Feasibility of a randomized controlled trial of functional strength training for people between six months and five years after stroke: FeSTivaLS trial

Background: Functional Strength Training (FST) could enhance recovery late after stroke. The aim of this study was to evaluate the feasibility of a subsequent fully powered, randomized controlled trial. Methods: The study was designed as a randomized, observer-blind trial. Both interventions were provided for up to one hour a day, four days a week, for six weeks. Evaluation points were before randomization (baseline), after six weeks intervention (outcome), and six weeks thereafter (follow-up). The study took place in participants’ own homes. Participants (n = 52) were a mean of 24.4 months after stroke with a mean age of 68.3 years with 67.3% male. All had difficulty using their paretic upper (UL) and lower limb (LL). Participants were allocated to FST-UL or FST-LL by an independent randomization service. The outcome measures were recruitment rate, attrition rate, practicality of recruitment strategies, occurrence of adverse reactions, acceptability of FST, and estimation of sample size for a subsequent trial. Primary clinical efficacy outcomes were the Action Research Arm Test (ARAT) and the Functional Ambulation Categories (FAC). Analysis was conducted using descriptive statistics and thematic analysis of participants’ views of FST. A power calculation used estimates of clinical efficacy variance to estimate sample size for a subsequent trial. Results: The screening process identified 1,127 stroke survivors of whom 52 (4.6%) were recruited. The recruitment rate was higher for referral from community therapists than for systematic identification of people discharged from an acute stroke unit. The attrition rate was 15.5% at the outcome and follow-up time-points. None of the participants experienced an adverse reaction. The participants who remained in the study at outcome had received 68% of the total possible amount of therapy. Participants reported that their experience of FST provided a sense of purpose and involvement and increased their confidence in performing activities. The power calculation provides estimation that 150 participants in each group will be required for a subsequent clinical trial. Conclusions: This study found that a subsequent clinical trial was feasible with modifications to the recruitment strategy to be used

Challenging Social Cognition Models of Adherence:Cycles of Discourse, Historical Bodies, and Interactional Order

Attempts to model individual beliefs as a means of predicting how people follow clinical advice have dominated adherence research, but with limited success. In this article, we challenge assumptions underlying this individualistic philosophy and propose an alternative formulation of context and its relationship with individual actions related to illness. Borrowing from Scollon and Scollon’s three elements of social action – “historical body,” “interaction order,” and “discourses in place” – we construct an alternative set of research methods and demonstrate their application with an example of a person talking about asthma management. We argue that talk- or illness-related behavior, both viewed as forms of social action, manifest themselves as an intersection of cycles of discourse, shifting as individuals move through these cycles across time and space. We finish by discussing how these dynamics of social action can be studied and how clinicians might use this understanding when negotiating treatment with patients

The hVPS34-SGK3 pathway counteracts inhibition of the PI3K-Akt to maintain mTORC1 and tumour growth

We explore mechanisms that enable cancer cells to tolerate PI3K or Akt inhibitors. Prolonged treatment of breast cancer cells with PI3K or Akt inhibitors leads to increased expression and activation of a kinase termed SGK3 that is related to Akt. Under these conditions, SGK3 is controlled by hVps34 that generates PtdIns(3)P, which binds to the PX domain of SGK3 promoting phosphorylation and activation by its upstream PDK1 activator. Furthermore, under conditions of prolonged PI3K/Akt pathway inhibition, SGK3 substitutes for Akt by phosphorylating TSC2 to activate mTORC1. We characterise 14h, a compound that inhibits both SGK3 activity and activation in vivo, and show that a combination of Akt and SGK inhibitors induced marked regression of BT‐474 breast cancer cell‐derived tumours in a xenograft model. Finally, we present the kinome‐wide analysis of mRNA expression dynamics induced by PI3K/Akt inhibition. Our findings highlight the importance of the hVps34‐SGK3 pathway and suggest it represents a mechanism to counteract inhibition of PI3K/Akt signalling. The data support the potential of targeting both Akt and SGK as a cancer therapeutic

Phosphorylation by Akt within the ST loop of AMPK-α1 down-regulates its activation in tumour cells

The insulin/IGF-1 (insulin-like growth factor 1)-activated protein kinase Akt (also known as protein kinase B) phosphorylates Ser(487) in the ‘ST loop’ (serine/threonine-rich loop) within the C-terminal domain of AMPK-α1 (AMP-activated protein kinase-α1), leading to inhibition of phosphorylation by upstream kinases at the activating site, Thr(172). Surprisingly, the equivalent site on AMPK-α2, Ser(491), is not an Akt target and is modified instead by autophosphorylation. Stimulation of HEK (human embryonic kidney)-293 cells with IGF-1 caused reduced subsequent Thr(172) phosphorylation and activation of AMPK-α1 in response to the activator A769662 and the Ca(2+) ionophore A23187, effects we show to be dependent on Akt activation and Ser(487) phosphorylation. Consistent with this, in three PTEN (phosphatase and tensin homologue deleted on chromosome 10)-null tumour cell lines (in which the lipid phosphatase PTEN that normally restrains the Akt pathway is absent and Akt is thus hyperactivated), AMPK was resistant to activation by A769662. However, full AMPK activation could be restored by pharmacological inhibition of Akt, or by re-expression of active PTEN. We also show that inhibition of Thr(172) phosphorylation is due to interaction of the phosphorylated ST loop with basic side chains within the αC-helix of the kinase domain. Our findings reveal that a previously unrecognized effect of hyperactivation of Akt in tumour cells is to restrain activation of the LKB1 (liver kinase B1)–AMPK pathway, which would otherwise inhibit cell growth and proliferation

Induction of labour care in the UK : a cross-sectional survey of maternity units

Objectives: To explore local induction of labour pathways in the UK National Health Service to provide insight into current practice. Design: National survey. Setting: Hospital maternity services in all four nations of the UK. Sample: Convenience sample of 71 UK maternity units. Methods: An online cross-sectional survey was disseminated and completed via a national network of obstetrics and gynaecology specialist trainees (October 2021-March 2022). Results were analysed descriptively, with associations explored using Fisher’s Exact and ANOVA. Main outcome measures: Induction rates, criteria, processes, delays, incidents, safety concerns. Results: 54/71 units responded (76%, 35% of UK units). Induction rate range 19.2%-53.4%, median 36.3%. 72% (39/54) had agreed induction criteria: these varied widely and were not all in national guidance. Multidisciplinary booking decision-making was not reported by 38/54 (70%). Delays reported ‘often/always’ in hospital admission for induction (19%, 10/54) and Delivery Suite transfer once induction in progress (63%, 34/54). Staffing was frequently reported cause of delay (76%, 41/54 ‘often/always’). Delays triggered incident reports in 36/54 (67%) and resulted in harm in 3/54 (6%). Induction was an area of concern (44%, 24/54); 61% (33/54) reported induction-focused quality improvement work. Conclusions: There is substantial variation in induction rates, processes and policies across UK maternity services. Delays appear to be common and are a cause of safety concerns. With induction rates likely to increase, improved guidance and pathways are critically needed to improve safety and experience of care

Hermansky-Pudlak syndrome type 1 causes impaired anti-microbial immunity and inflammation due to dysregulated immunometabolism

Hermansky-Pudlak syndrome (HPS) types 1 and 4 are caused by defective vesicle trafficking. The mechanism for Crohn's disease-like inflammation, lung fibrosis, and macrophage lipid accumulation in these patients remains enigmatic. The aim of this study is to understand the cellular basis of inflammation in HPS-1. We performed mass cytometry, proteomic and transcriptomic analyses to investigate peripheral blood cells and serum of HPS-1 patients. Using spatial transcriptomics, granuloma-associated signatures in the tissue of an HPS-1 patient with granulomatous colitis were dissected. In vitro studies were conducted to investigate anti-microbial responses of HPS-1 patient macrophages and cell lines. Monocytes of HPS-1 patients exhibit an inflammatory phenotype associated with dysregulated TNF, IL-1α, OSM in serum, and monocyte-derived macrophages. Inflammatory macrophages accumulate in the intestine and granuloma-associated macrophages in HPS-1 show transcriptional signatures suggestive of a lipid storage and metabolic defect. We show that HPS1 deficiency leads to an altered metabolic program and Rab32-dependent amplified mTOR signaling, facilitated by the accumulation of mTOR on lysosomes. This pathogenic mechanism translates into aberrant bacterial clearance, which can be rescued with mTORC1 inhibition. Rab32-mediated mTOR signaling acts as an immuno-metabolic checkpoint, adding to the evidence that defective bioenergetics can drive hampered anti-microbial activity and contribute to inflammation

Cost-utility analysis of adding abiraterone acetate plus prednisone/prednisolone to long-term hormone therapy in newly diagnosed advanced prostate cancer in England: Lifetime decision model based on STAMPEDE trial data

Adding abiraterone acetate (AA) plus prednisolone (P) to standard of care (SOC) improves survival in newly diagnosed advanced prostate cancer (PC) patients starting hormone therapy. Our objective was to determine the value for money to the English National Health Service (NHS) of adding AAP to SOC. We used a decision analytic model to evaluate cost-effectiveness of providing AAP in the English NHS. Between 2011-2014, the STAMPEDE trial recruited 1917 men with high-risk localised, locally advanced, recurrent or metastatic PC starting first-line androgen-deprivation therapy (ADT), and they were randomised to receive SOC plus AAP, or SOC alone. Lifetime costs and quality-adjusted life-years (QALYs) were estimated using STAMPEDE trial data supplemented with literature data where necessary, adjusting for baseline patient and disease characteristics. British National Formulary (BNF) prices (£98/day) were applied for AAP. Costs and outcomes were discounted at 3.5%/year. AAP was not cost-effective. The incremental cost-effectiveness ratio (ICER) was £149,748/QALY gained in the non-metastatic (M0) subgroup, with 2.4% probability of being cost-effective at NICE's £30,000/QALY threshold; and the metastatic (M1) subgroup had an ICER of £47,503/QALY gained, with 12.0% probability of being cost-effective. Scenario analysis suggested AAP could be cost-effective in M1 patients if priced below £62/day, or below £28/day in the M0 subgroup. AAP could dominate SOC in the M0 subgroup with price below £11/day. AAP is effective for non-metastatic and metastatic disease but is not cost-effective when using the BNF price. AAP currently only has UK approval for use in a subset of M1 patients. The actual price currently paid by the English NHS for abiraterone acetate is unknown. Broadening AAP's indication and having a daily cost below the thresholds described above is recommended, given AAP improves survival in both subgroups and its cost-saving potential in M0 subgroup

The body unbound: ritual scarification and autobiographical forms in Wole Soyinka’s Aké: the years of childhood

The scarification in Aké is invested with major significance apropos Soyinka’s ideas on African subjectivity. Scarification among the Yoruba is one of the rites of passage associated with personal development. Scarification literally and metaphorically “opens” the person up socially and cosmically. Personal formation and self-realization are enabled by the Yoruba social code brought into being by its mythology. The meaning of the scarification incident in Aké is profoundly different. Determined by the form of autobiography which creates a self-constituting subject, the enabling Yoruba sociocultural context is elided. The story of Soyinka’s personal development is allegorical of the story of the development of the modern African subject. For Soyinka, the African subject is a rational subject whose constitution precludes the splitting of the scientific and spiritual which is a consequence of the Cartesian rupture. The African subject should be open to other subjects and the object world. Subjectivity constituted by the autobiographical mode closes off the opening up symbolically signalled by scarification.Web of Scienc