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Background Fatigue is highly prevalent in adults with multiple sclerosis (MS) and current treatments offer limited benefit. It has been speculated that placebos only have an effect when they are administered with deception and concealment, which is unethical in clinical practice. Recent studies suggest that ethically informed, open-label placebos (OLP) can produce symptomatic benefits. As such, we primarily sought to investigate the feasibility and secondarily assess the preliminary effects of OLP to treat MS fatigue. Methods Feasibility outcomes including accrual, retention, and OLP adherence estimates were assessed in this 21-day assessor blinded, RCT. We compared results of assignment to three conditions: (1) OLP with a positive expectancy for beneficial effects along with the prescription to take 2 placebo pills twice a day (OLP), (2) positive expectancy (EXP) for beneficial placebo effects, or (3) a usual care only (UCO). We considered the study to be feasible if progression criteria, including the enrollment target of 48 participants, retention target of > 80% participants, and OLP adherence target of > 90%, were met. As secondary analyses, we provide descriptive statistics and crude linear mixed models (LMM) based estimates to assess the change in fatigue (assessed via Fatigue Severity Scale (FSS) and Modified Fatigue Impact Scale (MFIS)) at days 21, 28, and 35 versus baseline with corresponding 95%, 85%, and 75% confidence intervals. Results One-hundred and eight adults with MS were screened of which 48 were randomized (16 per group). Retention rate was 98% with one participant being lost to follow-up. Placebo adherence was over 90%. At day 21, 7 of 9 (78%) randomized to OLP considered prescribing placebos to treat fatigue as “moderately-to-completely” acceptable. Next, the LMM based change in FSS mean score at day 21 with respect to baseline in the OLP and EXP group versus UCO group was about 0.6 units lower (95% CI: − 1.206, − 0.003; − 1.301, − 0.065, respectively). Conclusions OLP was deemed feasible and acceptable by most participants and there was mild evidence that, compared to UCO, it may reduce fatigue severity in adults with MS. Larger trials of OLP are required to determine whether OLP might be a viable treatment for MS fatigue. Trial registration number NCT04002102 ( https://clinicaltrials.gov/show/NCT04002102 , 2019); registered 30 September 2019.

Background The Tele- Exercise and Multiple Sclerosis (TEAMS) study, funded by the Patient Centered Outcome Research Institute (PCORI), is a pragmatic, cluster randomized controlled trial aimed at comparing the effectiveness of a 12-week complementary and alternative medicine (CAM) program for people with multiple sclerosis (MS) delivered by a therapist at a clinic and the same program initiated by the participant at home using a tablet and pre-recorded videos. The 20-session CAM program consists of yoga, Pilates and dual tasking exercises. The study aimed to enroll 820 participants with MS living in Alabama, Mississippi and Tennessee. Main Body The information provided in this paper describes the strategies that led to the largest randomized controlled exercise trial ever conducted for people with multiple sclerosis. Specifically, the paper presents the result of incorporating stakeholder engagement, a novel participant recruitment method, to produce a successful recruitment outcome for a comparative effectiveness randomized controlled trial. This study used three tiers of engagement: panel members (9 members), clinical partners (88 occupational and physical therapists), and community organizations (6 non-profits). Conclusion Engagement of the stakeholder panel, clinical partners and community organizations led to interest of over 1700 people with MS across three states in the Deep South (final enrollment was n = 837). The diversity of our stakeholder groups and their extensive reach into various communities were a critical aspect for achieving our target sample size. The recruitment numbers reflect the importance of involving multiple stakeholder groups at project inception, developing relationships over time, utilizing member strengths, and monitoring their engagement on a regular basis to ensure a meaningful experience for all involved. Trial registration : NCT03117881. Registered 18 April 2017, https://clinicaltrials.gov/ct2/show/NCT03117881?term=tele+rehabilitation&cond=Multiple+Sclerosis&cntry=US&state=US%3AAL&draw=2&rank=1 . Plain English language The Tele Exercise and Multiple Sclerosis (TEAMS) study has been able to successfully screen over 1700 people with multiple sclerosis (MS) across three southern states (Alabama, Mississippi, Tenessee) largely due to the advice and input that the research team received from a stakeholder panel, clinic partners and community organizations. These groups met before the study was submitted for funding to the Patient-Centered Outcome Research Institute (PCORI), and was awarded in 2017. These engagement stages and framework established early in the study process were instrumental in generating strong enthusiasm for the study among various MS constituency groups. The feedback from our stakeholders, clinic partners, and community organizations led to the creation of a variety of recruitment methods (print material, email, social media, attendance at events, and health fairs) to connect with potential participants in a setting convenient within each location. In approximately 26 months, the study enrolled 837 participants with MS and baseline tested 759 individuals who participated in a rehabilitative exercise program at either a clinic site or in their home using a tablet that they were given (and kept) which included a set of preloaded videos. All milestones established by PCORI and research staff were met, leading to the largest exercise trail ever conducted with people with MS.

Treatment with natalizumab once every 4 weeks is approved for patients with relapsing-remitting multiple sclerosis, but is associated with a risk of progressive multifocal leukoencephalopathy. Switching to extended-interval dosing is associated with lower progressive multifocal leukoencephalopathy risk, but the efficacy of this approach is unclear. We aimed to assess the safety and efficacy of natalizumab once every 6 weeks compared with once every 4 weeks in patients with relapsing-remitting multiple sclerosis. We did a randomised, controlled, open-label, phase 3b trial (NOVA) at 89 multiple sclerosis centres across 11 countries in the Americas, Europe, and Western Pacific. Included participants were aged 18–60 years with relapsing-remitting multiple sclerosis and had been treated with intravenous natalizumab 300 mg once every 4 weeks with no relapses for at least 12 months before randomisation, with no missed doses in the previous 3 months. Participants were randomly assigned (1:1), using a randomisation sequence generated by the study funder and contract personnel with interactive response technology, to switch to natalizumab once every 6 weeks or continue with once every 4 weeks. The centralised MRI reader, independent neurology evaluation committee, site examining neurologists, site backup examining neurologists, and site examining technicians were masked to study group assignments. The primary endpoint was the number of new or newly enlarging T2 hyperintense lesions at week 72, assessed in all participants who received at least one dose of assigned treatment and had at least one postbaseline MRI, relapse, or neurological examination or efficacy assessment. Missing primary endpoint data were handled under prespecified primary and secondary estimands: the primary estimand included all data, regardless of whether participants remained on the assigned treatment; the secondary estimand classed all data obtained after treatment discontinuation or study withdrawal as missing. Safety was assessed in all participants who received at least one dose of study treatment. Study enrolment is closed and an open-label extension study is ongoing. This study is registered with EudraCT, 2018-002145-11, and ClinicalTrials.gov, NCT03689972. Between Dec 26, 2018, and Aug 30, 2019, 605 patients were assessed for eligibility and 499 were enrolled and assigned to receive natalizumab once every 6 weeks (n=251) or once every 4 weeks (n=248). After prespecified adjustments for missing data, mean numbers of new or newly enlarging T2 hyperintense lesions at week 72 were 0·20 (95% CI 0·07–0·63) in the once every 6 weeks group and 0·05 (0·01–0·22) in the once every 4 weeks group (mean lesion ratio 4·24 [95% CI 0·86–20·85]; p=0·076) under the primary estimand, and 0·31 (95% CI 0·12–0·82) and 0·06 (0·01–0·31; mean lesion ratio 4·93 [95% CI 1·05–23·20]; p=0·044) under the secondary estimand. Two participants in the once every 6 weeks group with extreme new or newly enlarging T2 hyperintense lesion numbers (≥25) contributed most of the excess lesions. Adverse events occurred in 194 (78%) of 250 participants in the once every 6 weeks group and 190 (77%) of 247 in the once every 4 weeks group, and serious adverse events occurred in 17 (7%) and 17 (7%), respectively. No deaths were reported. There was one case of asymptomatic progressive multifocal leukoencephalopathy (without clinical signs) in the once every 6 weeks group, and no cases in the once every 4 weeks group; 6 months after diagnosis, the participant was without increased disability and remained classified as asymptomatic. We found a numerical difference in the mean number of new or newly enlarging T2 hyperintense lesions at week 72 between the once every 6 weeks and once every 4 weeks groups, which reached significance under the secondary estimand, but interpretation of statistical differences (or absence thereof) is limited because disease activity in the once every 4 weeks group was lower than expected. The safety profiles of natalizumab once every 6 weeks and once every 4 weeks were similar. Although this trial was not powered to assess differences in risk of progressive multifocal leukoencephalopathy, the occurrence of the (asymptomatic) case underscores the importance of monitoring and risk factor consideration in all patients receiving natalizumab. Biogen.

Access to comprehensive exercise and rehabilitation services for people with multiple sclerosis (MS) remains a major challenge, especially in rural, low-income areas. Hence, the Tele-Exercise and Multiple Sclerosis (TEAMS) study aims to provide patient-centered, coordinated care by implementing a 12-week complementary and alternative medicine (CAM) intervention for adults with MS. However, due to the societal impact of coronavirus disease (COVID-19) in mid-March 2020, the University of Alabama at Birmingham announced a limited business model halting all nonessential research requiring on-site visits, which includes the TEAMS study. In compliance with the shelter-in-place policy and quarantine guidance, a modified testing and training protocol was developed to allow participants to continue the study. The modified protocol, which replaces on-site data collection and training procedures, includes a teleassessment package (computer tablet, blood pressure cuff, hand dynamometer, mini disc cone, measuring tape, an 8\" step, and a large-print 8\" × 11\" paper with ruler metrics and wall-safe tape) and a virtual meeting platform for synchronous interactive training between the therapist and the participant. The teleassessment measures include resting blood pressure and heart rate, grip strength, Five Times Sit to Stand, Timed Up & Go, and the Berg Balance Scale. The teletraining component includes 20 sessions of synchronous training sessions of dual tasking, yoga, and Pilates exercises designed and customized for a range of functional levels. Teletraining lasts 12 weeks and participants are instructed to continue exercising for a posttraining period of 9 months. The protocol modifications were supported with supplemental funding (from the Patient-Centered Outcomes Research Institute) and approved by the University Institutional Review Board for Human Use. At the time nonessential research visits were halted by the university, there were 759 people enrolled and baseline tested, accounting for 92.5% of our baseline testing completion target (N=820). Specifically, 325 participants completed the 12-week intervention and follow-up testing visits, and 289 participants needed to complete either the intervention or follow-up assessments. A modified analysis plan will include sensitivity analyses to ensure the robustness of the study results in the presence of uncertainty and protocol deviations. Study results are projected to be published in 2021. This modified remote teleassessment/teletraining protocol will impact a large number of participants with MS who would otherwise have been discontinued from the study. ClinicalTrials.gov NCT03117881; https://clinicaltrials.gov/ct2/show/NCT03117881. DERR1-10.2196/18415.

More than two-thirds of students are unprepared for college-level work when they arrive at a community college and therefore are tracked into developmental classes before taking credit-bearing coursework Almost one-third of the community college student population consists of parents. This study aimed to find out what literacy practices parent-students engage in at home with their children to discover if any of those practices correlate with college-level literacy skills. Information on home reading practices was gathered through the use of the CECER-DLL Child and Family Questionnaire (Hammer et al., 2015), and those practices were then correlated with student ACT English and Reading subscores and end-ofsemester grades in English Composition I. The study was implemented at a rural Mississippi community college and relied on volunteers to participate since the study site does not keep records of parenthood status of students. In total, 81 participants who live with children age 15 or under at least 50% of the time responded to the survey. Descriptive statistics showed differences in the home language and literacy activities depending on age of the parent and age of the child. Correlational statistics showed positive relationships between the number of children's books in participants' homes and ACT Reading subscores. There was an especially strong positive correlation between the number of children's books and ACT Reading scores for young mothers (ages 19-25) with young children (ages 0-5). The number of children's books in the home also correlated positively with Composition I grades for African Americans and younger parents (ages 19-25). On the other hand, for white parents, there was a negative correlation between the number of children's books and Composition I grades, and for mothers, there was a negative correlation between the value placed on the home language and literacy environment (HLE) and Composition I grade. As a result of these findings, the researcher recommends further study, including a larger, more geographically diverse sample, follow-up qualitative studies, and experimental pretest-posttest studies. In addition, colleges should offer increased services to support parent-students, including providing children's books, family literacy programs, childcare, support groups, and coaching.

Background In patients treated with dimethyl fumarate, absolute lymphocyte count decline typically occurs during the first year and then plateaus; early drops have been associated with the development of severe prolonged lymphopenia. Objective We investigated the effect of dimethyl fumarate on absolute lymphocyte counts and CD4+/CD8+ T cells in patients with relapsing–remitting multiple sclerosis treated with dimethyl fumarate in routine practice. Methods Lymphocyte data were collected via medical chart abstraction. Primary endpoint: change from baseline in absolute lymphocyte count and CD4+/CD8+ counts at 6‐month intervals following dimethyl fumarate initiation. Results Charts of 483 patients were abstracted and 476 patients included in the analysis. Mean baseline absolute lymphocyte count (2.23 × 109/l) decreased by ∼39% (95% confidence interval: –41.1 to –37.2) by month 6 and 44% (95% confidence interval: –46.6 to –42.1) by month 12. CD4+ and CD8+ T-cell subsets strongly correlated with absolute lymphocyte count, with greater decreases from baseline to 6 months vs 6–12 months, and in CD8+ vs CD4+ T cells. Prior natalizumab was not a risk factor for lymphopenia. Conclusion Dimethyl fumarate-associated decline in absolute lymphocyte count in the first 12 months correlated with decline in CD4+ and CD8+ T cells and was independent of prior natalizumab. Absolute lymphocyte count monitoring continues to be an effective strategy to identify patients at risk of prolonged lymphopenia.

Our objective was to infer the climate drivers of regionally synchronous fire years in dry forests of the U.S. northern Rockies in Idaho and western Montana. During our analysis period (1650-1900), we reconstructed fires from 9245 fire scars on 576 trees (mostly ponderosa pine, Pinus ponderosa P. & C. Lawson) at 21 sites and compared them to existing tree-ring reconstructions of climate (temperature and the Palmer Drought Severity Index [PDSI]) and large-scale climate patterns that affect modern spring climate in this region (El Niño-Southern Oscillation [ENSO] and the Pacific Decadal Oscillation [PDO]). We identified 32 regional-fire years as those with five or more sites with fire. Fires were remarkably widespread during such years, including one year (1748) in which fires were recorded at 10 sites across what are today seven national forests plus one site on state land. During regional-fire years, spring-summers were significantly warm and summers were significantly warm-dry whereas the opposite conditions prevailed during the 99 years when no fires were recorded at any of our sites (no-fire years). Climate in prior years was not significantly associated with regional- or no-fire years. Years when fire was recorded at only a few of our sites occurred under a broad range of climate conditions, highlighting the fact that the regional climate drivers of fire are most evident when fires are synchronized across a large area. No-fire years tended to occur during La Niña years, which tend to have anomalously deep snowpacks in this region. However, ENSO was not a significant driver of regional-fire years, consistent with the greater influence of La Niña than El Niño conditions on the spring climate of this region. PDO was not a significant driver of past fire, despite being a strong driver of modern spring climate and modern regional-fire years in the northern Rockies.

Background Prairie–forest ecotones are ecologically important for biodiversity and ecological processes. While these ecotones cover small areas, their sharp gradients in land cover promote rich ecological interaction and high conservation value. Our objective was to understand how historical and current fire occurrences and human development influenced the Palouse Prairie–forest ecotone. We used General Land Office survey field notes about the occurrence of bearing trees to locate historical (1870s to 1880s) prairie, pine savanna, and forest at the eastern edge of the bioregion. We combined LANDFIRE Existing Vegetation classes to contrast historical land cover with current land cover. We reconstructed historical fire occurrence (1650 to 1900) from fire-scarred trees. We used fire and lightning records from 1992 to 2015 to interpret the role of people and lightning. Results Historically, the ecotone was a matrix of prairie with extensive savanna and some forest. More than half of the ecotone area was prairie, which is now dominated by agriculture, with some residential development. The 16% of the landscape that was pine savanna is now forest or shrubs, agriculture, perennial vegetation under the Conservation Reserve Program, or developed; no savanna now exists. Forests covered 12% of the ecotone and these are still mostly forest. Fires were historically frequent, occurring on average every 5 to 8 years at most sites. Lightning was not frequent but could likely have been sufficient to ignite fires that could spread readily given the rolling terrain and long fire season. Conclusions Fire was far more frequent historically than currently. Conservation, restoration, and other ongoing land-use changes will likely result in more continuous vegetation and hence fuel for fires. Lightning and people may ignite fires that therefore spread readily in the future. Understanding the past and potential future of fire in the Palouse Prairie bioregion may help us live with fire while conserving ecological values here and in similar prairie–forest ecotones.

Studies suggest that pregnant women might be at increased risk for severe illness associated with coronavirus disease 2019 (COVID-19) (1,2). This report provides updated information about symptomatic women of reproductive age (15-44 years) with laboratory-confirmed infection with SARS-CoV-2, the virus that causes COVID-19. During January 22-October 3, CDC received reports through national COVID-19 case surveillance or through the National Notifiable Diseases Surveillance System (NNDSS) of 1,300,938 women aged 15-44 years with laboratory results indicative of acute infection with SARS-CoV-2. Data on pregnancy status were available for 461,825 (35.5%) women with laboratory-confirmed infection, 409,462 (88.7%) of whom were symptomatic. Among symptomatic women, 23,434 (5.7%) were reported to be pregnant. After adjusting for age, race/ethnicity, and underlying medical conditions, pregnant women were significantly more likely than were nonpregnant women to be admitted to an intensive care unit (ICU) (10.5 versus 3.9 per 1,000 cases; adjusted risk ratio [aRR] = 3.0; 95% confidence interval [CI] = 2.6-3.4), receive invasive ventilation (2.9 versus 1.1 per 1,000 cases; aRR = 2.9; 95% CI = 2.2-3.8), receive extracorporeal membrane oxygenation (ECMO) (0.7 versus 0.3 per 1,000 cases; aRR = 2.4; 95% CI = 1.5-4.0), and die (1.5 versus 1.2 per 1,000 cases; aRR = 1.7; 95% CI = 1.2-2.4). Stratifying these analyses by age and race/ethnicity highlighted disparities in risk by subgroup. Although the absolute risks for severe outcomes for women were low, pregnant women were at increased risk for severe COVID-19-associated illness. To reduce the risk for severe illness and death from COVID-19, pregnant women should be counseled about the importance of seeking prompt medical care if they have symptoms and measures to prevent SARS-CoV-2 infection should be strongly emphasized for pregnant women and their families during all medical encounters, including prenatal care visits. Understanding COVID-19-associated risks among pregnant women is important for prevention counseling and clinical care and treatment.

Pregnant women with coronavirus disease 2019 (COVID-19) are at increased risk for severe illness and might be at risk for preterm birth (1-3). The full impact of infection with SARS-CoV-2, the virus that causes COVID-19, in pregnancy is unknown. Public health jurisdictions report information, including pregnancy status, on confirmed and probable COVID-19 cases to CDC through the National Notifiable Diseases Surveillance System.* Through the Surveillance for Emerging Threats to Mothers and Babies Network (SET-NET), 16 jurisdictions collected supplementary information on pregnancy and infant outcomes among 5,252 women with laboratory-confirmed SARS-CoV-2 infection reported during March 29-October 14, 2020. Among 3,912 live births with known gestational age, 12.9% were preterm (<37 weeks), higher than the reported 10.2% among the general U.S. population in 2019 (4). Among 610 infants (21.3%) with reported SARS-CoV-2 test results, perinatal infection was infrequent (2.6%) and occurred primarily among infants whose mother had SARS-CoV-2 infection identified within 1 week of delivery. Because the majority of pregnant women with COVID-19 reported thus far experienced infection in the third trimester, ongoing surveillance is needed to assess effects of infections in early pregnancy, as well the longer-term outcomes of exposed infants. These findings can inform neonatal testing recommendations, clinical practice, and public health action and can be used by health care providers to counsel pregnant women on the risks of SARS-CoV-2 infection, including preterm births. Pregnant women and their household members should follow recommended infection prevention measures, including wearing a mask, social distancing, and frequent handwashing when going out or interacting with others or if there is a person within the household who has had exposure to COVID-19. .