Infectious and clinical tuberculosis trajectories: Bayesian modeling with case finding implications.

The importance of finding people with undiagnosed tuberculosis (TB) hinges on their future disease trajectories. Assays for systematic screening should be optimized to find those whose TB will contribute most to future transmission or morbidity. In this study, we constructed a mathematical model that tracks the future trajectories of individuals with TB at a cross-sectional timepoint ("baseline"), classifying them by bacterial burden (smear positive/negative) and symptom status (symptomatic/subclinical). We used Bayesian methods to calibrate this model to targets derived from historical survival data and notification, mortality, and prevalence data from five countries. We combined resulting disease trajectories with evidence on infectiousness to estimate each baseline TB state's contribution to future transmission. For a person with smear-negative subclinical TB at baseline, the expected future duration of disease was short (mean 4.8 [95% uncertainty interval 3.3 to 8.4] mo); nearly all disease courses ended in spontaneous resolution, not treatment. In contrast, people with baseline smear-positive subclinical TB had longer undiagnosed disease durations (15.9 [11.1 to 23.5] mo); nearly all eventually developed symptoms and ended in treatment or death. Despite accounting for only 11 to 19% of prevalent disease, smear-positive subclinical TB accounted for 35 to 51% of future transmission-a greater contribution than symptomatic or smear-negative TB. Subclinical TB with a high bacterial burden accounts for a disproportionate share of future transmission. Priority should be given to developing inexpensive, easy-to-use assays for screening both symptomatic and asymptomatic individuals at scale-akin to rapid antigen tests for other diseases-even if these assays lack the sensitivity to detect paucibacillary disease.

The Natural Disease Course of Pancreatic Cyst-Associated Neoplasia, Dysplasia, and Ductal Adenocarcinoma: Results of a Microsimulation Model.

BACKGROUND & AIMS: Estimates on the progression of precursor lesions to pancreatic cancer (PC) are scarce. We used microsimulation modeling to gain insight into the natural disease course of PC and its precursors. This information is pivotal to explore the efficacy of PC screening. METHODS: A Microsimulation Screening Analysis model was developed in which pancreatic intraepithelial neoplasms and cysts can evolve from low-grade dysplasia (LGD) to high-grade dysplasia (HGD) to PC. The model was calibrated to Dutch PC incidence data and Japanese precursor prevalence data (autopsy cases without PC) and provides estimates of PC progression (precursor lesion onset and stage duration). RESULTS: Mean LGD state durations of cysts and pancreatic intraepithelial neoplasms were 15.8 years and 17.1 years, respectively. Mean HGD state duration was 5.8 years. For lesions that progress to PC, the mean duration was 4.8-4.9 years for LGD lesions and 4.0-4.1 years for HGD lesions. In 13.7% of individuals who developed PC, the HGD state lasted less than 1 year. The probability that an individual at age 50 years developed PC in the next 20 years was estimated to be 1.8% in the presence of any cyst and 6.1% in case of an LGD mucinous cyst. This 20-year PC risk was estimated to be 5.1% for individuals with an LGD pancreatic intraepithelial neoplasm. CONCLUSIONS: Mean duration of HGD lesions before development of PC was estimated to be 4.0 years. This implies a window of opportunity for screening, presuming the availability of a reliable diagnostic test. The probability that an LGD cyst will progress to cancer was predicted to be low.

The effect of bovine dairy products and their components on the incidence and natural history of infection: a systematic literature review.

BACKGROUND: Dairy products and their components may impact immune function, although the current evidence base has some research gaps. As part of a larger systematic literature review of dairy products/components (including probiotics, dairy proteins, and dairy fats) and immune function, we identified the available epidemiologic research on the impact of dairy products/components on incidence and natural history of infectious diseases. METHODS: PubMed and Embase databases were systematically searched through May 2022 to identify eligible studies using pre-defined Population, Intervention, Comparator, Outcomes, and Study design criteria. Herein, we focused on describing the impacts of dairy product/component on infectious disease outcomes, including the effect on leukocyte and cytokine response in humans. Risk of bias assessment was performed using the Academy of Nutrition and Dietetics Quality Criteria Checklist. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were followed. RESULTS: Among 9,832 studies identified from the larger literature search, 133 relevant publications from 128 studies reported on dairy product/component and infectious disease outcomes. Few studies are available on the impact of non-fermented milk and traditional yogurt on infectious disease. Evidence was identified to suggest milk and yogurt drinks fermented with Lactobacillus strains reduce the risk and burden of common infectious diseases (CIDs), although the findings are mixed and difficult to reconcile due to heterogenous study populations, bacterial strains, and study methods. Few studies are available on the impact of dairy products/components on the natural history of infection, with the available findings indicating probiotics may both improve gastrointestinal symptoms among HIV-infected persons and help eradicate and alleviate the symptoms of Heliobacter (H.) pylori. The available evidence also suggests lactoferrin may reduce the virological burden of COVID-19 and hepatitis C virus. No consistent changes in leukocytes or cytokine production were observed for any type of dairy product or their components, but probiotics appeared to enhance natural killer cell levels/activity and the phagocytic process. CONCLUSIONS: Dairy products, particularly those with added probiotics, may represent an easily accessible nutritional intervention to prevent and improve the course of infectious diseases. This review highlights the need for additional research in this potentially impactful area. PROSPERO REGISTRATION: CRD42022333780.

Multiple sclerosis and COVID-19: a northern China survey.

BACKGROUND: There is insufficient data on severe acute respiratory syndrome coronavirus type-2 (SARS-CoV-2) infection in Chinese patients with multiple sclerosis (pwMS). This study aims to explore the manifestation of pwMS during the Coronavirus disease 2019 (COVID-19) pandemic and the effect of SARS-CoV-2 infection on the prognosis of MS in northern China. METHODS: In this cross-sectional study, an online self-administered questionnaire and telephone interviews were conducted among pwMS of northern China. Clinical correlation of SARS-CoV-2 infection since the onset of the COVID-19 pandemic in northern China was analyzed. RESULTS: 164 patients with an average age of 38.9 ± 12.2 years were included, of which 57.3% had a disease course ≤ 5 years. 33.5% of the patients were COVID-19 vaccinated. 87.2% received disease-modifying therapy (DMT), and the average immunotherapy duration was 1.9 ± 1.6 years. 83.5% were SARS-CoV-2 infected, 14.6% reported worsening of their original condition after infection, and 5.1% had a relapse of MS. Shorter disease course was independently related to infection risk (P = 0.046), whereas increasing age was related to aggravated behavioral symptoms (P = 0.008). However, gender, vaccination, and DMT were not associated with susceptibility or poor prognosis. CONCLUSION: A shorter disease course is independently associated with an increased risk of SARS-CoV-2 infection, and age is associated with worsening disability. It seems to be safe and necessary to use DMT during the pandemic, however, the use of B cell-depletion agents should be approached with caution.

Predictors of disease course in systemic juvenile idiopathic arthritis.

PURPOSE: To identify potential predictors of the disease course of systemic juvenile idiopathic arthritis (sJIA) at the time of diagnosis. METHODS: This retrospective observational study was conducted in patients diagnosed with sJIA in our hospital between April 2009 and October 2023. The relationship between the disease course of sJIA patients and demographic, clinical, laboratory findings and complications were analyzed. RESULTS: Of the 51 patients diagnosed with sJIA, 26 (51%) patients had monocyclic, 7 (13.7%) polycyclic and 18 (35.2%) persistent disease course. 3 (5.8%) patients had a persistent disease course with persistent arthritis developed flares with systemic manifestations during follow-up. The presence of arthritis, polyarticular involvement, and hip involvement at the time of diagnosis were associated with persistent disease course (p=0.009, p=0.003, p=0.003). Serositis and higher white blood cell and neutrophil counts at the time of diagnosis were associated with a monocyclic disease course (p=0.034, p=0.002, p=0.008). However, no significant correlation was found between macrophage activation syndrome (MAS) and disease course (p=1). CONCLUSIONS: Systemic JIA patients with polyarthritis and hip involvement at disease onset may develop a persistent course. Although MAS is an important complication of sJIA, its effect on the course of the disease was not found in this study.

Age of Onset and Disease Course in Biopsy-Proven Minimal Change Disease: An Analysis From the Cure Glomerulonephropathy Network.

RATIONALE & OBJECTIVE: Adolescent- and adult-onset minimal change disease (MCD) may have a clinical course distinct from childhood-onset disease. We characterized the course of children and adults with MCD in the Cure Glomerulonephropathy Network (CureGN) and assessed predictors of rituximab response. STUDY DESIGN: Prospective, multicenter, observational study. STUDY PARTICIPANTS: CureGN participants with proven MCD on biopsy. EXPOSURE: Age at disease onset, initiation of renin-angiotensin-aldosterone system (RAAS) blockade, and immunosuppression including rituximab during the study period. OUTCOME: Relapse and remission, change in estimated glomerular filtration rate (eGFR), and kidney failure. ANALYTICAL APPROACH: Remission and relapse probabilities were estimated using Kaplan-Meier curves and gap time recurrent event models. Linear regression models were used for the outcome of change in eGFR. Cox proportional hazards models were used to estimate the association between rituximab administration and remission. RESULTS: The study included 304 childhood- (≤12 years old), 49 adolescent- (13-17 years old), and 201 adult- (≥18 years) onset participants with 2.7-3.2 years of follow-up after enrollment. Children had a longer time to biopsy (238 vs 23 and 36 days in adolescent- and adult-onset participants, respectively; P<0.001) and were more likely to have received therapy before biopsy. Children were more likely to be treated with immunosuppression but not RAAS blockade. The rate of relapse was higher in childhood- versus adult-onset participants (HR, 1.69 [95% CI, 1.29-2.21]). The probability of remission was also higher in childhood-onset disease (HR, 1.33 [95%CI, 1.02-1.72]). In all groups eGFR loss was minimal. Children were more likely to remit after rituximab than those with adolescent- or adult-onset disease (adjusted HR, 2.1; P=0.003). Across all groups, glucocorticoid sensitivity was associated with a greater likelihood of achieving complete remission after rituximab (adjusted HR, 2.62; P=0.002). LIMITATIONS: CureGN was limited to biopsy-proven disease. Comparisons of childhood to nonchildhood cases of MCD may be subject to selection bias, given that childhood cases who undergo a biopsy may be limited to patients who are least responsive to initial therapy. CONCLUSIONS: Among patients with MCD who underwent kidney biopsy, there were differences in the course (relapse and remission) of childhood-onset compared with adolescent- and adult-onset disease, as well as rituximab response. PLAIN-LANGUAGE SUMMARY: Minimal change disease is a biopsy diagnosis for nephrotic syndrome. It is diagnosed in childhood, adolescence, or adulthood. Patients and clinicians often have questions about what to expect in the disease course and how to plan therapies. We analyzed a group of patients followed longitudinally as part of the Cure Glomerulonephropathy Network (CureGN) and describe the differences in disease (relapse and remission) based on the age of onset. We also analyzed rituximab response. We found that those with childhood-onset disease had a higher rate of relapse but also have a higher probability of reaching remission when compared with adolescent- or adult-onset disease. Children and all steroid-responsive patients are more likely to achieve remission after rituximab.

Temporal Dynamics of the Scale for the Assessment and Rating of Ataxia in Spinocerebellar Ataxias.

BACKGROUND: The Scale for the Assessment and Rating of Ataxia (SARA) is the reference clinical scale to assess the severity of cerebellar ataxia. In the context of upcoming therapeutic trials, a reliable clinical outcome is needed to assess the efficiency of treatments. OBJECTIVE: The aim is to precisely assess and compare temporal dynamics of SARA and a new f-SARA. METHODS: We analyzed data from four cohorts (EUROSCA, RISCA, CRC-SCA, and SPATAX) comprising 1210 participants and 4092 visits. The linearity of the progression and the variability were assessed using an ordinal Bayesian mixed-effect model (Leaspy). We performed sample size calculations for therapeutic trials with different scenarios to improve the responsiveness of the scale. RESULTS: Seven of the eight different items had a nonlinear progression. The speed of progression was different between most of the items, with an average time for a one-point increase from 3.5 years [3.4; 3.6] (median, 95% credible interval) for the fastest item to 11.4 [10.9; 12.0] years. The total SARA score had a linear progression with an average time for a one-point increase of 0.95 [0.92; 0.98] years. After removing the four last items and rescaling all items from 0 to 4, variability increased and progression was slower and thus would require a larger sample size in a future therapeutic trial. CONCLUSION: Despite a heterogeneous temporal dynamics at the item level, the global progression of SARA was linear. Changing the initial scale deteriorates the responsiveness. This new information about the temporal dynamics of the scale should help design the outcome of future clinical trials. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

MS becomes a treatable disease: 30 years later.

30 years ago the first disease-modifying therapy for relapsing multiple sclerosis was approved for use in the United States and soon thereafter across the globe. Since then the field of MS therapeutics, and studies of immunopathogenesis and genetics, have advanced our understanding of the disease and raised the hope of better addressing the next challenges of treating progressive disease, enhancing repair of the damaged nervous system and, hopefully, of a cure. Thirty years into the MS treatment era, the field continues to debate fundamental aspects of MS, and there exists a widening chasm between the triumphs in relapsing disease and the desolation of MS progression, which remains the principal unmet need. In this Personal Viewpoint, we outline lessons learned from the first era of great therapeutic development, as we look to the future of MS research and therapeutics.

Epidemiology, burden and clinical spectrum of cluster headache: a global update.

BACKGROUND: This narrative review aims to broaden our understanding of the epidemiology, burden and clinical spectrum of cluster headache based on updated findings with a global perspective. METHODS: We conducted a literature search on the following topics: (a) epidemiology; (b) burden: quality of life, disability, economic burden, job-related burden and suicidality; and (c) clinical spectrum: male predominance and its changes, age, pre-cluster and pre-attack symptoms, aura, post-drome, attack characteristics (location, severity, duration and associated symptoms), bout characteristics (attack frequency, bout duration and bout frequency), circadian and seasonal rhythmicity and disease course. RESULTS: New large-scale population-based reports have suggested a lower prevalence than previous estimations. The impact of cluster headache creates a significant burden in terms of the quality of life, disability, economic and job-related burdens and suicidality. Several studies have reported decreasing male-to-female ratios and a wide age range at disease onset. The non-headache phases of cluster headache, including pre-cluster, pre-attack and postictal symptoms, have recently been revisited. The latest data regarding attack characteristics, bout characteristics, and circadian and seasonal rhythmicity from different countries have shown variability among bouts, attacks, individuals and ethnicities. Studies on the disease course of cluster headache have shown typical characteristics of attacks or bouts that decrease with time. CONCLUSIONS: Cluster headache may be more than a "trigeminal autonomic headache" because it involves complex central nervous system phenomena. The spectrum of attacks and bouts is wider than previously recognised. Cluster headache is a dynamic disorder that evolves or regresses over time.

Serum neurofilament light chain levels in migraine patients: a monocentric case-control study in China.

PURPOSE: Serum neurofilament light chain (sNfL) can reflect nerve damage. Whether migraine can cause neurological damage remain unclear. This study assesses sNfL levels in migraine patients and explores whether there is nerve damage in migraine. METHODS: A case-control study was conducted in Xiamen, China. A total of 138 migraine patients and 70 healthy controls were recruited. sNfL (pg/mL) was measured on the single-molecule array platform. Univariate, Pearson correlation and linear regression analysis were used to assess the relationship between migraine and sNfL levels, with further subgroup analysis by migraine characteristics. RESULTS: Overall, 85.10% of the 208 subjects were female, with a median age of 36 years. sNfL levels were higher in the migraine group than in the control group (4.85 (3.49, 6.62) vs. 4.11 (3.22, 5.59)), but the difference was not significant (P = 0.133). The two groups showed an almost consistent trend in which sNfL levels increased significantly with age. Subgroup analysis showed a significant increase in sNfL levels in patients with a migraine course ≥ 10 years (ß = 0.693 (0.168, 1.220), P = 0.010). Regression analysis results show that age and migraine course are independent risk factors for elevated sNfL levels, and there is an interaction between the two factors. Patients aged < 45 years and with a migraine course ≥ 10 years have significantly increased sNfL levels. CONCLUSIONS: This is the first study to evaluate sNfL levels in migraine patients. The sNfL levels significantly increased in patients with a migraine course ≥ 10 years. More attention to nerve damage in young patients with a long course of migraine is required.

[Association between HBV viral load and severity of liver inflammation in patients with chronic hepatitis B virus infection].

Objective: To explore the relationship and dynamic changes between virological markers and hepatic pathological damage due to host anti-hepatitis B virus (HBV) immunity in the natural course of disease in chronic HBV infected patients. Methods: Two hundred and thirty-eight adult chronic HBV-infected patients who underwent liver biopsy from January 2016 to June 2022 in Taizhou Hospital, Zhejiang Province, were retrospectively selected. General clinical data such as age, gender, platelets, ALT, AST, albumin, HBV DNA, qHBsAg, HBeAg, and liver pathology diagnostic indexes such as the grade of liver necroinflammation and liver fibrotic stages of the patients were collected. The patients were grouped according to HBeAg status, and subgrouped according to different grades of liver necroinflammation and different HBV DNA loads. Statistical analyses were performed to compare the differences in HBV virologic marker levels between the groups, and the correlation between them and the indicators of hepatic inflammatory injury, such as ALT,AST, and the grade of liver necroinflammation in the patients. Results: The levels of HBV virological markers in HBeAg-positive patients with moderate or higher liver necroinflammatory grade (G≥2) were significantly lower than those with mild (no) liver necroinflammatory grade (G < 2) (P < 0.01); whereas the opposite trend was observed in HBeAg-negative patients, with the levels of HBV DNA, and qHBsAg in the G≥2 subgroup being significantly higher than those in the G < 2 subgroup (P < 0.01). Correspondingly, HBV DNA level and qHBsAg showed weak to moderately strong negative correlation with liver necroinflammatory grade and AST which was an indicator of hepatic inflammatory injury in HBeAg-positive patients (P < 0.05); whereas in HBeAg-negative patients, they showed weak to moderately strong positive correlation with hepatic inflammatory activity and ALT, AST (P < 0.001), in which qHBsAg showed only a weak positive correlation with patients' liver necroinflammatory grade (P = 0.003). Further subgroup analyses of HBeAg-positive patients according to whether the HBV DNA level was > 2×10(6) IU/ml showed weak to moderate negative correlations between HBV virological markers and liver necroinflammatory grade as well as ALT and AST in the subgroup of patients with HBV DNA > 2×10(6) IU/ml (P < 0.05); however, the negative correlation disappeared in patients who were still HBeAg positive and had HBV DNA ≤ 2×10(6) IU/ml. Moreover, HBV DNA and ALT, HBeAg and AST showed moderate positive correlation (P < 0.05). Conclusion: We speculate that the activation of host anti-HBV immunity can efficiently inhibit HBV replication by targeting the infected hepatocytes, but only in the early phase of disease progression in HBeAg positive patients with HBV DNA high (> 2×10(6) IU/ml).

Potential Use of Serum Proteomics for Monitoring COVID-19 Progression to Complement RT-PCR Detection.

RT-PCR is the primary method to diagnose COVID-19 and is also used to monitor the disease course. This approach, however, suffers from false negatives due to RNA instability and poses a high risk to medical practitioners. Here, we investigated the potential of using serum proteomics to predict viral nucleic acid positivity during COVID-19. We analyzed the proteome of 275 inactivated serum samples from 54 out of 144 COVID-19 patients and shortlisted 42 regulated proteins in the severe group and 12 in the non-severe group. Using these regulated proteins and several key clinical indexes, including days after symptoms onset, platelet counts, and magnesium, we developed two machine learning models to predict nucleic acid positivity, with an AUC of 0.94 in severe cases and 0.89 in non-severe cases, respectively. Our data suggest the potential of using a serum protein-based machine learning model to monitor COVID-19 progression, thus complementing swab RT-PCR tests. More efforts are required to promote this approach into clinical practice since mass spectrometry-based protein measurement is not currently widely accessible in clinic.

The disease course of Castleman disease patients with fatal outcomes in the ACCELERATE registry.

Castleman disease (CD) describes a group of rare, potentially fatal lymphoproliferative disorders. To determine factors associated with mortality in CD, we analysed data from deceased patients in the ACCELERATE registry and compared them with matched controls. We analysed demographic, treatment and laboratory data from all deceased CD patients, matched controls and a subgroup of idiopathic multicentric Castleman disease (iMCD) patients. Of the 140 patients in ACCELERATE with a confirmed CD diagnosis, 10 had died. There were 72 patients with confirmed iMCD; six were deceased. The deceased CD cohort had more hospitalisations per year, higher overall hospitalisations and more days hospitalised per month, and received more treatment regimens per year than the matched-control group. Analysis of laboratory values showed a significantly decreased absolute lymphocyte count at months 3 and 6 in the deceased cohort compared with controls. Among iMCD patients, there was a higher proportion of iMCD-TAFRO (thrombocytopenia, anasarca, fever, reticulin myelofibrosis, renal dysfunction and organomegaly) cases in the deceased group. The deceased iMCD group had significantly lower immunoglobulin M, international normalised ratio and platelet count. These data demonstrate that there may be differences between patients who have fatal and non-fatal outcomes, and provide preliminary suggestions for parameters to evaluate further.

New Therapeutic Strategies Have Changed the Natural History of Pediatric Crohn's Disease: A Two-Decade Population-Based Study.

BACKGROUND & AIMS: We evaluated the impact of immunosuppressants (IS) and anti-tumor necrosis factor (TNF) introduction on Crohn's disease (CD) long-term outcomes in a large population-based, pediatric-onset cohort. METHODS: All patients included in the EPIMAD registry with a diagnosis of CD occurring when they were younger than age 17 years and between 1988 and 2011 were followed up retrospectively until 2013. Three diagnostic periods were defined: 1988 to 1993 (period [P]1; pre-IS era), 1994 to 2000 (P2; pre-anti-TNF era), and 2001 to 2011 (P3; anti-TNF era). Medication exposure and disease outcomes were compared between the 3 diagnostic periods. RESULTS: A total of 1007 patients diagnosed with CD were followed up for a median duration of 8.8 years (interquartile range, 4.6-14.2 y). The IS and anti-TNF exposure rate at 5 years increased over time from 33.9% (in P1) to 76.5% (in P3) and from 0% (in P1) to 50.5% (in P3), respectively. In parallel, the risk for intestinal resection at 5 years decreased significantly over time (P1, 35%; P2, 31%; and P3, 22%; P = .0003, Ptrend < .0001), and between the pre-anti-TNF era (P1 + P2, 32%) and the anti-TNF era (P3, 22%) (P = .0007). The risk for progression from inflammatory to stricturing behavior decreased significantly over time (P1, 27%; P2, 28%; and P3, 20%; P = .11, Ptrend = .041) and between the pre-anti-TNF era (P1 + P2, 28%) and the anti-TNF era (P3, 20%) (P = .040). The risk for a CD flare-related hospitalization at 5 years remained stable over time (P1, 31%; P2, 31%; and P3, 29%; P = .76, Ptrend = .53). CONCLUSIONS: In parallel with the increased use of IS and anti-TNF, positive changes in the natural history of pediatric-onset CD were observed at the population level. A decreased risk of both intestinal resections and stricturing complications were observed during the anti-TNF era.

Comorbidities in unclassifiable interstitial lung disease.

BACKGROUND: Comorbidities are common in interstitial lung diseases (ILD) and have an important association with survival, but the frequency and prognostic impact of comorbidities in unclassifiable interstitial lung disease (uILD) remains elusive. We aimed to describe the prevalence of comorbidities and assess the impact on survival in patients with uILD. Furthermore, we aimed to identify and characterize potential phenotypes based on clusters of comorbidities and examine their association with disease progression and survival. METHODS: Incident patients diagnosed with uILD were identified at two ILD referral centers in Denmark and Germany from 2003 to 2018. The diagnosis uILD was based on multidisciplinary team meetings. Clinical characteristics and comorbidities were extracted from ILD registries and patient case files. Survival analyses were performed using Cox regression analyses, disease progression was analyzed by linear mixed effects models, and clusters of comorbidities were analyzed using self-organizing maps. RESULTS: A total of 249 patients with uILD were identified. The cohort was dominated by males (60%), former (49%) or current (15%) smokers, median age was 70 years, mean FVC was 75.9% predicted, and mean DLCO was 49.9% predicted. One-year survival was 89% and three-year survival was 73%. Eighty-five percent of the patients had ≥ 1 comorbidities, 33% had ≥ 3 comorbidities and 9% had ≥ 5 comorbidities. The only comorbidity associated with excess mortality was dyslipidemia. No association between survival and number of comorbidities or the Charlson comorbidity index was observed. Three clusters with different comorbidities profiles and clinical characteristics were identified. A significant annual decline in FVC and DLCO % predicted was observed in cluster 1 and 2, but not in cluster 3. No difference in mortality was observed between the clusters. CONCLUSIONS: The comorbidity burden in uILD is lower than reported in other types of ILD and the impact of comorbidities on mortality needs further clarification. Three clusters with distinct comorbidity profiles were identified and could represent specific phenotypes. No difference in mortality was observed between clusters, but slower disease progression was observed in cluster 3. Better understanding of disease behavior and mortality will require further studies of subgroups of uILD with longer observation time.

In Vivo 18 F-APN-1607 Tau Positron Emission Tomography Imaging in MAPT Mutations: Cross-Sectional and Longitudinal Findings.

BACKGROUND: Frontotemporal lobar degeneration with tauopathy caused by MAPT (microtubule-associated protein tau) mutations is a highly heterogenous disorder. The ability to visualize and longitudinally monitor tau deposits may be beneficial to understand disease pathophysiology and predict clinical trajectories. OBJECTIVE: The aim of this study was to investigate the cross-sectional and longitudinal 18 F-APN-1607 positron emission tomography/computed tomography (PET/CT) imaging findings in MAPT mutation carriers. METHODS: Seven carriers of MAPT mutations (six within exon 10 and one outside of exon 10) and 15 healthy control subjects were included. All participants underwent 18 F-APN-1607 PET/CT at baseline. Three carriers of exon 10 mutations received follow-up 18 F-APN-1607 PET/CT scans. Standardized uptake value ratio (SUVR) maps were obtained using the cerebellar gray matter as the reference region. SUVR values observed in MAPT mutation carriers were normalized to data from healthy control subjects. A regional SUVR z score ≥ 2 was used as the criterion to define positive 18 F-APN-1607 PET/CT findings. RESULTS: Although the seven study patients had heterogenous clinical phenotypes, all showed a significant 18 F-APN-1607 uptake characterized by high-contrast signals. However, the anatomical localization of tau deposits differed in patients with distinct clinical symptoms. Follow-up imaging data, which were available for three patients, demonstrated worsening trends in patterns of tau accumulation over time, which were paralleled by a significant clinical deterioration. CONCLUSIONS: Our data represent a promising step in understanding the usefulness of 18 F-APN-1607 PET/CT imaging for detecting tau accumulation in MAPT mutation carriers. Our preliminary follow-up data also suggest the potential value of 18 F-APN-1607 PET/CT for monitoring the longitudinal trajectories of frontotemporal lobar degeneration caused by MAPT mutations. © 2021 International Parkinson and Movement Disorder Society.

EDSS 0 is not normal: Multiple sclerosis disease burden below the clinical threshold.

Little to no above-threshold deficits may be evident in early multiple sclerosis (MS). The Expanded Disability Status Scale (EDSS) is a standard measure of neurologic function, with an EDSS score of 0 defined as "neurologically normal." The topographical model of MS proposes that sub-threshold disease is compensated for by functional reserve. In this short report, we found that physically high-challenge measures of balance and upper extremity coordination reveal sub-threshold deficits in patients with EDSS score of 0 compared with healthy controls. Challenge task performance was correlated with imaging markers of both lesional burden of disease and a volumetric measure of brain reserve.

Association of disease course and brain structural alterations in major depressive disorder.

INTRODUCTION: The investigation of disease course-associated brain structural alterations in Major Depressive Disorder (MDD) have resulted in heterogeneous findings, possibly due to low reliability of single clinical variables used for defining disease course. The present study employed a principal component analysis (PCA) on multiple clinical variables to investigate effects of cumulative lifetime illness burden on brain structure in a large and heterogeneous sample of MDD patients. METHODS: Gray matter volumes (GMV) was estimated in n = 681 MDD patients (mean age: 35.87 years; SD = 12.89; 66.6% female) using voxel-based-morphometry. Five clinical variables were included in a PCA to obtain components reflecting disease course to associate resulting components with GMVs. RESULTS: The PCA yielded two main components: Hospitalization reflected by patients' frequency and duration of inpatient treatment and Duration of Illness reflected by the frequency and duration of depressive episodes. Hospitalization revealed negative associations with bilateral dorsolateral prefrontal cortex (DLPFC) and left insula volumes. Duration of Illness showed significant negative associations with left hippocampus and right DLPFC volumes. Results in the DLPFC and hippocampus remained significant after additional control for depressive symptom severity, psychopharmacotherapy, psychiatric comorbidities, and remission status. CONCLUSION: This study shows that a more severe and chronic lifetime disease course in MDD is associated with reduced volume in brain regions relevant for executive and cognitive functions and emotion regulation in a large sample of patients representing the broad heterogeneity of MDD disease course. These findings were only partly influenced by other clinical characteristics (e.g., remission status, psychopharmacological treatment).

Natural history of MRI brain volumes in patients with neuronal ceroid lipofuscinosis 3: a sensitive imaging biomarker.

PURPOSE: Grey matter (GM) atrophy due to neuronal loss is a striking feature of patients with CLN3 disease. A precise and quantitative description of disease progression is needed in order to establish an evaluation tool for current and future experimental treatments. In order to develop a quantitative marker to measure brain volume outcome, we analysed the longitudinal volumetric development of GM, white matter (WM) and lateral ventricles and correlated those with the clinical course. METHODS: One hundred twenty-two MRI scans of 35 patients (21 females; 14 males; age 15.3 ± 4.8 years) with genetically confirmed CLN3 disease were performed. A three-dimensional T1-weighted sequence was acquired with whole brain coverage. Volumetric segmentation of the brain was performed with the FreeSurfer image analysis suite. The clinical severity was assessed by the Hamburg jNCL score, a disease-specific scoring system. RESULTS: The volumes of supratentorial cortical GM and supratentorial WM, cerebellar GM, basal ganglia/thalamus and hippocampus significantly (r = - 0.86 to - 0.69, p < 0.0001) decreased with age, while the lateral ventricle volume increased (r = 0.68, p < 0.0001). Supratentorial WM volume correlated poorer with age (r = - 0.56, p = 0.0001). Supratentorial cortical GM volume showed the steepest (4.6% (± 0.2%)) and most uniform decrease with strongest correlation with age (r = - 0.86, p < 0.0001). In addition, a strong correlation with disease specific clinical scoring existed for the supratentorial cortical GM volume (r = 0.85, p = < 0.0001). CONCLUSION: Supratentorial cortical GM volume is a sensitive parameter for assessment of disease progression even in early and late disease stages and represents a potential reliable outcome measure for evaluation of experimental therapies.

Impact of Pregnancy on Hidradenitis Suppurativa Disease Course: A Systematic Review and Meta-Analysis.

BACKGROUND: Hormones are thought to play a role in hidradenitis suppurativa (HS). However, data on the HS disease course during pregnancy and the postpartum period has not been well established. The objective of this study is to analyze the available literature to determine HS disease activity during pregnancy and the postpartum period. METHODS: The PubMed and Embase databases were systematically searched for relevant articles from database inception until November 22, 2020. The inclusion criteria were a study population with the diagnosis of HS and discussion of pregnancy impact on the HS disease course or postpartum flare. Study characteristics, patient demographics, HS severity, and HS disease course during pregnancy and the postpartum period were extracted by 2 independent reviewers. The quality of included studies was assessed using the Newcastle-Ottawa Scale for observational studies. Heterogeneity was assessed using Cochran's Q statistic and I2 index. The random-effects meta-analytical model was used. The primary study outcome was the pooled odds ratio of improvement or of worsening of HS disease activity during pregnancy. RESULTS: The systematic search identified 8 studies for analysis. There was a total of 672 cases for which data on the patient-reported HS disease course during pregnancy were available, and 164 cases for which data on patient-reported postpartum flare were available. In the meta-analyses, the rate of HS disease improvement was 24% (95% CI 0.13-0.40) and the rate of HS disease worsening was 20% (95% CI 0.11-0.34). Sixty percent (99/164) of patients experienced a postpartum flare. CONCLUSION: While about a quarter of women will experience an improvement in HS during pregnancy, the majority will have a stable or worsened disease course, and over half of patients will experience a postpartum flare. Close monitoring of HS patients is needed during pregnancy and postpartum periods, as patients may need continued, or even escalated, disease management.