The loops facing the active site of prolyl oligopeptidase are crucial components in substrate gating and specificity

Prolyl oligopeptidase (POP) has emerged as a drug target for neurological diseases. A flexible loop structure comprising loop A (res. 189–209) and loop B (res. 577–608) at the domain interface is implicated in substrate entry to the active site. Here we determined kinetic and structural properties of POP with mutations in loop A, loop B, and in two additional flexible loops (the catalytic His loop, propeller Asp/Glu loop). POP lacking loop A proved to be an inefficient enzyme, as did POP with a mutation in loop B (T590C). Both variants displayed an altered substrate preference profile, with reduced ligand binding capacity. Conversely, the T202C mutation increased the flexibility of loop A, enhancing the catalytic efficiency beyond that of the native enzyme. The T590C mutation in loop B increased the preference for shorter peptides, indicating a role in substrate gating. Loop A and the His loop are disordered in the H680A mutant crystal structure, as seen in previous bacterial POP structures, implying coordinated structural dynamics of these loops. Unlike native POP, variants with a malfunctioning loop A were not inhibited by a 17-mer peptide that may bind non-productively to an exosite involving loop A. Biophysical studies suggest a predominantly closed resting state for POP with higher flexibility at the physiological temperature. The flexible loop A, loop B and His loop system at the active site is the main regulator of substrate gating and specificity and represents a new inhibitor target

The effect of chair-based exercise on physical function in older adults: a systematic review and meta-analysis

Physical activity is an important determinant of health in later life. The public health restrictions in response to COVID-19 have interrupted habitual physical activity behaviours in older adults. In response, numerous exercise programmes have been developed for older adults, many involving chair-based exercise. The aim of this systematic review was to synthesise the effects of chair-based exercise on the health of older adults. Ovid Medline, EMBASE, CINAHL, AMED, PyscInfo and SPORTDiscus databases were searched from inception to 1 April 2020. Chair-based exercise programmes in adults ≥50 years, lasting for at least 2 weeks and measuring the impact on physical function were included. Risk of bias of included studies were assessed using Cochrane risk of bias tool v2. Intervention content was described using TiDieR Criteria. Where sufficient studies (≥3 studies) reported data on an outcome, a random effects meta-analysis was performed. In total, 25 studies were included, with 19 studies in the meta-analyses. Seventeen studies had a low risk of bias and five had a high risk of bias. In this systematic review including 1388 participants, results demonstrated that chair-based exercise programmes improve upper extremity (handgrip strength: MD = 2.10; 95%CI = 0.76, 3.43 and 30 s arm curl test: MD = 2.82; 95%CI = 1.34, 4.31) and lower extremity function (30 s chair stand: MD 2.25; 95%CI = 0.64, 3.86). The findings suggest that chair-based exercises are effective and should be promoted as simple and easily implemented activities to maintain and develop strength for older adults

Peer-led walking programme to increase physical activity in inactive 60- to 70-year-olds: Walk with Me pilot RCT

Background Levels of physical activity decline with age. Some of the most disadvantaged individuals in society, such as those with a lower rather than a higher socioeconomic position, are also the most inactive. Peer-led physical activity interventions may offer a model to increase physical activity in these older adults and thus help reduce associated health inequalities. This study aims to develop and test the feasibility of a peer-led, multicomponent physical activity intervention in socioeconomically disadvantaged community-dwelling older adults. Objectives The study aimed to develop a peer-led intervention through a rapid review of previous peer-led interventions and interviews with members of the target population. A proposed protocol to evaluate its effectiveness was tested in a pilot randomised controlled trial (RCT). Design A rapid review of the literature and the pilot study informed the intervention design; a pilot RCT included a process evaluation of intervention delivery. Setting Socioeconomically disadvantaged communities in the South Eastern Health and Social Care Trust and the Northern Health and Social Care Trust in Northern Ireland. Participants Fifty adults aged 60–70 years, with low levels of physical activity, living in socioeconomically disadvantaged communities, recruited though community organisations and general practices. Interventions ‘Walk with Me’ is a 12-week peer-led walking intervention based on social cognitive theory. Participants met weekly with peer mentors. During the initial period (weeks 1–4), each intervention group participant wore a pedometer and set weekly step goals with their mentor’s support. During weeks 5–8 participants and mentors met regularly to walk and discuss step goals and barriers to increasing physical activity. In the final phase (weeks 9–12), participants and mentors continued to set step goals and planned activities to maintain their activity levels beyond the intervention period. The control group received only an information booklet on active ageing. Main outcome measures Rates of recruitment, retention of participants and completeness of the primary outcome [moderate- and vigorous-intensity physical activity measured using an ActiGraph GT3X+ accelerometer (ActiGraph, LLC, Pensacola, FL, USA) at baseline, 12 weeks (post intervention) and 6 months]; acceptability assessed through interviews with participants and mentors. Results The study planned to recruit 60 participants. In fact, 50 eligible individuals participated, of whom 66% (33/50) were female and 80% (40/50) were recruited from general practices. At 6 months, 86% (43/50) attended for review, 93% (40/43) of whom returned valid accelerometer data. Intervention fidelity was assessed by using weekly step diaries, which were completed by both mentors and participants for all 12 weeks, and checklists for the level of delivery of intervention components, which was high for the first 3 weeks (range 49–83%). However, the rate of return of checklists by both mentors and participants diminished thereafter. Outcome data indicate that a sample size of 214 is required for a definitive trial. Limitations The sample was predominantly female and somewhat active. Conclusions The ‘Walk with Me’ intervention is acceptable to a socioeconomically disadvantaged community of older adults and a definitive RCT to evaluate its effectiveness is feasible. Some modifications are required to ensure fidelity of intervention delivery is optimised. Future research needs to identify methods to recruit males and less active older adults into physical activity interventions

Complications and reoperations of the SB Charité lumbar disc prosthesis: experience in 75 patients

Artificial disc prosthesis show fair to good short- and mid-term results. Long-term results are becoming apparent now, however, the incidence of late complications with this procedure remain poorly understood. In this report we will analyse late complications and discuss our experiences with salvage operations in patients with persistent pain after SB Charité disc prosthesis implantation. Seventy-five patients with persistent leg and back pain after insertion of an artificial disc prosthesis were enrolled in the study. In this negative selection frequently occurring late-complications were subsidence, wear, adjacent disc degeneration, facet joint degeneration and migration. In 15 patients we performed a posterior fusion without disc removal, and in 22 patients we removed 26 prostheses and performed a posterior and anterior fusion. The visual analogue scale (VAS) and Oswestry were examined before the salvage operation and after a follow-up period of at least 1 year, which is not yet available in all patients. The VAS and Oswestry decreased in the posterior group (n = 10) respectively from 8.0 (SD 0.9) to 6.3 (SD 2.1) and from 57.0 (SD 17.0) to 44.6 (SD 20.4); and in the disc removal group (n = 14) respectively from 8.0 (SD 0.9) to 5.6 (SD 2.7) and from 56.3 (SD 14.0) to 43.0 (SD 20.7). Serious late complications may occur following total disc replacement. Removal of the SB Charité artificial disc is feasible but with inherent risks. Removal of the disc prosthesis gives slightly better results than posterior fusion alone after a follow-up of at least 1 year

Idarubicin dose escalation during consolidation therapy for adult acute myeloid leukemia

Purpose Higher doses of the anthracycline daunorubicin during induction therapy for acute myeloid leukemia (AML) have been shown to improve remission rates and survival. We hypothesized that improvements in outcomes in adult AML may be further achieved by increased anthracycline dose during consolidation therapy. Patients and Methods Patients with AML in complete remission after induction therapy were randomly assigned to receive two cycles of consolidation therapy with cytarabine 100 mg/m daily for 5 days, etoposide 75 mg/m daily for 5 days, and idarubicin 9 mg/m daily for either 2 or 3 days (standard and intensive arms, respectively). The primary end point was leukemia-free survival (LFS). Results Two hundred ninety-three patients 16 to 60 years of age, excluding those with core binding factor AML and acute promyelocytic leukemia, were randomly assigned to treatment groups (146 to the standard arm and 147 to the intensive arm). Both groups were balanced for age, karyotypic risk, and FLT3–internal tandem duplication and NPM1 gene mutations. One hundred twenty patients in the standard arm (82%) and 95 patients in the intensive arm (65%) completed planned consolidation (P, .001). Durations of severe neutropenia and thrombocytopenia were prolonged in the intensive arm, but there were no differences in serious nonhematological toxicities. With a median follow-up of 5.3 years (range, 0.6 to 9.9 years), there was a statistically significant improvement in LFS in the intensive arm compared with the standard arm (3-year LFS, 47% [95% CI, 40% to 56%] v 35% [95% CI, 28% to 44%]; P = .045). At 5 years, the overall survival rate was 57% in the intensive arm and 47% in the standard arm (P = .092). There was no evidence of selective benefit of intensive consolidation within the cytogenetic or FLT3–internal tandem duplication and NPM1 gene mutation subgroups. Conclusion An increased cumulative dose of idarubicin during consolidation therapy for adult AML resulted in improved LFS, without increased nonhematologic toxicity

Implementing peer review of teaching: a guide for dental educators

Peer review of teaching (PRT) is well established and valued within higher education. Increasingly, dental educators involved in undergraduate or postgraduate teaching are required to undertake PRT as part of their teaching development. Despite this, there is a paucity of literature relating to PRT within dental education, and none that considers the implementation of PRT within large dental teaching establishments. This article describes in detail a staged process for the planning and implementation of PRT within a UK dental school. It uses relevant educational literature to supplement the authors' experiences and recommendations. By highlighting aspects of the process which are key to successful implementation, it is a useful guide for all dental educator teams who wish to successfully introduce, restructure or refresh a PRT scheme

Is Physical Activity Associated With Loneliness or Social Isolation In Older Adults? Results of a longitudinal analysis using the TILDA Study

Social relationships are central to the health and well-being of older adults. Evidence exploring the association of physical activity (PA) with social isolation and loneliness is limited. This study uses a path analysis to investigate the longitudinal association between loneliness and social isolation with PA using the Irish Longitudinal Study on Ageing. Higher levels of social isolation measured using the Berkman–Syme Social Network Index were directly and indirectly associated with lower levels of walking, moderate PA, and vigorous PA over 6 years. Additionally, higher levels of walking were associated with lower levels of loneliness measured using a modified version of the University of California, Los Angeles loneliness scale over a 3-year period. Future interventions should target individuals who are more socially isolated and explore the effects of different types of PA on loneliness over time

Examination of CD302 as a potential therapeutic target for acute myeloid leukemia.

Acute myeloid leukemia (AML) is the most common form of adult acute leukemia with ~20,000 new cases yearly. The disease develops in people of all ages, but is more prominent in the elderly, who due to limited treatment options, have poor overall survival rates. Monoclonal antibodies (mAb) targeting specific cell surface molecules have proven to be safe and effective in different haematological malignancies. However, AML target molecules are currently limited so discovery of new targets would be highly beneficial to patients. We examined the C-type lectin receptor CD302 as a potential therapeutic target for AML due to its selective expression in myeloid immune populations. In a cohort of 33 AML patients with varied morphological and karyotypic classifications, 88% were found to express CD302 on the surface of blasts and 80% on the surface of CD34+ CD38- population enriched with leukemic stem cells. A mAb targeting human CD302 was effective in mediating antibody dependent cell cytotoxicity and was internalised, making it amenable to toxin conjugation. Targeting CD302 with antibody limited in vivo engraftment of the leukemic cell line HL-60 in NOD/SCID mice. While CD302 was expressed in a hepatic cell line, HepG2, this molecule was not detected on the surface of HepG2, nor could HepG2 be killed using a CD302 antibody-drug conjugate. Expression was however found on the surface of haematopoietic stem cells suggesting that targeting CD302 would be most effective prior to haematopoietic transplantation. These studies provide the foundation for examining CD302 as a potential therapeutic target for AML