Globally, there are now over 160 million confirmed cases of COVID-19 and more than 3 million deaths. While the majority of infected individuals recover, a significant proportion continue to ...experience symptoms and complications after their acute illness. Patients with ‘long COVID’ experience a wide range of physical and mental/psychological symptoms. Pooled prevalence data showed the 10 most prevalent reported symptoms were fatigue, shortness of breath, muscle pain, joint pain, headache, cough, chest pain, altered smell, altered taste and diarrhoea. Other common symptoms were cognitive impairment, memory loss, anxiety and sleep disorders. Beyond symptoms and complications, people with long COVID often reported impaired quality of life, mental health and employment issues. These individuals may require multidisciplinary care involving the long-term monitoring of symptoms, to identify potential complications, physical rehabilitation, mental health and social services support. Resilient healthcare systems are needed to ensure efficient and effective responses to future health challenges.
Convalescent plasma is a leading treatment for coronavirus disease 2019 (COVID-19), but there is a paucity of data identifying its therapeutic efficacy. Among 126 potential convalescent plasma ...donors, the humoral immune response was evaluated using a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus neutralization assay with Vero-E6-TMPRSS2 cells; a commercial IgG and IgA ELISA to detect the spike (S) protein S1 domain (EUROIMMUN); IgA, IgG, and IgM indirect ELISAs to detect the full-length S protein or S receptor-binding domain (S-RBD); and an IgG avidity assay. We used multiple linear regression and predictive models to assess the correlations between antibody responses and demographic and clinical characteristics. IgG titers were greater than either IgM or IgA titers for S1, full-length S, and S-RBD in the overall population. Of the 126 plasma samples, 101 (80%) had detectable neutralizing antibody (nAb) titers. Using nAb titers as the reference, the IgG ELISAs confirmed 95%-98% of the nAb-positive samples, but 20%-32% of the nAb-negative samples were still IgG ELISA positive. Male sex, older age, and hospitalization for COVID-19 were associated with increased antibody responses across the serological assays. There was substantial heterogeneity in the antibody response among potential convalescent plasma donors, but sex, age, and hospitalization emerged as factors that can be used to identify individuals with a high likelihood of having strong antiviral antibody responses.
Hearing loss (HL) can affect communication in complex ways. Understanding how adults with HL reflect on and conceptualise the way they listen (metacognition) is required if interventions, and the ...outcome measures used to evaluate them, are to address barriers to functional communication arising from HL. This study describes how adults with HL experience and report the processes, behaviours, and components of listening, as presented in published studies. Systematic searches identified English-language, peer-reviewed journal articles reporting the results of qualitative or mixed-methods studies of adults' with HL perceived listening abilities. Medline, PsychInfo, Web of Science, Embase, and Google Scholar were searched from inception to November 2021. Handsearching reference lists of included studies identified additional studies for inclusion. The Critical Appraisal Skills Programme (CASP) qualitative checklist was used to appraise studies' methodological quality. Data from included studies were analysed using thematic meta-synthesis. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) Confidence in the Evidence from Reviews of QUALitative (CERQual) approach assessed confidence in the review findings. Two reviewers independently completed all screening and quality appraisal. Thematic meta-synthesis and GRADE CERQual assessment was completed by one reviewer and confirmed by a second reviewer. Discrepancies were resolved through discussion. Data from 46 studies were included in the review. Thematic meta-synthesis identified six descriptive themes: 1) perceived listening ability; 2) external modifiers; 3) psychosocial impacts of hearing loss; 4) communication partner perspectives; 5) self-efficacy for listening; and 6) cognitive load. GRADE CERQual ratings for descriptive themes ranged from low to moderate confidence. Descriptive themes were related by analytic themes of liminality and reciprocity. Adults with HL provide in-depth accounts of components and processes of listening, with studies reporting both cognitive and affective experiences consistent with theoretical models of metacognition. The findings will inform content generation for a hearing-specific patient-reported outcome measure of perceived listening ability in everyday communication.
The Krebs cycle-derived metabolite itaconate is highly upregulated in inflammatory macrophages and exerts immunomodulatory effects through cysteine modifications on target proteins. The NLRP3 ...inflammasome, which cleaves IL-1β, IL-18, and gasdermin D, must be tightly regulated to avoid excessive inflammation. Here we provide evidence that itaconate modifies NLRP3 and inhibits inflammasome activation. Itaconate and its derivative, 4-octyl itaconate (4-OI), inhibited NLRP3 inflammasome activation, but not AIM2 or NLRC4. Conversely, NLRP3 activation was increased in itaconate-depleted Irg1−/− macrophages. 4-OI inhibited the interaction between NLRP3 and NEK7, a key step in the activation process, and “dicarboxypropylated” C548 on NLRP3. Furthermore, 4-OI inhibited NLRP3-dependent IL-1β release from PBMCs isolated from cryopyrin-associated periodic syndrome (CAPS) patients, and reduced inflammation in an in vivo model of urate-induced peritonitis. Our results identify itaconate as an endogenous metabolic regulator of the NLRP3 inflammasome and describe a process that may be exploited therapeutically to alleviate inflammation in NLRP3-driven disorders.
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•Itaconate and its derivative 4-OI (which generates itaconate) block NLRP3 activation•Itaconate-depleted Irg1−/− BMDMs exhibit increased NLRP3 inflammasome activation•4-OI “dicarboxypropylates” C548 on NLRP3 and blocks the NLRP3-NEK7 interaction•4-OI reduces peritonitis in vivo and blocks IL-1β release from CAPS patient PBMCs
Hooftman et al. reveal a role for the Krebs cycle-derived metabolite itaconate in regulating the NLRP3 inflammasome. Itaconate specifically blocks NLRP3 inflammasome activation by reducing the NLRP3-NEK7 interaction, likely due to modification of C548 on NLRP3. Furthermore, itaconate inhibits IL-1β release from cells isolated from patients with the NLRP3-mediated disease CAPS.
Nanomaterials have great potential to offer effective treatment against devastating diseases by providing sustained release of high concentrations of therapeutic agents locally, especially when the ...route of administration allows for direct access to the diseased tissues. Biodegradable polyphosphoester-based polymeric micelles and shell cross-linked knedel-like nanoparticles (SCKs) have been designed from amphiphilic block-graft terpolymers, PEBP-b-PBYP-g-PEG, which effectively incorporate high concentrations of paclitaxel (PTX). Well-dispersed nanoparticles physically loaded with PTX were prepared, exhibiting desirable physiochemical characteristics. Encapsulation of 10 wt% PTX, into either micelles or SCKs, allowed for aqueous suspension of PTX at concentrations up to 4.8 mg/mL, as compared to <2.0 μg/mL for the aqueous solubility of the drug alone. Drug release studies indicated that PTX released from these nanostructures was defined through a structure–function relationship, whereby the half-life of sustained PTX release was doubled through cross-linking of the micellar structure to form SCKs. In vitro, physically loaded micellar and SCK nanotherapeutics demonstrated IC50 values against osteosarcoma cell lines, known to metastasize to the lungs (CCH-OS-O and SJSA), similar to the pharmaceutical Taxol formulation. Evaluation of these materials in vivo has provided an understanding of the effects of nanoparticle structure–function relationships on intratracheal delivery and related biodistribution and pharmacokinetics. Overall, we have demonstrated the potential of these novel nanotherapeutics toward future sustained release treatments via administration directly to the sites of lung metastases of osteosarcoma.
The safety and efficacy of ibrutinib (420 mg) in chronic lymphocytic leukemia (CLL) were evaluated in a phase 2 study; 51 patients had TP53 aberration (TP53 cohort) and 35 were enrolled because of ...age 65 years or older (elderly cohort). Both cohorts included patients with treatment-naive (TN) and relapsed/refractory (RR) CLL. With the median follow-up of 4.8 years, 49 (57.0%) of 86 patients remain on study. Treatment was discontinued for progressive disease in 20 (23.3%) patients and for adverse events in 5 (5.8%). Atrial fibrillation occurred in 18 (20.9%) patients for a rate of 6.4 per 100 patient-years. No serious bleeding occurred. The overall response rate at 6 months, the primary study endpoint, was 95.8% for the TP53 cohort (95% confidence interval, 85.7%-99.5%) and 93.9% for the elderly cohort (95% confidence interval, 79.8%-99.3%). Depth of response improved with time: at best response, 14 (29.2%) of 48 patients in the TP53 cohort and 9 (27.3%) of 33 in the elderly cohort achieved a complete response. Median minimal residual disease (MRD) in peripheral blood was 3.8 × 10−2 at 4 years, with MRD-negative (<10−4) remissions in 5 (10.2%) patients. In the TP53 cohort, the estimated 5-year progression-free survival (PFS) was 74.4% in TN-CLL compared with 19.4% in RR-CLL (P = .0002), and overall survival (OS) was 85.3% vs 53.7%, respectively (P = .023). In the elderly cohort, the estimated 5-year PFS and OS in RR-CLL were 64.8% and 71.6%, respectively, and no event occurred in TN-CLL. Long-term administration of ibrutinib was well tolerated and provided durable disease control for most patients. This trial was registered at www.clinicaltrials.gov as #NCT01500733.
•With 5-year median follow-up, continuous single-agent ibrutinib therapy was well tolerated with deepening of response.•Previously untreated patients, even those with TP53 aberration, achieved durable responses.
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Benign familial infantile epilepsy (BFIE) is a self-limited seizure disorder that occurs in infancy and has autosomal-dominant inheritance. We have identified heterozygous mutations in PRRT2, which ...encodes proline-rich transmembrane protein 2, in 14 of 17 families (82%) affected by BFIE, indicating that PRRT2 mutations are the most frequent cause of this disorder. We also report PRRT2 mutations in five of six (83%) families affected by infantile convulsions and choreoathetosis (ICCA) syndrome, a familial syndrome in which infantile seizures and an adolescent-onset movement disorder, paroxysmal kinesigenic choreoathetosis (PKC), co-occur. These findings show that mutations in PRRT2 cause both epilepsy and a movement disorder. Furthermore, PRRT2 mutations elicit pleiotropy in terms of both age of expression (infancy versus later childhood) and anatomical substrate (cortex versus basal ganglia).
Objective: Hearing impairment is linked to increased fatigue, yet little is known about the real-world impact of this fatigue. This qualitative study investigated the experience of daily-life fatigue ...in people with a hearing impairment.
Design: Individual face-to-face semi-structured interviews were conducted. Thematic analysis was then used to analyse the data.
Study sample: Fourteen hearing impaired participants (aged 44-70 years) who varied in terms of hearing loss, hearing aid status, age and gender.
Results: The themes and sub-themes that emerged from the transcripts were: Fatigue (effort-driven fatigue, emotion-driven fatigue, breaks and recovery, the perceived relationship between hearing impairment and fatigue, and sleep), Effort (cognitive effort and physical effort), Coping Strategies (withdrawal, avoidance and planning), Relationships and Emotions, Hearing Aid Impact.
Conclusions: The study highlights that hearing impairment-related fatigue is experienced by many but not all, and to different extents. Hearing aids were weakly linked to a beneficial effect on fatigue. In addition to the more widely researched effort-driven fatigue, participants described fatigue linked to the negative emotions related to having a hearing impairment. These findings, in conjunction with the widespread utilisation of different coping strategies, demonstrate that the experience of fatigue is varied and likely dependent on personal factors and lifestyle.
In this article, we examine ecological validity in hearing science from a qualitative methodological perspective. We present an overview of qualitative methods, presenting their key characteristics ...and contrasting these techniques with quantitative approaches to enquiry. We argue that ecological validity sits at the heart of the qualitative paradigm and seek to clearly emphasize the methodological gap that could be effectively filled by qualitative or mixed methods. In doing so, we discuss qualitative methods that may work particularly well in enhancing ecological validity in hearing science and explore their range of applications in this field. These approaches can be applied to a wide range of hearing health research questions to present a unique understanding of people’s experiences of disease and disability, indicating gradations of personal health and illness in nuanced ways. We acknowledge and commend the current expansion of qualitative methods within hearing science and present recommendations for increasing ecological validity, both in the design of future studies and in the context of the wider research cycle. We call on qualitative researchers to strive for transparency, rigor, and trustworthiness and highlight challenges to be overcome if qualitative methods are to contribute to effective, efficient research strategies. To facilitate the transference of high-quality research findings into practice, we stress the need for joined-up working to create a research culture that promotes coproduction of ecologically valid research designs, involving not only hearing researchers but also implementation scientists, hearing healthcare professionals and, most importantly, people with hearing loss for whom these efforts could make a difference.
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