPAL FINDINGS: CMS’s baseline readmission model performed worse than all four SDOH‐augmented models in goodness of fit. The added SDOH variables reached the highest levels of statistical significance in the model using the lowest level block group SDOH data, which also tended to have the highest levels of goodness of fit. Among all models, the model with a block group level SDOH composite showed the greatest measured performance improvement in readmission rate for those hospitals with the highest proportion of patients with SDOH high rates, compared to CMS’s current model. We also find that lower geographic levels, which have more numerous, smaller areas, have more widely distributed SDOH rates around the NYC average. As a result, when measuring SDOH at low geographic levels, more patients exhibited high‐risk levels for individual variables, compared to measuring at high geographic levels. CONCLUSIONS: Not only does including SDOH data improve model performance with statistically significant model variables and lead to changes in the distribution of hospital measurement, as compared to CMS’s readmission model, but smaller geographic composite variables tended to have even larger effects than those at larger geographies. IMPLICATIONS FOR POLICY OR PRACTICE: The absence of granular SDOH data means stakeholders face trade‐offs between precision and accessibility: While data at a higher geographic level might be less representative of the patient’s risk level, data at a more granular lever may be harder to obtain and measure accurately. This research suggests that SDOH data at more granular geographic levels provide better predictions of hospital readmission.

OBJECTIVE Osteoarthritis (OA) is a common cause of joint pain and disability, and effective treatments are lacking. Extracellular adenosine has antiinflammatory effects and can prevent and treat OA in animal models. Ticagrelor and clopidogrel are both used in patients with coronary artery disease, but only ticagrelor increases extracellular adenosine levels. This study was undertaken to determine whether treatment with ticagrelor was associated with a lower risk of OA. METHODS We conducted a 1:2 propensity score-matching analysis using data from 2011-2017 in the Optum Clinformatics Data Mart. Patients who had received either ticagrelor or clopidogrel for ≥90 days were included in our study, and patients with a prior diagnosis of OA or inflammatory arthritis were excluded. OA was identified using International Classification of Diseases codes. The primary outcome was the time to diagnosis of OA after treatment with ticagrelor versus clopidogrel. RESULTS Our propensity score-matched cohort consisted of 7,007 ticagrelor-treated patients and 14,014 clopidogrel-treated patients, with a median number of days receiving treatment of 287 and 284, respectively. For both groups, the mean age was 64 years, and 73% of the patients were male. Multivariate Cox regression analysis estimated a hazard ratio for developing OA of 0.71 (95% confidence interval 0.64-0.79) (P < 0.001) after treatment with ticagrelor compared to clopidogrel. CONCLUSION Treatment with ticagrelor was associated with a 29% lower risk of developing OA compared to treatment with clopidogrel over 5 years of follow-up. We hypothesize that the reduction in OA seen in patients who received ticagrelor may in part be due to increased extracellular adenosine levels.

In states with Certificate of Need (CON) laws, medical services providers must file an application and demonstrate community need before being permitted to start or expand a service. We examine CON laws for magnetic resonance imaging (MRI), computed tomography (CT), and positron emission tomography (PET) scanners to test the hypothesis that the approval process favors established incumbent hospitals over new hospital entrants and nonhospital providers. Using Medicare claims data in 2013, we find that states with CON laws have 20 to 33% fewer providers, depending on the type of scanners to which the laws apply. As a result, residents of CON law states are 3.4–5.3 percentage points more likely to travel outside their home county to obtain imaging services than residents of non-CON states. In addition, there is a notable shift in the type of provider: CON laws are associated with 27–53% fewer scans by nonhospital providers per beneficiary, 23 to 70% fewer by new hospitals, but 6 to 21% more scans in older hospitals.

To evaluate certificate-of-need (CON) laws in rural areas and their relationship with selected healthcare outcomes and with common measures of potentially avoidable spending, we regress county-level Medicare data and state-level all-patient spending and utilization data to compare healthcare outcomes and common measures of wasteful spending in rural states with and without CON laws. Results show that patients residing in counties restricted by CON laws spend more per Medicare beneficiary and have higher utilization rates in ambulance services, emergency departments, and readmissions, both before and after controlling for social risk factors such as race, education, and poverty status. These findings imply that policies countering CON restrictions may reverse the outcome gap for rural states in access to care, which in turn may reduce wasteful spending and utilization.

Background Tumor necrosis factor alpha (TNF-α) inhibitors are increasingly being used for treating refractory cardiac sarcoidosis. There is a theoretical risk, however, that these therapies can worsen heart failure, and reports on efficacy and safety are lacking. Methods We conducted a retrospective review of all cardiac sarcoidosis patients seen at Stanford University from 2009 to 2018. Data were collected on patient demographics, diagnostic testing, and treatment outcomes. Results We identified 77 cardiac sarcoidosis patients, of which 20 (26%) received TNF-α inhibitor treatment. The majority were treated for progressive heart failure or tachyarrhythmia, along with worsening imaging findings. All TNF-α inhibitor treated patients demonstrated meaningful benefit, as assessed by changes in advanced imaging, echocardiographic measures of cardiac function, and prednisone use. Conclusions A large cohort (n = 77) of cardiac sarcoidosis patients has been treated at Stanford University. Roughly one-fourth of these patients (n = 20) received TNF-α inhibitors. Of these patients, none had worsening heart failure and all saw clinical benefit. These results help support the use of TNF-α inhibitors for the treatment of cardiac sarcoidosis based on real-world evidence and highlight the need for future prospective studies.

Importance Infusion reactions occur in 7% to 20% of patients receiving biologics. Home infusions are convenient and incur lower costs but may be associated with more adverse events; the safety of receiving biologic infusions for immune-mediated diseases at home remains unclear. Objective To assess whether patients receiving home biologic infusions have increased adverse events requiring emergency department (ED) or hospital admission compared with patients receiving facility infusions. Design, Setting, and Participants This retrospective cohort study used administrative claims data from a large national insurer for adult patients who received biologic infusions for immune-mediated disease between January 2007 and December 2017. Patients with hematologic malignant neoplasms or bone marrow transplantation were excluded. Data were analyzed from August 2019 to October 2020. Main Outcomes and Measures ED or hospital admission on the same or next day after administration of a biologic infusion at home vs at a facility; secondary outcomes included discontinuation of the biologic after an ED or hospital admission and postinfusion mortality. Results Of a total of 57 220 patients (mean [SD] age, 50.1 [14.8] years; 512 314 [68.1%] women) who received 752 150 biologic infusions (34 078 home infusions [4.5%] to 3954 patients and 718 072 facility infusions [95.5%] to 54 770 patients), patients who received home infusions were younger (mean [SD] age, 43.2 [13.2] vs 51.3 [14.8] years), more likely to be men (14 031 [41.2%] vs 225 668 [31.4%]), and had a lower Charlson comorbidity score compared with patients who received facility infusions (mean [SD] score, 0.5 [1.0] vs 1.1 [1.3]). Home infusions were associated with 25% increased odds of ED or hospital admission on the same or next day after the infusion (odds ratio [OR], 1.25; 95% CI, 1.09-1.44;P = .002) and 28% increased odds of discontinuation of the biologic after the ED or hospital admission (OR, 1.28; 95% CI, 1.08-1.51;P = .005). There was no difference in postinfusion mortality between home or facility infusions. The rates of adverse events were highest with home infusions of tocilizumab (48 of 481 infusions [10.0%]), vedolizumab (150 of 2681 infusions [5.6%]), and infliximab (1085 of 20 653 infusions [5.3%]), although the number of tocilizumab and vedolizumab infusions was low. Conclusions and Relevance In this study, biologic infusions administered at home, compared with those administered at a facility, were associated with increased adverse events requiring escalation of care. Because the number of home infusions has increased and is expected to continue to rise, the safety implications of administering biologic infusions at home needs to be further assessed.

Background:Despite the clinical benefits of current pharmacological treatments for rheumatoid arthritis (RA), there remains an unmet need for alternative treatment approaches. Initial results of a 12-week proof-of-concept study of non-invasive, vagus nerve stimulation (VNS) of the auricular branch of the vagus nerve from a wearable device to treat RA showed the device to be well-tolerated with significant reductions in the DAS28-CRP and RA disease severity1.Objectives:This analysis presents data from the 9-month extension of the original proof-of-concept study.Methods:Following the completion of the 12-week proof-of-concept study, responding patients (defined as achieving a reduction in DAS28-CRP of ≥1.2 from baseline and/or achievement of ACR20) were given the option to enroll in a 9-month extension study. Use of the wearable device continued daily for up to 30 minutes as in the first 12 weeks of the study. Alteration of baseline medication and addition of conventional synthetic disease-modifying antirheumatic drugs (DMARDs) and biologic DMARDs were allowed during the extension phase.Results:20/27 patients who completed the initial 12-week study met the enrollment criteria for the extension phase; 19 of those patients consented to participate. 4/19 patients (21%) discontinued the extension study due to lack of efficacy (1 patient after 1 month, 2 patients after 3 months, and 1 patient after 6 months in the extension); 15 patients completed the extension phase. 2/15 patients (13%) added biologic therapy to their treatment regimen. Mean DAS28-CRP reduction from baseline to the end of the extension (12 months total) in all patients completing the extension was 2.23 (95% CI: -1.60, -2.86). For patients who did and did not add biologic therapy, mean DAS28-CRP reduction was 2.98 and 2.11, respectively. Individual DAS28-CRP reductions are shown in the figure 1. Mean HAQ-DI reduction from baseline to the end of the extension in all patients was 0.70. 2 non-device related adverse events were reported in the study extension: one related to cornea transplant and one related to dysesthesia. No serious adverse events were reported during the study extension phase.Conclusion:Benefits from the use of the wearable device were maintained over longer periods of time from the initial 12-week proof-of-concept study, with few safety concerns as no additional side effects were observed.References:[1]Marsal S et al. Non-invasive Vagus Nerve Stimulation Improves Signs and Symptoms of Rheumatoid Arthritis: Results of a Pilot Study [in press]. The Lancet Rheumatol, 2021Disclosure of Interests:Sara Marsal Speakers bureau: BMS, Pfizer, UCB, Celgene, Roche, Sanofi, Consultant of: Pfizer, Abbvie, Roche, Celgene, Galapagos, MSD, UCB, BMS, Sanofi, Grant/research support from: Pfizer, Abbvie, Roche, Celgene, MSD, UCB, BMS, Novartis, Janssen, Sanofi, Héctor Corominas: None declared, Juan Jose de Agustin: None declared, Carolina Perez-Garcia: None declared, Maria Lopez Lasanta: None declared, Helena Borrell Paños: None declared, D Reina-Sanz: None declared, Raimón Sanmartí: None declared, J. Narváez: None declared, Clara Franco-Jarava: None declared, Charles Peterfy Speakers bureau: Novartis, Bristol Myers Squibb, Amgen, Consultant of: Multiple companies on behalf of Spire Sciences Inc., Jose Antonio Narvaez: None declared, Vivek Sharma Shareholder of: Nēsos Corp, Employee of: Nēsos Corp, Konstantinos Alataris Shareholder of: Nēsos Corp, Employee of: Nēsos Corp, Mark C. Genovese Shareholder of: Gilead Sciences, Nēsos Corp, Employee of: Gilead Sciences, Matthew Baker Shareholder of: Nēsos Corp, Consultant of: Nēsos Corp