Explore the vast range of titles available.

Objective Our objectives were to (1) obtain the prevalence and demography of people with multiple sclerosis (MS) in a representative Colorado population, and (2) to assess the utilization of disease‐modifying therapy within this prevalent cohort. Methods This is a retrospective, observational study of patients that had contact with the University of Colorado Health System from 2012 to 2020. We queried Health Data Compass, a data warehouse, for patient data and applied the MS Prevalence Workgroup Algorithm to generate a prevalent cohort. We calculated prevalence as of 31 December 2020, and stratified by age, sex, race, and ethnicity. Payer information and treatment exposure were obtained from linked claims from the Colorado All Payers Claim Database. Disease‐modifying therapies were classified as highly effective and moderately effective based on the clinical trial, TREAT‐MS (NCT03500328). Results From a population of 1,382,821 individuals, 8557 people with MS were captured. Age‐adjusted prevalence of MS as of 31 December 2020 was 572.3 per 100,000 with a mean age of 47.36. Prevalence varied between demographic subgroups, with the lowest prevalence in Hispanic men (215.6) and highest in White (824.1) and Black women (820.1). Overall disease‐modifying therapy exposure was 62.4%, with increased highly effective therapy use and a corresponding decrease in moderately effective therapy use on a yearly basis. Interpretation MS is highly prevalent in a representative Colorado cohort. Overall treatment and proportion of highly effective therapy exposure increased significantly during a critical period of MS therapeutic advances, indicating a shift in disease management driven sharply by the availability of on‐label anti‐CD20 therapy.

Objective To define the epidemiology and clinical presentation of seropositive neuromyelitis optica spectrum disorder (NMOSD) in a large US health system. Methods We completed a retrospective observational study of adult patients in the University of Colorado Health System from 1 January 2011 to 31 December 2020, using Health Data Compass (HDC), a data warehouse that combines electronic health information with claims and public health data in Colorado. We screened HDC for patients with either (1) an abnormal aquaporin‐4 IgG test or (2) any G36 ICD‐10 code. We extracted key clinical elements by chart review and confirmed diagnosis by the 2015 International Panel for NMO Diagnosis criteria. Annual incidence and prevalence rates were calculated. Results Our population consisted of 2,475,591 individuals contributing 11,103,522.72 person‐years of observation. In total, 115 seropositive NMOSD patients were identified. The average yearly incidence was 0.22 per 100,000 person‐years. Age and sex‐adjusted prevalence (per 100,000) was 4.33, and highest among those identifying as Asian or Pacific Islander (17.72), and Black (14.74), as separately by Hispanic ethnicity (8.02). Prevalence was higher in women (6.20:1 female:male ratio). Transverse myelitis (45%) and optic neuritis (43%) were the most common presenting clinical syndromes. In total, 6% of initial presentations were characterized by short‐segment transverse myelitis without other features. Interpretation Seropositive NMOSD incidence is higher in our cohort than many contemporary studies. Women and those identifying as Asian or Pacific Islander, Black, and Hispanic shoulder the highest burden of disease. Clinical onset with short‐segment myelitis underscores the need for serum aquaporin‐4 IgG testing in acute myelitis presentations.

BackgroundX-linked adrenoleukodystrophy (ALD) is the most common genetic peroxisomal disorder with an estimated prevalence of 1:15,000. Approximately two-thirds of males with ALD manifest the inflammatory demyelinating cerebral phenotype (cALD) at some disease stage, in which focal, inflammatory lesions progress over months to years. Hematopoietic stem-cell transplantation can permanently halt cALD progression, but it is only effective if initiated early. Although most cALD lesions progress relentlessly, a subset may spontaneously arrest; subsequent reactivation of these arrested lesions has not been previously detailed.ObjectiveWe describe a novel arresting-relapsing variant of cALD.MethodsSalient clinical and radiographic studies were reviewed and summarized for cALD patients with episodic deteriorations.ResultsWe report a series of five unrelated men with spontaneously arrested cALD lesions that subsequently manifested signs of clinical and radiologic lesion progression during longitudinal follow-up. In three of five patients, functional status was too poor to attempt transplant by the time the recurrence was identified. One patient experienced reactivation followed by another period of spontaneous arrest.ConclusionsThese cases emphasize the need for continued clinical and radiologic vigilance for adult men with ALD to screen for evidence of new or reactivated cALD lesions to facilitate prompt treatment evaluation.

Background Pathogenic heterozygous mutations in the progranulin gene ( GRN ) are a key cause of frontotemporal dementia (FTD), leading to significantly reduced biofluid concentrations of the progranulin protein (PGRN). This has led to a number of ongoing therapeutic trials aiming to treat this form of FTD by increasing PGRN levels in mutation carriers. However, we currently lack a complete understanding of factors that affect PGRN levels and potential variation in measurement methods. Here, we aimed to address this gap in knowledge by systematically reviewing published literature on biofluid PGRN concentrations. Methods Published data including biofluid PGRN concentration, age, sex, diagnosis and GRN mutation were collected for 7071 individuals from 75 publications. The majority of analyses (72%) had focused on plasma PGRN concentrations, with many of these (56%) measured with a single assay type (Adipogen) and so the influence of mutation type, age at onset, sex, and diagnosis were investigated in this subset of the data. Results We established a plasma PGRN concentration cut-off between pathogenic mutation carriers and non-carriers of 74.8 ng/mL using the Adipogen assay based on 3301 individuals, with a CSF concentration cut-off of 3.43 ng/mL. Plasma PGRN concentration varied by GRN mutation type as well as by clinical diagnosis in those without a GRN mutation. Plasma PGRN concentration was significantly higher in women than men in GRN mutation carriers ( p  = 0.007) with a trend in non-carriers ( p  = 0.062), and there was a significant but weak positive correlation with age in both GRN mutation carriers and non-carriers. No significant association was seen with weight or with TMEM106B rs1990622 genotype. However, higher plasma PGRN levels were seen in those with the GRN rs5848 CC genotype in both GRN mutation carriers and non-carriers. Conclusions These results further support the usefulness of PGRN concentration for the identification of the large majority of pathogenic mutations in the GRN gene. Furthermore, these results highlight the importance of considering additional factors, such as mutation type, sex and age when interpreting PGRN concentrations. This will be particularly important as we enter the era of trials for progranulin-associated FTD.

Inflammation is the physiologic reaction to cellular and tissue damage caused by trauma, ischemia, infection, and other pathologic conditions. Elevation of white blood cell count (WBC) and altered levels of other acute phase reactants are cardinal signs of inflammation, but the dynamics of these changes and their resolution are not well established. Here we studied inflammatory recovery from trauma, ischemia, and infection by tracking longitudinal dynamics of clinical laboratory measurements in hospitalized patients. We identified a universal recovery trajectory defined by exponential WBC decay and delayed linear growth of platelet count (PLT). Co-regulation of WBC-PLT dynamics is a fundamental mechanism of acute inflammatory recovery and provides a generic approach for identifying high-risk patients: 32x relative risk (RR) of adverse outcomes for cardiac surgery, 9x RR of death from COVID-19, 9x RR of death from sepsis, and 5x RR of death from myocardial infarction. Inflammation is a protective response of the body. Here, authors show that healthy inflammation induces remarkably consistent changes in white cell and platelet populations, regardless of the underlying cause, including heart attack, infection and trauma.

Coronavirus disease 2019 (COVID-19) is an acute respiratory illness with a high rate of hospitalization and mortality. Biomarkers are urgently needed for patient risk stratification. Red blood cell distribution width (RDW), a component of complete blood counts that reflects cellular volume variation, has been shown to be associated with elevated risk for morbidity and mortality in a wide range of diseases. To investigate whether an association between mortality risk and elevated RDW at hospital admission and during hospitalization exists in patients with COVID-19. This cohort study included adults diagnosed with SARS-CoV-2 infection and admitted to 1 of 4 hospitals in the Boston, Massachusetts area (Massachusetts General Hospital, Brigham and Women's Hospital, North Shore Medical Center, and Newton-Wellesley Hospital) between March 4, 2020, and April 28, 2020. The main outcome was patient survival during hospitalization. Measures included RDW at admission and during hospitalization, with an elevated RDW defined as greater than 14.5%. Relative risk (RR) of mortality was estimated by dividing the mortality of those with an elevated RDW by the mortality of those without an elevated RDW. Mortality hazard ratios (HRs) and 95% CIs were estimated using a Cox proportional hazards model. A total of 1641 patients were included in the study (mean [SD] age, 62[18] years; 886 men [54%]; 740 White individuals [45%] and 497 Hispanic individuals [30%]; 276 nonsurvivors [17%]). Elevated RDW (>14.5%) was associated with an increased mortality risk in patients of all ages. The RR for the entire cohort was 2.73, with a mortality rate of 11% in patients with normal RDW (1173) and 31% in those with an elevated RDW (468). The RR in patients younger than 50 years was 5.25 (normal RDW, 1% [n = 341]; elevated RDW, 8% [n = 65]); 2.90 in the 50- to 59-year age group (normal RDW, 8% [n = 256]; elevated RDW, 24% [n = 63]); 3.96 in the 60- to 69-year age group (normal RDW, 8% [n = 226]; elevated RDW, 30% [104]); 1.45 in the 70- to 79-year age group (normal RDW, 23% [n = 182]; elevated RDW, 33% [n = 113]); and 1.59 in those ≥80 years (normal RDW, 29% [n = 168]; elevated RDW, 46% [n = 123]). RDW was associated with mortality risk in Cox proportional hazards models adjusted for age, D-dimer (dimerized plasmin fragment D) level, absolute lymphocyte count, and common comorbidities such as diabetes and hypertension (hazard ratio of 1.09 per 0.5% RDW increase and 2.01 for an RDW >14.5% vs ≤14.5%; P < .001). Patients whose RDW increased during hospitalization had higher mortality compared with those whose RDW did not change; for those with normal RDW, mortality increased from 6% to 24%, and for those with an elevated RDW at admission, mortality increased from 22% to 40%. Elevated RDW at the time of hospital admission and an increase in RDW during hospitalization were associated with increased mortality risk for patients with COVID-19 who received treatment at 4 hospitals in a large academic medical center network.

Complete blood count indices and their ratios are associated with adverse clinical outcomes for many acute illnesses, but the mechanisms generating these associations are not fully understood. Recent identification of a consistent pattern of white blood cell and platelet count co-regulation during acute inflammatory recovery provides a potentially unifying explanation. Here we show that the platelet-to-white-cell ratio, which was selected based on this conserved recovery pattern, is more strongly associated with mortality than other blood count markers and ratios in four important illnesses involving acute inflammation: COVID-19, acute heart failure, myocardial infarction, and stroke. Patients recovering well from these acute illnesses tend to follow a joint white cell and platelet trajectory that can be reduced to this one-dimensional ratio. The platelet-to-white-cell ratio’s association with prognosis is consistent with recently identified inflammatory dynamics and may provide a convenient and interpretable summary of patient inflammatory state. Here the authors show that the ratio of platelet count to white blood cell count is a better prognostic marker for acute illnesses than other blood count markers. This suggests a conserved inflammatory recovery pattern, in general, helps link blood count markers to prognosis.

Although you might not think it, it's hard to catch HIV. Less than 1% of unprotected sexual exposures result in infection. What then leads to transmission? Carlson et al. determined the amino acid sequence of viruses infecting 137 Zambian heterosexual couples in which one partner infected the other (see the Perspective by Joseph and Swanstrom). The authors then used statistical modeling and found that transmitted viruses are typically the most evolutionarily fit. That is, compared to other viral variants in the infected person, the transmitted virus most closely matches the most common viral sequence found in the Zambian population. Science , this issue 10.1126/science.1254031 ; see also p. 136 An analysis of discordant couples reveals that transmitted HIV-1 viruses are typically the most evolutionarily fit. [Also see Perspective by Joseph and Swanstrom ] Heterosexual transmission of HIV-1 typically results in one genetic variant establishing systemic infection. We compared, for 137 linked transmission pairs, the amino acid sequences encoded by non-envelope genes of viruses in both partners and demonstrate a selection bias for transmission of residues that are predicted to confer increased in vivo fitness on viruses in the newly infected, immunologically naïve recipient. Although tempered by transmission risk factors, such as donor viral load, genital inflammation, and recipient gender, this selection bias provides an overall transmission advantage for viral quasispecies that are dominated by viruses with high in vivo fitness. Thus, preventative or therapeutic approaches that even marginally reduce viral fitness may lower the overall transmission rates and offer long-term benefits even upon successful transmission.

Due to the stringent population bottleneck that occurs during sexual HIV-1 transmission, systemic infection is typically established by a limited number of founder viruses. Elucidation of the precise forces influencing the selection of founder viruses may reveal key vulnerabilities that could aid in the development of a vaccine or other clinical interventions. Here, we utilize deep sequencing data and apply a genetic distance-based method to investigate whether the mode of sexual transmission shapes the nascent founder viral genome. Analysis of 74 acute and early HIV-1 infected subjects revealed that 83% of men who have sex with men (MSM) exhibit a single founder virus, levels similar to those previously observed in heterosexual (HSX) transmission. In a metadata analysis of a total of 354 subjects, including HSX, MSM and injecting drug users (IDU), we also observed no significant differences in the frequency of single founder virus infections between HSX and MSM transmissions. However, comparison of HIV-1 envelope sequences revealed that HSX founder viruses exhibited a greater number of codon sites under positive selection, as well as stronger transmission indices possibly reflective of higher fitness variants. Moreover, specific genetic \"signatures\" within MSM and HSX founder viruses were identified, with single polymorphisms within gp41 enriched among HSX viruses while more complex patterns, including clustered polymorphisms surrounding the CD4 binding site, were enriched in MSM viruses. While our findings do not support an influence of the mode of sexual transmission on the number of founder viruses, they do demonstrate that there are marked differences in the selection bottleneck that can significantly shape their genetic composition. This study illustrates the complex dynamics of the transmission bottleneck and reveals that distinct genetic bottleneck processes exist dependent upon the mode of HIV-1 transmission.

Percutaneous coronary intervention (PCI) for chronic total occlusions (CTOs) has been traditionally associated with lower success rates in patients with previous coronary artery bypass graft surgery (CABG). We sought to examine the success and complication rates of CTO PCI using the “hybrid” crossing algorithm among patients with a history of previous CABG. The procedural outcomes of 496 consecutive CTO PCIs performed at 5 high-volume PCI centers in the United States from January 2012 to August 2013 were assessed. The outcomes of patients with previous CABG were compared with those of patients without previous CABG. Compared with patients without previous CABG (n = 320), patients with previous CABG (n = 176, 35%) were older, had more coronary artery disease risk factors, and had less favorable baseline angiographic CTO characteristics. Technical and procedural success was slightly lower among patients with previous CABG (88.1% vs 93.4%, p = 0.044 and 87.5 vs 92.5%, p = 0.07, respectively). Patients with previous CABG more commonly underwent CTO PCI using the retrograde approach (39% vs 24%, respectively, p <0.001) and received higher air kerma radiation exposure (4.8 [interquartile range 3.0 to 6.4] vs 3.1 [1.9 to 5.3] Gray, p <0.001) and fluoroscopy time (59 [38 to 77] vs 34 [21 to 55] minutes, p <0.001). Major procedural complications were similar in the 2 groups: 2 of 176 (1.1%) patients with previous CABG versus 7 of 320 (2.1%) patients without previous CABG (p = 0.40). In conclusion, with application of the “hybrid” approach to CTO PCI, success was slightly lower, and complication rates were similar between patients with and without previous CABG.