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Monoallelic IFT140 variants causing childhood-onset autosomal dominant polycystic kidney disease
Get PDFIFT140 is a component of the intraflagellar transport-complex A involved in retrograde ciliary trafficking of proteins into primary cilia. Monoallelic IFT140 variants have been identified as an important cause of adult-onset autosomal dominant polycystic kidney disease (ADPKD), accounting for ∼2% of prevalent cases. Patients with ADPKD-IFT140 usually present in later life with small numbers of large cysts and rarely develop kidney failure. Here, we report 3 genetically resolved cases of ADPKD-IFT140 diagnosed in childhood or infancy from 3 unrelated pedigrees with ages at presentation ranging from in utero to 14 years. Each pedigree had a different familial IFT140 variant, with no evidence of a second ADPKD gene variant on whole genome sequencing. All 3 children had normal kidney function and normal blood pressure, although 1 child presented initially with a high cyst burden in utero and had impaired function on a DMSA scan. Despite the negative family history, cascade screening of first-degree relatives revealed previously undiagnosed ADPKD with features typical of adult-onset ADPKD-IFT140. Our findings highlight the need to consider IFT140 as a potential cause of childhood early-onset ADPKD and expand the phenotypic spectrum of ADPKD-IFT140
Characterising the periodontal granulation tissue using scRNAseq
Get PDFAim
To investigate the cellular composition and molecular mechanisms of periodontal granulation tissue formation using single-cell RNA sequencing (scRNA-seq), aiming to enhance the understanding of periodontal disease pathogenesis and identify potential targets for regenerative therapies.
Materials and Methods
Granulation tissue samples were collected from patients undergoing periodontal surgery (n = 3). Fresh tissues were processed into single-cell suspensions and subjected to scRNA-seq. The data were integrated and compared with existing datasets from healthy gingiva and periodontal ligament. Computational analyses were performed and validated through immunofluorescence staining.
Results
Ten distinct cell clusters were identified across the samples. Granulation tissue exhibited a higher abundance of immune cells compared to healthy tissues. A novel endothelial cell subpopulation, exclusive to granulation tissue, was discovered and characterised by NOTCH3 expression and involvement in ossification pathways. Additionally, granulation tissue fibroblast subpopulations demonstrated a progenitor-like state, characterised by extracellular matrix reorganisation and low differentiation, similar to cancer-associated fibroblasts.
Conclusion
This study identified a novel endothelial subpopulation offering new insights into the disease's pathogenesis and presenting potential targets for regenerative therapies. These findings will help advance the understanding of periodontal disease granulation tissue formation and provide information for the development of materials to modulate specific cellular pathways to improve periodontal disease management
Sotrovimab versus usual care in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial
Get PDFBackground: Sotrovimab is a neutralising monoclonal antibody targeting the SARS-CoV-2 spike protein. We aimed to evaluate the efficacy and safety of sotrovimab in the RECOVERY trial, an investigator-initiated, individually randomised, controlled, open-label, adaptive platform trial testing treatments for patients admitted to hospital with COVID-19.
Methods: Patients admitted with COVID-19 pneumonia to 107 UK hospitals were randomly assigned (1:1) to either usual care alone or usual care plus a single 1 g infusion of sotrovimab, using web-based unstratified randomisation. Participants were eligible if they were aged at least 18 years, or aged 12–17 years if weighing at least 40kg, and had confirmed COVID-19 pneumonia with no medical history that would put them at significant risk if they participated in the trial. Participants were retrospectively categorised as having a high antigen level if baseline serum SARS-CoV-2 nucleocapsid antigen was above the median concentration (the prespecified primary efficacy population), otherwise they were categorised as having a low antigen level. The primary outcome was 28-day mortality assessed by intention to treat. Safety outcomes were assessed among all participants, regardless of antigen level. Recruitment closed on March 31, 2024, when funding ended. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936).
Findings: From Jan 4, 2022, to March 19, 2024, 1723 patients were enrolled in the RECOVERY sotrovimab comparison. Of these, 828 (48%) were assigned to usual care plus sotrovimab and 895 (52%) were assigned to usual care only. Mean patient age was 70·7 years (SD 14·8) and 1033 (60%) were male. 720 (42%) patients were classified as having a high antigen level, 717 (42%) as having a low antigen level, and 286 (17%) had unknown antigen status. 1389 (81%) patients were vaccinated, 1179 (82%) of 1438 patients with known serostatus had anti-spike antibodies at randomisation, and 1021 (>99%) of 1026 patients with sequenced samples were infected with omicron variants. Among patients with a high antigen level, 82 (23%) of 355 assigned to sotrovimab versus 106 (29%) of 365 assigned usual care died within 28 days (rate ratio 0·75, 95% CI 0·56–0·99; p=0·046). In an analysis of all randomly assigned patients (regardless of antigen status), 177 (21%) of 828 patients assigned to sotrovimab versus 201 (22%) of 895 assigned to usual care died within 28 days (0·95, 0·77–1·16; p=0·60). Infusion reactions were recorded in 12 (2%) of 781 patients receiving sotrovimab. We found no difference between groups in any other safety outcome.
Interpretation: In patients admitted to hospital with COVID-19 pneumonia, sotrovimab was associated with reduced mortality in the primary analysis population who had a high serum SARS-CoV-2 antigen concentration at baseline, but not in the overall population. Treatment options for patients admitted to hospital are limited, and mortality in those receiving current standard of care was high. The emergence of high-level resistance to sotrovimab among subsequent SARS-CoV-2 variants restricts its current usefulness, but these results indicate that targeted neutralising antibody therapy could potentially still benefit some patients admitted to hospital who are at high risk of death in an era of widespread vaccination and omicron infection.
Funding: UK Research and Innovation (Medical Research Council) and National Institute for Health and Care Research
Extinction, Cut-Up:Species Revival and Literary Ecomodernism
No full textThis article examines the fantasies of species revival through the lens of William Burroughs’s literary ecomodernism—a characterization tied to his practice of the cut-up, and expanded through a reading of his late novella Ghost of Chance (1991). The first section traces Burroughs’s connection to the interdisciplinary cultures surrounding the Whole Earth Catalog (1968–71) and CoEvolution Quarterly (1974–85). The second reads de-extinction’s dreams of genetic agency through the lens of the cut-up, which helps to understand the implications of DNA’s linguistic analogy for species revival. The final section reads Ghost of Chance as a satirically misanthropic vision of species resurrection
Waiting around for Unruh
No full textHow long does a uniformly rotating observer need to interact with a quantum field in order to register an approximately thermal response due to the circular motion Unruh effect? We address this question for a massless scalar field in dimensions, defining the effective temperature via the ratio of excitation and de-excitation rates of an Unruh-DeWitt detector in the long interaction time limit. In this system, the effective temperature is known to be significantly smaller than the linear motion Unruh effect prediction when the detector's energy gap is small: the effective temperature tends to zero in the small gap limit, linearly in the gap. We show that a positive small gap temperature at long interaction times can be regained via a controlled long-time-small-gap double limit, provided the detector's coupling to the field is allowed to change sign. The resulting small gap temperature depends on the parameters of the circular motion but not on the details of the detector's switching. The results broaden the energy range for pursuing an experimental verification of the circular motion Unruh effect in analogue spacetime experiments. As a mathematical tool, we provide a new implementation of the long interaction time limit that controls in a precise way the asymptotics of both the switching function and its Fourier transform
The prevalence and burden of avoidant/restrictive food intake disorder symptoms in adults with disorders of gut-brain interaction: a population-based study
Get PDFBackground & Aims
Individuals with disorders of gut-brain interaction (DGBI) may experience avoidant/restrictive food intake disorder (ARFID) symptoms. However, extant findings have been limited to specialist neurogastroenterology clinics. We assessed the association between DGBI and ARFID within the adult general population.
Methods
A population-based Internet survey with predefined demographic quotas was conducted across the United Kingdom and the United States in 2023. The survey included the Rome IV diagnostic questionnaire for DGBI, the Nine-Item ARFID Screen, and questions regarding demographics, body mass index, nongastrointestinal somatic symptoms, anxiety and depression, quality of life, and healthcare use.
Results
In this study, 4002 adults (median age, 46 [range, 18–91] years; 50% female) completed the survey, of whom 1704 (42.6%) had symptoms compatible with at least 1 DGBI. The prevalence of ARFID-positive screens was significantly higher among participants with DGBI compared with those without DGBI (34.6% vs 19.4%; adjusted odds ratio, 1.67; 95% confidence interval, 1.43–1.94), with similar findings noted in each country. Among participants with DGBI, positive ARFID screens using the Nine-Item ARFID Screen subscale were lack of interest in eating (21.5%), sensory-based avoidance (18.1%), and fear of aversive consequences (9.9%). The presence of ARFID increased with the number of DGBI anatomic regions, ranging from 19.4% in those with no DGBI, 27.7% with DGBI in 1 region, 39.5% for DGBI in 2 regions, 50.0% for DGBI in 3 regions, and 61.4% for DGBI in 4 regions (P < .001). Individuals with DGBI plus ARFID, compared with those with DGBI alone, were significantly more likely to be underweight (7.9% vs 1.5%), have greater nongastrointestinal somatic symptoms and psychological distress, reduced mental and physical quality of life, and increased healthcare use.
Conclusions
Positive ARFID screens are common in DGBI and associated with increased general health burden. Routine screening for ARFID in DGBI will inform the multi-integrated care plan provided by clinicians, dietitians, and psychologists
The Battle for Interpretation:The 1826 Chatterton Massacre and “Riot as Denial”
No full textThis article evaluates the usefulness of Stan Cohen’s ‘techniques of denial’ (2001) for understanding how the discourse of ‘riot’ is deployed in response to accusations of state violence against those engaged in social protest. It does so through a historical case study defined by the state as a ‘riot’: the Pennine Lancashire working-class protests, and most notably, the killings at Chatterton, in April 1826. By examining how the state used techniques of historical, literal, and interpretive denial to obscure both the motivations of the protesters and the violence of the state, the article highlights the ways in which these dominant narratives uphold existing power relations. We further develop Cohen’s work by applying a dialogical lens (Bakhtin, 1981; Steinberg, 1999), which foregrounds the multivocal struggle over meaning between state and subaltern actors. In doing so, we introduce the concept of ‘dialogical acknowledgement’ – a deliberate counter-strategy to denial that affirms protestors’ narratives, reclaims historical truth, and challenges dominant frames. Conceptualising Chatterton as an essentially contested event, the article examines how campaigns and commemorative work have begun to subvert official memory and redefine the moral legitimacy of the state. Ultimately, we argue that interpretive struggles over the language of ‘riot’ are not only historical but political, shaping contemporary efforts to contest denial and restore epistemic justice
‘Better sleep, better wellbeing’: qualitative process evaluation of a hybrid, digital cognitive behavioural therapy programme for employees with sleep and emotion regulation problems
Get PDFIntroduction
Sleep and mental health problems are common across the working adult population. This process evaluation provides insight into the experiences of employees who took part in a digital intervention trial: Supporting Employees with Insomnia and Emotional Regulation Problems (SLEEP). The programme combined digital CBT for insomnia with emotion regulation. Digital content was supported by remote therapy. The objectives of this process evaluation were to explore participants' experiences of the intervention, and identify how the intervention achieved change.
Methods
Twenty-one semi-structured interviews were conducted using videoconferencing. A stratified sample of participants from within each of five cohorts of the SLEEP trial was interviewed. Thematic analysis utilized a collaborative codebook and framework approach. To conceptualize mechanisms of change, behaviour change techniques were retrospectively coded onto participant interview data.
Results
An overarching theme: ‘Better sleep, better wellbeing’ was generated, with three interlinking themes conceptualizing the process by which positive changes to sleep and wellbeing were achieved. These were: ‘Procedure: The value of therapy sessions versus digital-only’, ‘Context: Working on mental health from home during COVID-19’, and ‘Mechanisms: Practice, feedback and problem solving.’
Conclusions
Participants' experiences of SLEEP were predominantly positive and suggested a spillover effect of improved sleep on overall wellbeing. Triangulation of quantitative outcomes showed congruent improvements. Maintaining therapist contact to facilitate behaviour change throughout the programme was important. Furthermore, providing a private space for therapist calls was essential to facilitate the intervention in the workplace; an important insight for the development of digital mental health interventions intended for the workplace
Judith Shklar’s ethos of skeptical vigilance
No full textJudith Shklar’s negative brand of liberalism is sometimes thought to have little to say about the ethical character required of citizens in liberal democracies, beyond the injunction to avoid cruelty. In this article, however, we argue that Shklar’s negative liberalism prescribes four distinctively political virtues—rational empathy, a healthy apprehension of state power, self-restraining tolerance, and being a good loser—that, taken together, constitute an ethos of skeptical vigilance. We survey Shklar’s criticisms of republican and communitarian accounts of civic virtue to clarify her concerns about attempts by the liberal state to cultivate these virtues and analyze the case of passive injustice to highlight tensions between active citizenship and liberal values. We conclude with some reflections on how Shklar’s political theory attempts to persuade her readers of the importance of adopting and practicing an ethos of skeptical vigilance
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