Search

Background: the antiviral drug molnupiravir was licensed for treating at-risk patients with COVID-19 on the basis of data from unvaccinated adults. We aimed to evaluate the safety and virological efficacy of molnupiravir in vaccinated and unvaccinated individuals with COVID-19.Methods: this randomised, placebo-controlled, double-blind, phase 2 trial (AGILE CST-2) was done at five National Institute for Health and Care Research sites in the UK. Eligible participants were adult (aged ≥18 years) outpatients with PCR-confirmed, mild-to-moderate SARS-CoV-2 infection who were within 5 days of symptom onset. Using permuted blocks (block size 2 or 4) and stratifying by site, participants were randomly assigned (1:1) to receive either molnupiravir (orally; 800 mg twice daily for 5 days) plus standard of care or matching placebo plus standard of care. The primary outcome was the time from randomisation to SARS-CoV-2 PCR negativity on nasopharyngeal swabs and was analysed by use of a Bayesian Cox proportional hazards model for estimating the probability of a superior virological response (hazard ratio [HR]>1) for molnupiravir versus placebo. Our primary model used a two-point prior based on equal prior probabilities (50%) that the HR was 1·0 or 1·5. We defined a priori that if the probability of a HR of more than 1 was more than 80% molnupiravir would be recommended for further testing. The primary outcome was analysed in the intention-to-treat population and safety was analysed in the safety population, comprising participants who had received at least one dose of allocated treatment. This trial is registered in ClinicalTrials.gov, NCT04746183, and the ISRCTN registry, ISRCTN27106947, and is ongoing.Findings: between Nov 18, 2020, and March 16, 2022, 1723 patients were assessed for eligibility, of whom 180 were randomly assigned to receive either molnupiravir (n=90) or placebo (n=90) and were included in the intention-to-treat analysis. 103 (57%) of 180 participants were female and 77 (43%) were male and 90 (50%) participants had received at least one dose of a COVID-19 vaccine. SARS-CoV-2 infections with the delta (B.1.617.2; 72 [40%] of 180), alpha (B.1.1.7; 37 [21%]), omicron (B.1.1.529; 38 [21%]), and EU1 (B.1.177; 28 [16%]) variants were represented. All 180 participants received at least one dose of treatment and four participants discontinued the study (one in the molnupiravir group and three in the placebo group). Participants in the molnupiravir group had a faster median time from randomisation to negative PCR (8 days [95% CI 8-9]) than participants in the placebo group (11 days [10-11]; HR 1·30, 95% credible interval 0·92-1·71; log-rank p=0·074). The probability of molnupiravir being superior to placebo (HR>1) was 75·4%, which was less than our threshold of 80%. 73 (81%) of 90 participants in the molnupiravir group and 68 (76%) of 90 participants in the placebo group had at least one adverse event by day 29. One participant in the molnupiravir group and three participants in the placebo group had an adverse event of a Common Terminology Criteria for Adverse Events grade 3 or higher severity. No participants died (due to any cause) during the trial.Interpretation: we found molnupiravir to be well tolerated and, although our predefined threshold was not reached, we observed some evidence that molnupiravir has antiviral activity in vaccinated and unvaccinated individuals infected with a broad range of SARS-CoV-2 variants, although this evidence is not conclusive.Funding: Ridgeback Biotherapeutics, the UK National Institute for Health and Care Research, the Medical Research Council, and the Wellcome Trust.

PURPOSE: To explore the recalled experiences of women with CP regarding sexual health education and services they received. METHODS: Semi-structured interviews and focus groups were conducted at four academic tertiary hospitals with 33 adult women with CP. Templates were used to ask about four key content domains: appointment planning (including planning for a gynecologic exam), accessibility of services, experiences with providers, and recommendations for improvement. Sessions were transcribed verbatim and analyzed to generate a coding dictionary. Blinded coding was carried out for each transcript, with duplicate coding used to confirm identified themes. Iterative analysis was used to identify and consolidate coding and key themes. RESULTS: Similar barriers were discussed at the four sites, including lack of accessible exam tables, hospital staff unfamiliar with physical disabilities, and assumptions that women with CP are not sexually active. Many described the sexual education they received as brief, omitted, or mistimed. Self-advocacy was crucial, and recommended strategies ranged from pre-gynecologic exam medication to visit checklists. CONCLUSION: Reproductive health education for young women with CP is frequently inadequate. Medical professionals lack relevant knowledge and awareness; medical facilities lack necessary infrastructure. Recommendations for improvements are made.

Children with cerebral palsy (CP) are five times more likely than typically developing children to have sleep problems, resulting in adverse outcomes for both children and their families. The purpose of this systematic review was to gather current evidence regarding assessments and interventions for sleep in children under age 2 years with or at high risk for CP and integrate these findings with parent preferences.Five databases (CINAHL, EMBASE, OVID/Medline, SCOPUS, and PsycINFO) were searched. Included articles were screened using preferred reporting items for systematic reviews and meta-analyses guidelines, and quality of the evidence was reviewed using best evidence tools by two independent reviewers at minimum. An online survey was conducted regarding parent preferences through social media channels.Eleven articles met inclusion criteria. Polysomnography emerged as the only high-quality assessment for the population. Three interventions (medical cannabis, surgical interventions, and auditory, tactile, visual, and vestibular stimulations) were identified; however, each only had one study of effectiveness. The quality of evidence for polysomnography was moderate, while the quality and quantity of the evidence regarding interventions was low. Survey respondents indicated that sleep assessments and interventions are highly valued, with caregiver-provided interventions ranked as the most preferable.Further research is needed to validate affordable and feasible sleep assessments compared to polysomnography as the reference standard. In the absence of diagnosis-specific evidence of safety and efficacy of sleep interventions specific to young children with CP, it is conditionally recommended that clinicians follow guidelines for safe sleep interventions for typically developing children.

Background Children with cerebral palsy (CP) are five times more likely than typically developing children to have sleep problems, resulting in adverse outcomes for both children and their families. The purpose of this systematic review was to gather current evidence regarding assessments and interventions for sleep in children under age 2 years with or at high risk for CP and integrate these findings with parent preferences. Methods Five databases (CINAHL, EMBASE, OVID/Medline, SCOPUS, and PsycINFO) were searched. Included articles were screened using preferred reporting items for systematic reviews and meta-analyses guidelines, and quality of the evidence was reviewed using best evidence tools by two independent reviewers at minimum. An online survey was conducted regarding parent preferences through social media channels. Results Eleven articles met inclusion criteria. Polysomnography emerged as the only high-quality assessment for the population. Three interventions (medical cannabis, surgical interventions, and auditory, tactile, visual, and vestibular stimulations) were identified; however, each only had one study of effectiveness. The quality of evidence for polysomnography was moderate, while the quality and quantity of the evidence regarding interventions was low. Survey respondents indicated that sleep assessments and interventions are highly valued, with caregiver-provided interventions ranked as the most preferable. Conclusions Further research is needed to validate affordable and feasible sleep assessments compared to polysomnography as the reference standard. In the absence of diagnosis-specific evidence of safety and efficacy of sleep interventions specific to young children with CP, it is conditionally recommended that clinicians follow guidelines for safe sleep interventions for typically developing children.

The prevalence of atherosclerosis is increased in type 1 diabetes despite normal-to-high HDL-cholesterol levels. The cholesterol efflux capacity (CEC) of HDL is a better predictor of cardiovascular events than static HDL-cholesterol. This cross-sectional study addressed the hypothesis that impaired HDL function contributes to enhanced CVD risk within type 1 diabetes. We compared HDL particle size and concentration (by NMR), total CEC, ATP-binding cassette subfamily A, member 1 (ABCA1)-dependent CEC and ABCA1-independent CEC (by determining [3H]cholesterol efflux from J774-macrophages to ApoB-depleted serum), and carotid intima–media thickness (CIMT) in 100 individuals with type 1 diabetes (37.6 ± 1.2 years; BMI 26.9 ± 0.5 kg/m2) and 100 non-diabetic participants (37.7 ± 1.1 years; 27.1 ± 0.5 kg/m2). Compared with non-diabetic participants, total HDL particle concentration was lower (mean ± SD 31.01 ± 8.66 vs 34.33 ± 8.04 μmol/l [mean difference (MD) −3.32 μmol/l]) in participants with type 1 diabetes. However, large HDL particle concentration was greater (9.36 ± 3.98 vs 6.99 ± 4.05 μmol/l [MD +2.37 μmol/l]), resulting in increased mean HDL particle size (9.82 ± 0.57 vs 9.44 ± 0.56 nm [MD +0.38 nm]) (p

Scope Metabolic inflammation is a classic hallmark of obesity that is associated with numerous cardiometabolic complications. Disturbances in fatty acid and cholesterol metabolism are evident in obesity and likely intricately linked to the development and/or sustainment of metabolic inflammation and insulin resistance. Elevations in triglyceride-rich lipoproteins and reductions in high-density lipoprotein-cholesterol in turn are two major disturbances that accompany obesity. Methods and results How metabolic dyslipidemia may contribute to metabolic inflammation is discussed. How aberrant cholesterol homeostasis coupled with excessive fatty acid accumulation prime pro-IL-1β and the evidence to support a synergistic partnership between cholesterol and fatty acids in driving metabolic inflammation are also discussed. Further, pharmaceutical and nutraceutical strategies aimed at attenuating low-grade inflammation and implications for cardiometabolic complications of obesity are reviewed. The current literature on the importance of the local tissue microenvironment in activating adipose tissue macrophages within obese adipose tissue and the contribution of these local immune cells to metabolic inflammation is reviewed. Finally, the limitations to current biomarkers of metabolic inflammation and the importance of novel sensitive biomarkers in driving obesity sub-type characterization to direct personalized medicine approaches to obesity treatment in the future are discussed.

Background Women with disabilities (WWD) have reported lower mammography rates than the general population, however rates for women with cerebral palsy (CP) have not been specifically studied. Objective To evaluate mammography rates in women with CP and to identify strengths and barriers with their screening experience. Methods Women with CP 40 years or older (n = 118) participating in a prospective cross-sectional survey were queried regarding screening status, imaging modality, and accommodation needs and availability. Categorical variables were summarized and Chi-square testing used to assess factors contributing to screening compliance. The effect of functional factors on screening was evaluated using logistic regression. Results 77 women (65.3%) had mammograms within the past two years; 56 (47.5%) were screening mammograms. Severity of fine motor deficits was associated with lack of screening (OR 0.559, p = 0.019). 85 (72.0%) experienced positive staff attitudes. Facilities most often met needs for ramps, elevators, and/or wide doorways (92.9%), exam explanations (84.4%), and accessible parking (82.5%). Needs least often met included accommodations for standing (59.3%) or for difficulties with arm/shoulder positioning (57.1%), and wheelchair-accessible mammogram machines (59.1%). Conclusions The screening compliance rate for women with CP is low, although the 2-year mammography rate is comparable to that reported for WWD and the general female U.S. population. Women were usually offered respectful care. Adequate physical accommodations during the procedure were reported less often than overall facility environmental accommodations. These findings demonstrate the need for improved screening rates in women with CP, and highlight areas for improving their screening experience.

Cerebral palsy is the most common physical disability in childhood, and is mostly diagnosed after age 2 years. Delays in diagnosis can have negative long-term consequences for children and parents. New guidelines for early cerebral palsy diagnosis and intervention were recently published, after systematic review of the evidence by international multidisciplinary experts aiming to decrease age at diagnosis. The current study tested the feasibility of implementing these guidelines in an American clinical setting.We designed a stepwise implementation process in a neonatal intensive care follow-up clinic. Efficacy was tested by comparing 10-month pre- and post-implementation periods. Clinic visit types, cerebral palsy diagnosis, provider competencies and perspectives, and balancing measures were analyzed.Changes to infrastructure, assessments, scheduling algorithms, documentation and supports in diagnosis or counseling were successfully implemented. Number of three- to four-month screening visits increased (255 to 499, P 0.001); mean age at diagnosis decreased (18 to 13 months, P 0.001). Clinic team awareness of early diagnosis and interventions increased (P 0.001). There was no decrease in family satisfaction with overall clinic function. Opportunities for improvements included documentation for transitioning patients, generalizabilty across hospital clinics, systematic identification of high-risk status during hospitalization, and need for cerebral palsy care guidelines for infants under age 2 years.We demonstrated for the first time in a US clinical setting the feasibility of implementation of international early diagnosis and treatment guidelines for cerebral palsy. This process is adaptable to other settings and underscores the necessity of future research on cerebral palsy treatments in infancy.

Objective To assess the patterns of sacral sparing and recovery in newly injured persons with traumatic spinal cord injury (SCI). Design Retrospective analysis of data from the national Spinal Cord Injury Model Systems (SCIMS) database for patients enrolled from January 2011 to February 2015. Setting SCIMS centers. Participants Individuals (N=1738; age ≥16y) with traumatic SCI admitted to rehabilitation within 30 days after injury with follow-up at discharge, at 1 year, or both. Interventions Not applicable. Main Outcome Measures International Standards for Neurological Classification of Spinal Cord Injury examination results at admission and follow-up (discharge or 1y, or both). Results Conversion from an initial American Spinal Injury Association Impairment Scale (AIS) grade A to incomplete status was 20% at rehabilitation discharge and 27.8% at 1 year, and was greater in cervical and low paraplegia levels (T10 and below) than in high paraplegia level injuries (T1-9). Conversion from AIS B to motor incomplete was 33.9% at discharge and 53.6% at 1 year, and the initial sparing of all sacral sensory components was correlated with the greatest conversion to motor incomplete status at discharge and at 1 year. For patients with initial AIS C, the presence of voluntary anal contraction (VAC) in association with other sacral sparing was most frequently observed to improve to AIS D status at discharge. However, the presence of VAC alone as the initial sacral sparing component had the poorest prognosis for recovery to AIS D status. At follow-up, regaining sacral sparing components correlated with improvement in conversion for patients with initial AIS B and C. Conclusions The components of initial and follow-up sacral sparing indicated differential patterns of neurologic outcome in persons with traumatic SCI. The more sacral components initially spared, the greater the potential for recovery; and the more sacral components gained, the greater the chance of motor recovery. Consideration of whether VAC should remain a diagnostic criterion sufficient for motor incomplete classification in the absence of other qualifying sublesional motor sparing is recommended.

Background: Although literature suggests that parents need support when their child is diagnosed with cerebral palsy (CP), it is unclear to what extent providers implement these supports in practice and what parental perspectives surround provider early diagnosis and management of CP. Therefore, we aimed to characterize and compare experiences of providers and parents of children with CP with regards to early detection and intervention. Method: Seventeen parents participated in day-long world-cafe style workshops focused on categories extracted from the International Classification of Function framework and recent systematic reviews of early detection for CP. Thirty regional providers (generalists, specialists, and therapists) caring for infants with CP completed surveys with scaled score and open-ended questions. Quantitative and qualitative data were independently assessed by two reviewers to identify prominent themes. Results: All parents (100%) stated early diagnosis or high risk for CP classification was beneficial compared with only 50% of providers who often gave early CP diagnoses before 12 months. Top parent priorities were honesty and positively phrased messages. Providers most often addressed cognition, primary care need, motor, and feeding issues (80%, 62%, 54%, 54% frequently/sometimes). Matching priorities for discussion were neuroimaging timing/risk/benefit, cognition, primary care, motor, and feeding/nutrition. Discordance occurred for participation, parent well-being, pain and vision, with parents wanting more education and resources. Conclusions: Receiving early diagnoses or high-risk for CP classification is a parent priority. Alignment between parents and providers exists for International Classification of Function domains of body functions/structures and activity, but less for those of environment, personal, and participation.

Scope High-fat diet (HFD)-induced obesity impairs macrophage-to-feces reverse cholesterol transport (RCT). It is hypothesized that dietary supplementation with the polyunsaturated fatty acids conjugated linoleic acid (CLA) or alpha linolenic acid (ALA) would prevent HFD-impaired RCT by modulating hepatic protein pathways. Methods and results ApoE3L.CETP mice are fed a HFD supplemented ± CLA or ALA for 12 weeks and in vivo macrophage-to-feces RCT is determined. Hepatic cholesterol transporters and the hepatic proteome are assessed by immunoblotting and mass spectrometry, respectively. Mice fed HFD alone, but not ALA-HFD or CLA-HFD, exhibit increased systemic cholesterol levels, increased 3 H-cholesterol levels in plasma and liver but not feces during RCT, and reduced hepatic ABCG5/8 expression relative to LFD. ALA-HFD significantly reduces liver weight, hepatic cholesterol levels, and expression of the cholesterol synthesis enzyme farnesyl pyrophosphate synthase relative to HFD. ALA further increases the expression of acetyl-coA oxidase-associated proteins and suppress PPARα-induced proteins relative to HFD. CLA does not significantly attenuate hepatic lipid levels but is associated with reduced hepatic expression of fatty acid binding protein (FABP)-1/FABP4 levels relative to HFD, and reduced inflammatory pathway activation relative to ALA-HFD. Conclusion ALA and CLA exert distinct mechanistic advantages on cholesterol homeostasis and RCT in obesity.

STRUCTURED ABSTRACT Study Design Secondary analysis of cross-sectional data from a multisite cohort study. Objectives To analyze the association between the built environment and physical functioning reported by adults living with chronic spinal cord injury (SCI). Setting Four United States Spinal Cord Injury Model Systems centers in New Jersey, Colorado, Illinois, and Michigan. Methods Participants were from the Spinal Cord Injury-Functional Index/Capacity (SCI-FI/C) development study. Survey data from N=402 participants were geocoded for analysis. Geographic Information Systems (GIS) analysis was used to define five- and half-mile buffer areas around participants’ residential addresses to represent the community and neighborhood environments, respectively, and to create measures of land use, residential density, destination density, and park space. The relationships between these built environment features and four domains of physical functioning—basic mobility, wheelchair mobility, self-care, and fine motor function—were modeled using ordinary least squares (OLS) regression. Results People with paraplegia living in neighborhoods with more destinations and a nearby park reported higher levels of self-care functioning. For people with tetraplegia, living in a community with more destinations was associated with better wheelchair mobility and fine motor functioning, and living in a neighborhood with high land use mix was associated with higher fine motor functioning scores. Conclusions The association between the built environment and functioning after SCI is supported and in need of further investigation. Understanding the environmental context of disability may lead to community-based interventions and effective public policy that will attenuate the experience of limitations and promote accessibility on a larger scale.

In this study, we investigated the contribution of inhibition and maternal socialisation of children's fear to observed emotion regulation during a fear induction. Fifty-three parent–child dyads (Mage = 3.76 years) participated. Parents completed a series of questionnaires, and parent–child dyads were observed during a fear induction. Children's behaviour was coded for latency to approach the fear stimulus, expressions of fear, and regulation of emotion during the fear episode. Inhibition positively predicted orientation to mother and negatively predicted task orientation during the fear episode. In addition, the interaction between inhibition and supportive reactions to fear predicted children's engagement in distraction during the fear episode; the relation between inhibition and distraction was significant when mothers reported high levels of support to children's fear. The results indicated that mothers’ supportive reactions to children's fear bolster their emotion regulatory skills.

Background Little is known about pregnancy rates in women with disabilities in general and even less is known about women with child-onset disabilities such as cerebral palsy (CP). Hypothesis We hypothesized that discussions about pregnancy with healthcare providers and pregnancy rates for woman with CP would be related to their functional levels. Methods Survey methodology was used to gather information about demographics, function, whether women were asked about their desire for children, pregnancy outcomes, and services offered during pregnancy and postpartum. Results Of the 375 women with CP who participated in the survey, 76 (20%) reported 149 pregnancies resulting in 100 live births. Using Chi square statistics, mobility, manual dexterity, and communication function were significantly higher in women who were queried about or who experienced pregnancy. More than half of the women experienced a loss of mobility during pregnancy but few received referrals for physical or occupational therapy. Few reported screening for postpartum depression. A higher rate of Cesarean sections (50.4%), preterm births (12.1%), low birth weight infants (15.7%), and very low birth weight infants (7.1%) was reported by women with CP compared to national statistics. Conclusions Pregnancy rates and discussions were related to functional levels. As 20% of women with CP surveyed experienced pregnancy, there is a need to increase awareness, education, support, and advocacy for achievement of optimal reproductive health. More research is needed to identify factors contributing to maternal and infant health in women with CP.

To identify medically relevant aspects of blood pressure dysregulation (BPD) related to quality of life in individuals with spinal cord injury (SCI), and to propose an integrated conceptual framework based on input from both individuals with SCI and their clinical providers. This framework will serve as a guide for the development of a patient-reported outcome (PRO) measure specifically related to BPD.Three focus groups with individuals with SCI and 3 groups with SCI providers were analyzed using grounded-theory based qualitative analysis to ascertain how blood pressure impacts health-related quality of life (HRQOL) in individuals with SCI.Focus groups were conducted at 2 Veterans Affairs medical centers and a research center.Individuals with SCI (n=27) in 3 focus groups and clinical providers (n=25) in 3 focus groups.Not applicable.Not applicable.Qualitative analysis indicated that all focus groups spent the highest percentage of time discussing symptoms of BPD (39%), followed by precipitators/causes of BPD (16%), preventative actions (15%), corrective actions (12%), and the impact that BPD has on social or emotional functioning (8%). While patient/consumer focus groups and provider focus groups raised similar issues, providers spent more time discussing precipitators/causes of BPD and preventative actions (38%) than patient/consumer groups (24%).These results suggest that BPD uniquely and adversely impacts HRQOL in persons with SCI. While both individuals with SCI and their providers highlighted the relevant symptoms of BPD, the SCI providers offered additional detailed information regarding the precipitators/causes and what can be done to prevent/treat BPD. Further, the results suggest that persons with SCI are aware of how BPD impacts their HRQOL and are able to distinguish between subtle signs and symptoms. These findings exemplify the need for a validated and sensitive clinical measurement tool that can assess the extent to which BPD impacts HRQOL in patients with SCI.

Three patients with different obscure hematologic disorders are presented. All 3 patients had abnormalities of chromosome number confined to marrow cells. Case 1 is a 23-year-old man with aplastic anemia; most of his bone marrow cells contained 45 chromosomes, with one missing from group C. Case 2 is a 62-year-old man who died of idiopathic sideroachrestic anemia; most of his bone marrow cells contained 47 chromosomes with an extra C group chromosome which appeared to be an autosome. Case 3 is a 59-year-old woman with idiopathic thrombocythemia; while the majority of her bone marrow cells contained 46 chromosomes, a stable minority cell line had 48 chromosomes. Although many of the reported patients with myelodysplastic-myeloproliferative disorders have normal chromosomes, 5 cases with some chromosomal aberration, previously reported by others, are summarized. None of these patients had clinical evidence of leukemia. In 4 of the patients, the chromosomal anomaly involved a chromosome in group C, which is the group in which aneuploidy occurred in all 3 of our patients. It is postulated that a stable, aneuploid stem line does not of itself produce neoplasia, but rather that this alteration of the genome may provide a more favorable milieu for the action of some transforming agent. Because of the frequent occurrence of C group abnormalities in these cases of marrow disorders, it is further postulated that genes on one or more C chromosomes might be responsible for homeostatic control of hemopoiesis, and that a change in genetic balance involving a C group chromosome(s) coupled with a transforming agent might result in leukemia in a greater proportion of individuals than aneuploidy of some other chromosomal group.