Harmful algal blooms plague bodies of freshwater globally. These blooms are often composed of outgrowths of cyanobacteria capable of producing the heptapeptide Microcystin-LR (MC-LR) which is a ...well-known hepatotoxin. Recently, MC-LR has been detected in aerosols generated from lake water. However, the risk for human health effects due to MC-LR inhalation exposure have not been extensively investigated. In this study, we exposed a fully differentiated 3D human airway epithelium derived from 14 healthy donors to MC-LR-containing aerosol once a day for 3 days. Concentrations of MC-LR ranged from 100 pM to 1 µM. Although there were little to no detrimental alterations in measures of the airway epithelial function (i.e. cell survival, tissue integrity, mucociliary clearance, or cilia beating frequency), a distinct shift in the transcriptional activity was found. Genes related to inflammation were found to be upregulated such as C-C motif chemokine 5 (CCL5; log2FC = 0.57, p = 0.03) and C-C chemokine receptor type 7 (CCR7; log2FC = 0.84, p = 0.03). Functionally, conditioned media from MC-LR exposed airway epithelium was also found to have significant chemo-attractive properties for primary human neutrophils. Additionally, increases were found in the concentration of secreted chemokine proteins in the conditioned media such as CCL1 (log2FC = 5.07, p = 0.0001) and CCL5 (log2FC = 1.02, p = 0.046). These results suggest that MC-LR exposure to the human airway epithelium is capable of inducing an inflammatory response that may potentiate acute or chronic disease.
To combat the high burden of rotavirus gastroenteritis, multiple African countries have introduced rotavirus vaccines into their childhood immunization programs. Malawi incorporated a G1P8 rotavirus ...vaccine (Rotarix) into its immunization schedule in 2012. Utilizing a surveillance platform of hospitalized rotavirus gastroenteritis cases, we examined the phylodynamics of G1P8 rotavirus strains that circulated in Malawi before (1998 to 2012) and after (2013 to 2014) vaccine introduction. Analysis of whole genomes obtained through next-generation sequencing revealed that all randomly selected prevaccine G1P8 strains sequenced (
= 32) possessed a Wa-like genetic constellation, whereas postvaccine G1P8 strains (
= 18) had a DS-1-like constellation. Phylodynamic analyses indicated that postvaccine G1P8 strains emerged through reassortment events between human Wa- and DS-1-like rotaviruses that circulated in Malawi from the 1990s and hence were classified as atypical DS-1-like reassortants. The time to the most recent common ancestor for G1P8 strains was from 1981 to 1994; their evolutionary rates ranged from 9.7 × 10
to 4.1 × 10
nucleotide substitutions/site/year. Three distinct G1P8 lineages chronologically replaced each other between 1998 and 2014. Genetic drift was the likely driver for lineage turnover in 2005, whereas replacement in 2013 was due to reassortment. Amino acid substitution within the outer glycoprotein VP7 of G1P8 strains had no impact on the structural conformation of the antigenic regions, suggesting that it is unlikely that they would affect recognition by vaccine-induced neutralizing antibodies. While the emergence of DS-1-like G1P8 rotavirus reassortants in Malawi was therefore likely due to natural genotype variation, vaccine effectiveness against such strains needs careful evaluation.
The error-prone RNA-dependent RNA polymerase and the segmented RNA genome predispose rotaviruses to genetic mutation and genome reassortment, respectively. These evolutionary mechanisms generate novel strains and have the potential to lead to the emergence of vaccine escape mutants. While multiple African countries have introduced a rotavirus vaccine, there are few data describing the evolution of rotaviruses that circulated before and after vaccine introduction. We report the emergence of atypical DS-1-like G1P8 strains during the postvaccine era in Malawi. Three distinct G1P8 lineages circulated chronologically from 1998 to 2014; mutation and reassortment drove lineage turnover in 2005 and 2013, respectively. Amino acid substitutions within the outer capsid VP7 glycoprotein did not affect the structural conformation of mapped antigenic sites, suggesting a limited effect on the recognition of G1-specific vaccine-derived antibodies. The genes that constitute the remaining genetic backbone may play important roles in immune evasion, and vaccine effectiveness against such atypical strains needs careful evaluation.
Objective
Data on sustained remission of granulomatosis with polyangiitis (GPA) after discontinuation of therapy (referred to as GPA with sustained remission off‐therapy SROT) are scarce. In the ...present study, SROT among GPA patients from the French Vasculitis Study Group Registry was evaluated to identify factors associated with its occurrence and durability.
Methods
For inclusion of patients in the study, the diagnosis of GPA had to meet the GPA classification criteria defined by the American College of Rheumatology and/or the revised Chapel Hill Consensus Conference nomenclature for vasculitis. SROT was defined as achievement of remission (a Birmingham Vasculitis Activity Score of 0) that was sustained for ≥6 consecutive months after having discontinued glucocorticoid (GC) and immunosuppressant treatments. The characteristics of the patients at baseline and treatments received were compared at 3, 5, and 10 years postdiagnosis according to whether or not SROT had been reached and maintained.
Results
Among 795 patients with GPA, 92 GPA patients with SROT at 3 years postdiagnosis were compared to 342 control subjects who had experienced disease relapse and/or were still receiving GCs or immunosuppressants. No baseline differences were found, but patients with SROT at 3 years postdiagnosis had more frequently received intravenous cyclophosphamide as induction therapy compared to control subjects (P = 0.01), with a higher median number of infusions (P = 0.05). At 5 years postdiagnosis, no baseline differences were observed between groups, but patients with SROT at 5 years postdiagnosis had received more cyclophosphamide infusions compared to control subjects (P = 0.03). More patients with SROT had received rituximab as maintenance therapy than control subjects at 3 years and 5 years postdiagnosis (P = 0.09 and P < 0.001, respectively). Of the 74 patients enrolled in the GPA Registry with 10‐year follow‐up data after having received conventional maintenance therapy, 15 (20%) had reached SROT at 3 years, and 5 (7%) maintained SROT at 10 years postdiagnosis.
Conclusion
After conventional therapies, 7% of GPA patients had reached SROT at 10 years postdiagnosis. No baseline vasculitis characteristics distinguished patients who achieved/maintained SROT from those who experienced disease relapse and/or those who continued to receive GCs or immunosuppressant therapy, but patients with SROT had received more intensive induction therapy and rituximab as maintenance therapy more frequently.
Abstract
As the proportion of older adults in the United States is projected to increase dramatically in the coming decades, it is imperative that public health address and maintain the cognitive ...health of this growing population. More than 5 million Americans live with Alzheimer’s disease and related dementias (ADRD) today, and this number is projected to more than double by 2050. The public health community must be proactive in outlining the response to this growing crisis. Promoting cognitive decline risk reduction, early detection and diagnosis, and increasing the use and availability of timely data are critical components of this response. To prepare state, local, and tribal organizations, CDC and the Alzheimer’s Association have developed a series of Road Maps that chart the public health response to dementia. Since the initial Healthy Brain Initiative (HBI) Road Map release in 2007, the Road Map has undergone two new iterations, with the most recent version, The HBI’s State and Local Public Health Partnerships to Address Dementia: The 2018–2023 Road Map, released in late 2018. Over the past several years, significant advances were made in the science of risk reduction and early detection of ADRD. As a result, the public health response requires a life-course approach that focuses on reducing risk and identifying memory issues earlier to improve health outcomes. The most recent Road Map was revised to accommodate these strides in the science and to effect change at the policy, systems, and environment levels. The 2018–2023 Road Map identifies 25 actions that state and local public health agencies and their partners can implement to promote cognitive health and address cognitive impairment and the needs of caregivers. The actions are categorized into four traditional domains of public health, and the Road Map can help public health and its partners chart a course for a dementia-prepared future.
We hypothesized that patients with heart failure (HF) who recover left ventricular function (HF-Recovered) have a distinct clinical phenotype, biology, and prognosis compared with patients with HF ...with reduced ejection fraction (HF-REF) and those with HF with preserved ejection fraction (HF-PEF).
The Penn Heart Failure Study (PHFS) is a prospective cohort of 1821 chronic HF patients recruited from tertiary HF clinics. Participants were divided into 3 categories based on echocardiograms: HF-REF if EF was <50%, HF-PEF if EF was consistently ≥50%, and HF-Recovered if EF on enrollment in PHFS was ≥50% but prior EF was <50%. A significant portion of HF-Recovered patients had an abnormal biomarker profile at baseline, including 44% with detectable troponin I, although in comparison, median levels of brain natriuretic factor, soluble fms-like tyrosine kinase receptor-1, troponin I, and creatinine were greater in HF-REF and HF-PEF patients. In unadjusted Cox models over a maximum follow-up of 8.9 years, the hazard ratio for death, transplantation, or ventricular assist device placement in HF-REF patients was 4.1 (95% confidence interval, 2.4-6.8; P<0.001) and in HF-PEF patients was 2.3 (95% confidence interval, 1.2-4.5; P=0.013) compared with HF-Recovered patients. The unadjusted hazard ratio for cardiac hospitalization in HF-REF patients was 2.0 (95% confidence interval, 1.5-2.7; P<0.001) and in HF-PEF patients was 1.3 (95% confidence interval, 0.90-2.0; P=0.15) compared with HF-Recovered patients. Results were similar in adjusted models.
HF-Recovered is associated with a better biomarker profile and event-free survival than HF-REF and HF-PEF. However, these patients still have abnormalities in biomarkers and experience a significant number of HF hospitalizations, suggesting persistent HF risk.
Despite signs of infection-including taste loss, dry mouth and mucosal lesions such as ulcerations, enanthema and macules-the involvement of the oral cavity in coronavirus disease 2019 (COVID-19) is ...poorly understood. To address this, we generated and analyzed two single-cell RNA sequencing datasets of the human minor salivary glands and gingiva (9 samples, 13,824 cells), identifying 50 cell clusters. Using integrated cell normalization and annotation, we classified 34 unique cell subpopulations between glands and gingiva. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral entry factors such as ACE2 and TMPRSS members were broadly enriched in epithelial cells of the glands and oral mucosae. Using orthogonal RNA and protein expression assessments, we confirmed SARS-CoV-2 infection in the glands and mucosae. Saliva from SARS-CoV-2-infected individuals harbored epithelial cells exhibiting ACE2 and TMPRSS expression and sustained SARS-CoV-2 infection. Acellular and cellular salivary fractions from asymptomatic individuals were found to transmit SARS-CoV-2 ex vivo. Matched nasopharyngeal and saliva samples displayed distinct viral shedding dynamics, and salivary viral burden correlated with COVID-19 symptoms, including taste loss. Upon recovery, this asymptomatic cohort exhibited sustained salivary IgG antibodies against SARS-CoV-2. Collectively, these data show that the oral cavity is an important site for SARS-CoV-2 infection and implicate saliva as a potential route of SARS-CoV-2 transmission.
We were the first to previously report that microcystin-LR (MC-LR) has limited effects within the colons of healthy mice but has toxic effects within colons of mice with pre-existing inflammatory ...bowel disease. In the current investigation, we aimed to elucidate the mechanism by which MC-LR exacerbates colitis and to identify effective therapeutic targets. Through our current investigation, we report that there is a significantly greater recruitment of macrophages into colonic tissue with pre-existing colitis in the presence of MC-LR than in the absence of MC-LR. This is seen quantitatively through IHC staining and the enumeration of F4/80-positive macrophages and through gene expression analysis for
,
, and
. Exposure of isolated macrophages to MC-LR was found to directly upregulate macrophage activation markers
and
. Through a high-throughput, unbiased kinase activity profiling strategy, MC-LR-induced phosphorylation events were compared with potential inhibitors, and doramapimod was found to effectively prevent MC-LR-induced inflammatory responses in macrophages.
Adjuvant endocrine therapy (AET) reduces breast cancer recurrence and mortality in women with early-stage breast cancer. Unintentional nonadherence to AET is common (eg, forgetting to take ...medication). Forming habits surrounding medication taking could reduce reliance on memory and improve AET adherence. SMS text messaging interventions may offer a low-cost approach for promoting medication-taking habits. To optimize the likely effectiveness of such SMS text messages, the content should be developed using a transparent approach to ensure fidelity to relevant psychological theory and with user input to increase acceptability.
This study aimed to develop a pool of brief SMS text messages promoting habit formation to support AET adherence, which are acceptable to women with breast cancer and show fidelity to theory-based behavior change techniques (BCTs).
According to published literature, we selected 6 BCTs derived from the habit formation model: action planning, habit formation, restructuring the physical environment, adding objects to the environment, prompts/cues, and self-monitoring of behavior. In study 1, behavior change experts (n=10) created messages, each based on 1 of the 6 BCTs, in a web-based workshop and rated the fidelity of the messages to the intended BCT. In study 2, women with experience of taking AET discussed the acceptability of the messages in a focus group (n=5), and the messages were refined following this. In study 3, women with breast cancer rated the acceptability of each message in a web-based survey (n=60). In study 4, additional behavior change experts rated the fidelity of the remaining messages to the intended BCT in a web-based survey (n=12). Finally, a consultant pharmacist reviewed a selection of messages to ensure that they did not contradict general medical advice.
In study 1, 189 messages were created targeting the 6 BCTs. In total, 92 messages were removed because they were repetitious, unsuitable, or >160 characters, and 3 were removed because of low fidelity (scoring <5.5/10 on a fidelity rating scale). Following study 2, we removed 13 messages considered unacceptable to our target population. In study 3, all remaining messages scored above the midpoint on an acceptability scale (1-5); therefore, no messages were removed (mean 3.9/5, SD 0.9). Following study 4, we removed 13 messages owing to low fidelity (scoring <5.5/10 on a fidelity rating scale). All the remaining messages showed fidelity to the intended BCTs (mean 7.9/10, SD 1.3). Following the pharmacist review, 2 messages were removed, and 3 were amended.
We developed a pool of 66 brief SMS text messages targeting habit formation BCTs to support AET adherence. These showed acceptability to women with breast cancer and fidelity to the intended BCTs. The delivery of the messages will be further evaluated to assess their effect on medication adherence.
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