Consequences of the ‘Legs at odd angles’ mutation within the motor protein dynein and its possible implications in neurological disease

Cytoplasmic dynein is a retrograde motor protein complex that carries cargo such as organelles and growth factors along microtubules from the cell periphery towards the peri-nuclear region. The cytoplasmic dynein complex is centred around two homodimerised heavy chains, within which multiple mutations have been identified in human neurological diseases. The ‘Legs at odd angles’ (Loa) mouse has a missense ‘T’ to ‘A’ point mutation in the cytoplasmic dynein heavy chain gene (Dync1h1), resulting in a phenylalanine to tyrosine substitution at position 580. Mice homozygous for this mutation die within 24 hours of birth whilst heterozygote’s manifest an age-related and progressive neurodegeneration. Fixed and live-cell microscopy shows aberrant movement of endocytosed growth factors in Loa. Retrograde speed is reduced with a distinct lack of the fastest moving carriers. Moreover, the overall pattern of movement is altered with increased anterograde and side-steps occurring in Loa. Impaired endosomal trafficking of growth factors for degradation prolongs the activation of extracellular signal related kinases 1 and 2 (ERK 1/2) and increases the expression of the immediate early gene c-Fos in mouse embryonic fibroblasts. Motor neurons also show increased levels c-Fos however this can be induced by starvation, indicating their enhanced susceptibility to stress. The light chain (KLC) of dynein’s opposing motor - kinesin is one of many genes differentially expressed in Loa compared to wild-type. In addition, associations of KLC with the dynein complex is altered in Loa. Similarities between human neurological diseases and Loa both at the organism and cellular level make Loa a valuable tool towards understanding cellular mechanisms fundamental to the process of disease. Through understanding comes advancement towards therapeutic targets to improve the lives of thousands of people worldwide

D-Shape: Demonstration-Shaped Reinforcement Learning via Goal Conditioning

While combining imitation learning (IL) and reinforcement learning (RL) is a promising way to address poor sample efficiency in autonomous behavior acquisition, methods that do so typically assume that the requisite behavior demonstrations are provided by an expert that behaves optimally with respect to a task reward. If, however, suboptimal demonstrations are provided, a fundamental challenge appears in that the demonstration-matching objective of IL conflicts with the return-maximization objective of RL. This paper introduces D-Shape, a new method for combining IL and RL that uses ideas from reward shaping and goal-conditioned RL to resolve the above conflict. D-Shape allows learning from suboptimal demonstrations while retaining the ability to find the optimal policy with respect to the task reward. We experimentally validate D-Shape in sparse-reward gridworld domains, showing that it both improves over RL in terms of sample efficiency and converges consistently to the optimal policy in the presence of suboptimal demonstrations

Diabetes Prevention

Introduction: Gestational diabetes mellitus (GDM) is one of the most common medical complications of pregnancy. If not treated properly, medicine is recommended = A2GDM. Both are preventable

Test–retest repeatability of the NX-16: a three-dimensional (3D) body scanner in a male cohort

© 2019, The Author(s). Purpose: Whole-body three-dimensional scanning is a tool utilised for the collection of body girths, volume, and surface area measurements. Few studies have investigated the validity and repeatability of this technology. The aim of the present study was to investigate the test retest variability of the NX-16 body scanner (NX-16, TC2, Cary, North Carolina, USA). Methods: Phase one involved the measurement of a mannequin on 300 occasions (30 scans over 10 sessions). In phase two, 13 apparently healthy male participants were recruited; each participant was scanned a total of four times (two scans over two sessions). Stature, body mass, and body fat % were obtained. Fourteen girth measurements were obtained (chest, underbust, stomach, waist, seat, hip, R/L bicep, R/L thigh, R/L mid-thigh, and R/L calf). Coefficient of variation was calculated for measurements obtained. Results: Coefficient of variation for phase one ranged from 0.0% for the R calf, to 3.3% for the L thigh measurement. For phase two, values were higher, ranging from 0.5% for calf and chest to 4.6% for thigh measurements. Conclusions: Test–retest variability of the measurements provided by the NX-16 body scanner varied according to body location. However, variability within measurements was low using a mannequin or human participant. The NX-16 body scanner (TC2, Cary, North Carolina, USA) may be a useful tool for tracking changes in body composition over time during large population studies

A qualitative exploration of older people’s lived experiences of homelessness and memory problems – stakeholder perspectives

Background: The numbers of older people experiencing both homelessness and memory problems are growing, yet their complex health, housing and care needs remain undelineated and unmet. There is a critical gap in understanding what can improve the care, support and experiences of this group. In this qualitative study we explore how stakeholders understand memory problems among older people in the context of homelessness and consider what they judge gets in the way of achieving positive outcomes. Method: We conducted reflexive thematic analysis of qualitative interviews (n = 49) using a semi-structured topic guide, with 17 older people (aged ≥ 50 years) experiencing memory problems and homelessness, 15 hostel staff and managers, and 17 health, housing and social care practitioners. We recruited participants from six homelessness hostels, one specialist care home and National Health and Local Authority Services in England. Results: We identified four overarching themes. The population is not taken seriously; multiple causes are hard to disentangle; risk of exploitation and vulnerability; and (dis)connection and social isolation. The transience and lack of stability associated with homelessness intensified the disorienting nature of memory and cognitive impairment, and those providing direct and indirect support required flexibility and persistence, with staff moving beyond traditional roles to advocate, provide care and safeguard individuals. Memory problems were perceived by frontline staff and older people to be overlooked, misinterpreted, and misattributed as being caused by alcohol use, resulting in pervasive barriers to achieving positive and desired outcomes. Conclusions: Efforts to meet the needs of older people living with memory problems and experiencing homelessness and future interventions must reflect the complexity of their lives, often in the context of long-term alcohol use and current service provision and we make suggestions as to what could be done to improve the situation

A qualitative exploration of older people's lived experiences of homelessness and memory problems - stakeholder perspectives

BACKGROUND: The numbers of older people experiencing both homelessness and memory problems are growing, yet their complex health, housing and care needs remain undelineated and unmet. There is a critical gap in understanding what can improve the care, support and experiences of this group. In this qualitative study we explore how stakeholders understand memory problems among older people in the context of homelessness and consider what they judge gets in the way of achieving positive outcomes. METHOD: We conducted reflexive thematic analysis of qualitative interviews (n = 49) using a semi-structured topic guide, with 17 older people (aged ≥ 50 years) experiencing memory problems and homelessness, 15 hostel staff and managers, and 17 health, housing and social care practitioners. We recruited participants from six homelessness hostels, one specialist care home and National Health and Local Authority Services in England. RESULTS: We identified four overarching themes. The population is not taken seriously; multiple causes are hard to disentangle; risk of exploitation and vulnerability; and (dis)connection and social isolation. The transience and lack of stability associated with homelessness intensified the disorienting nature of memory and cognitive impairment, and those providing direct and indirect support required flexibility and persistence, with staff moving beyond traditional roles to advocate, provide care and safeguard individuals. Memory problems were perceived by frontline staff and older people to be overlooked, misinterpreted, and misattributed as being caused by alcohol use, resulting in pervasive barriers to achieving positive and desired outcomes. CONCLUSIONS: Efforts to meet the needs of older people living with memory problems and experiencing homelessness and future interventions must reflect the complexity of their lives, often in the context of long-term alcohol use and current service provision and we make suggestions as to what could be done to improve the situation

Randomised controlled trial of a behaviour change physiotherapy intervention to increase physical activity following hip and knee replacement: the PEP-TALK trial

OBJECTIVE: To test the effectiveness of a behaviour change physiotherapy intervention to increase physical activity compared with usual rehabilitation after Total Hip Replacement (THR) or Total Knee Replacement (TKR). DESIGN: Multicentre, pragmatic, two-arm, open, randomised controlled, superiority trial SETTING National Health Service providers in nine English hospitals. PARTICIPANTS: 224 individuals aged >18 years, undergoing a primary THR or TKR deemed “moderately inactive” or “inactive”. INTERVENTION: Participants received either six, 30-minute, weekly, group-based exercise sessions (usual care), or the same six-weekly, group-based, exercise sessions each preceded by a 30-minute cognitive behaviour discussion group aimed at challenging barriers to physical inactivity following surgery (experimental). RANDOMISATION & BLINDING: Initial 75 participants were randomised 1:1 before changing the allocation ratio to 2:1 (experimental:usual care). Allocation was based on minimisation, stratifying on comorbidities, operation type and hospital. There was no blinding. MAIN OUTCOME MEASURES: Primary: UCLA Activity Score at 12 months. Secondary: six and 12 month assessed function, pain, self-efficacy, kinesiophobia, psychological distress and quality of life. RESULTS: Of the 1254 participants assessed for eligibility, 224 were included (139 experimental:85 usual care). Mean age was 68.4 years (standard deviation: 8.7), 63% were female, 52% underwent TKR. There was no between-group difference in UCLA score (mean difference: -0.03 (95% CI: -0.52 to 0.45, p=0.89)). There were no differences observed in any of the secondary outcomes at six or 12 months. There were no important adverse events in either group. The COVID-19 pandemic contributed to the reduced intended sample size (target 260) and reduced intervention compliance. CONCLUSIONS: There is no evidence to suggest attending usual care physiotherapy sessions plus a group-based behaviour change intervention differs to attending usual care physiotherapy alone. As the trial could not reach its intended sample size, nor a proportion of participants receive their intended rehabilitation, this should be interpreted with caution

Macrophages sustain HIV replication in vivo independently of T cells

Macrophages have long been considered to contribute to HIV infection of the CNS; however, a recent study has contradicted this early work and suggests that myeloid cells are not an in vivo source of virus production. Here, we addressed the role of macrophages in HIV infection by first analyzing monocytes isolated from viremic patients and patients undergoing antiretroviral treatment. We were unable to find viral DNA or viral outgrowth in monocytes isolated from peripheral blood. To determine whether tissue macrophages are productively infected, we used 3 different but complementary humanized mouse models. Two of these models (bone marrow/liver/thymus [BLT] mice and T cell–only mice [ToM]) have been previously described, and the third model was generated by reconstituting immunodeficient mice with human CD34+ hematopoietic stem cells that were devoid of human T cells (myeloid-only mice [MoM]) to specifically evaluate HIV replication in this population. Using MoM, we demonstrated that macrophages can sustain HIV replication in the absence of T cells; HIV-infected macrophages are distributed in various tissues including the brain; replication-competent virus can be rescued ex vivo from infected macrophages; and infected macrophages can establish de novo infection. Together, these results demonstrate that macrophages represent a genuine target for HIV infection in vivo that can sustain and transmit infection

Spartalizumab or placebo in combination with dabrafenib and trametinib in patients with BRAF\textit{BRAF}V600-mutant melanoma: exploratory biomarker analyses from a randomized phase 3 trial (COMBI-i)

BackgroundThe randomized phase 3 COMBI-i trial did not meet its primary endpoint of improved progression-free survival (PFS) with spartalizumab plus dabrafenib and trametinib (sparta-DabTram) vs placebo plus dabrafenib and trametinib (placebo-DabTram) in the overall population of patients with unresectable/metastatic $\textit{BRAF}$V600-mutant melanoma. This prespecified exploratory biomarker analysis was performed to identify subgroups that may derive greater treatment benefit from sparta-DabTram.MethodsIn COMBI-i (ClinicalTrials.gov, NCT02967692), 532 patients received spartalizumab 400 mg intravenously every 4 weeks plus dabrafenib 150 mg orally two times daily and trametinib 2 mg orally one time daily or placebo-DabTram. Baseline/on-treatment pharmacodynamic markers were assessed via flow cytometry-based immunophenotyping and plasma cytokine profiling. Baseline programmed death ligand 1 (PD-L1) status and T-cell phenotype were assessed via immunohistochemistry; $\textit{BRAF}$V600 mutation type, tumor mutational burden (TMB), and circulating tumor DNA (ctDNA) via DNA sequencing; gene expression signatures via RNA sequencing; and CD4$^{+}$/CD8$^{+}$ T-cell ratio via immunophenotyping.ResultsExtensive biomarker analyses were possible in approximately 64% to 90% of the intention-to-treat population, depending on sample availability and assay. Subgroups based on PD-L1 status/TMB or T-cell inflammation did not show significant differences in PFS benefit with sparta-DabTram vs placebo-DabTram, although T-cell inflammation was prognostic across treatment arms. Subgroups defined by $\textit{BRAF}$V600K mutation (HR 0.45 (95% CI 0.21 to 0.99)), detectable ctDNA shedding (HR 0.75 (95% CI 0.58 to 0.96)), or CD4$^{+}$/CD8$^{+}$ ratio above median (HR 0.58 (95% CI 0.40 to 0.84)) derived greater PFS benefit with sparta-DabTram vs placebo-DabTram. In a multivariate analysis, ctDNA emerged as strongly prognostic (p=0.007), while its predictive trend did not reach significance; in contrast, CD4$^{+}$/CD8$^{+}$ ratio was strongly predictive (interaction p=0.0131).ConclusionsThese results support the feasibility of large-scale comprehensive biomarker analyses in the context of a global phase 3 study. T-cell inflammation was prognostic but not predictive of sparta-DabTram benefit, as patients with high T-cell inflammation already benefit from targeted therapy alone. Baseline ctDNA shedding also emerged as a strong independent prognostic variable, with predictive trends consistent with established measures of disease burden such as lactate dehydrogenase levels. CD4$^{+}$/CD8$^{+}$ T-cell ratio was significantly predictive of PFS benefit with sparta-DabTram but requires further validation as a biomarker in melanoma. Taken together with previous observations, further study of checkpoint inhibitor plus targeted therapy combination in patients with higher disease burden may be warranted