The efficacy of gemcitabine and docetaxel chemotherapy for the treatment of relapsed and refractory osteosarcoma: A systematic review and pre-clinical study.

INTRODUCTION: Osteosarcoma is the most common primary malignancy of the bone. There is a lack of effective treatments for patients who experience relapsed osteosarcoma. One treatment for relapsed patients is gemcitabine and docetaxel combination chemotherapy (GEMDOX). This systematic review aimed to establish the efficacy of this chemotherapy regimen, as well as identify the common severe toxicities that are associated with it. Resistant osteosarcoma cell lines developed from MG-63 and HOS-143B were used to represent relapsed osteosarcoma patients in a pre-clinical study. RESULTS: We identified 11 retrospective and Phase II studies that were suitable for inclusion in our review. 10.65% of patients had a response to gemcitabine and docetaxel combination therapy and the disease control rate was 35% (n = 197). 36%, 35.3% and 18.04% of patients experienced grade 3 or 4 neutropenia, thrombocytopenia and anaemia respectively (n = 133). Male patients (X2 = 9.14, p < 0.05) and those below the age of 18 (X 2 = 10.94, p < 0.05) responded better to GEMDOX treatment than females and patients older than 18 years. The resistant osteosarcoma cell lines remained sensitive to either single-agent gemcitabine, docetaxel, and the combination of both. Cisplatin-resistant models (MG-63/CISR8 & HOS-143B/CISR8) were the most responsive to GEMDOX treatment compared to doxorubicin, methotrexate, and triple-combination resistant models. CONCLUSION: GEMDOX treatment has potential efficacy in relapsed osteosarcoma patients especially those with cisplatin resistance. To directly compare the efficacy of GEMDOX therapy against other therapies randomised phase III clinical trials with adequate patient follow up must be performed to improve treatment options for osteosarcoma.

What makes a multidisciplinary medication review and deprescribing intervention for older people work well in primary care? A realist review and synthesis.

BACKGROUND: A third of older people take five or more regular medications (polypharmacy). Conducting medication reviews in primary care is key to identify and reduce/ stop inappropriate medications (deprescribing). Recent recommendations for effective deprescribing include shared-decision making and a multidisciplinary approach. Our aim was to understand when, why, and how interventions for medication review and deprescribing in primary care involving multidisciplinary teams (MDTs) work (or do not work) for older people. METHODS: A realist synthesis following the Realist And Meta-narrative Evidence Syntheses: Evolving Standards guidelines was completed. A scoping literature review informed the generation of an initial programme theory. Systematic searches of different databases were conducted, and documents screened for eligibility, with data extracted based on a Context, Mechanisms, Outcome (CMO) configuration to develop further our programme theory. Documents were appraised based on assessments of relevance and rigour. A Stakeholder consultation with 26 primary care health care professionals (HCPs), 10 patients and three informal carers was conducted to test and refine the programme theory. Data synthesis was underpinned by Normalisation Process Theory to identify key mechanisms to enhance the implementation of MDT medication review and deprescribing in primary care. FINDINGS: A total of 2821 abstracts and 175 full-text documents were assessed for eligibility, with 28 included. Analysis of documents alongside stakeholder consultation outlined 33 CMO configurations categorised under four themes: 1) HCPs roles, responsibilities and relationships; 2) HCPs training and education; 3) the format and process of the medication review 4) involvement and education of patients and informal carers. A number of key mechanisms were identified including clearly defined roles and good communication between MDT members, integration of pharmacists in the team, simulation-based training or team building training, targeting high-risk patients, using deprescribing tools and drawing on expertise of other HCPs (e.g., nurses and frailty practitioners), involving patents and carers in the process, starting with 'quick wins', offering deprescribing as 'drug holidays', and ensuring appropriate and tailored follow-up plans that allow continuity of care and management. CONCLUSION: We identified key mechanisms that could inform the design of future interventions and services that successfully embed deprescribing in primary care.

A Machine Learning-Based Image Segmentation Method to Quantify In Vitro Osteoclast Culture Endpoints.

Quantification of in vitro osteoclast cultures (e.g. cell number) often relies on manual counting methods. These approaches are labour intensive, time consuming and result in substantial inter- and intra-user variability. This study aimed to develop and validate an automated workflow to robustly quantify in vitro osteoclast cultures. Using ilastik, a machine learning-based image analysis software, images of tartrate resistant acid phosphatase-stained mouse osteoclasts cultured on dentine discs were used to train the ilastik-based algorithm. Assessment of algorithm training showed that osteoclast numbers strongly correlated between manual- and automatically quantified values (r = 0.87). Osteoclasts were consistently faithfully segmented by the model when visually compared to the original reflective light images. The ability of this method to detect changes in osteoclast number in response to different treatments was validated using zoledronate, ticagrelor, and co-culture with MCF7 breast cancer cells. Manual and automated counting methods detected a 70% reduction (p < 0.05) in osteoclast number, when cultured with 10 nM zoledronate and a dose-dependent decrease with 1-10 µM ticagrelor (p < 0.05). Co-culture with MCF7 cells increased osteoclast number by ≥ 50% irrespective of quantification method. Overall, an automated image segmentation and analysis workflow, which consistently and sensitively identified in vitro osteoclasts, was developed. Advantages of this workflow are (1) significantly reduction in user variability of endpoint measurements (93%) and analysis time (80%); (2) detection of osteoclasts cultured on different substrates from different species; and (3) easy to use and freely available to use along with tutorial resources.

What are the modifiable factors of treatment burden and capacity among people with Parkinson's disease and their caregivers: A qualitative study.

BACKGROUND: People with long-term conditions must complete many healthcare tasks such as take medications, attend appointments, and change their lifestyle. This treatment burden and ability to manage it (capacity) is not well-researched in Parkinson's disease. OBJECTIVE: To explore and identify potentially modifiable factors contributing to treatment burden and capacity in people with Parkinson's disease and caregivers. METHODS: Semi-structured interviews with nine people with Parkinson's disease and eight caregivers recruited from Parkinson's disease clinics in England (ages 59-84 years, duration of Parkinson's disease diagnosis 1-17 years, Hoehn and Yahr (severity of Parkinson's disease) stages 1-4) were conducted. Interviews were recorded and analyzed thematically. RESULTS: Four themes of treatment burden with modifiable factors were identified: 1) Challenges with appointments and healthcare access: organizing appointments, seeking help and advice, interactions with healthcare professionals, and caregiver role during appointments; 2) Issues obtaining satisfactory information: sourcing and understanding information, and satisfaction with information provision; 3) Managing medications: getting prescriptions right, organizing polypharmacy, and autonomy to adjust treatments; and 4) Lifestyle changes: exercise, dietary changes, and financial expenses. Aspects of capacity included access to car and technology, health literacy, financial capacity, physical and mental ability, personal attributes and life circumstances, and support from social networks. CONCLUSIONS: There are potentially modifiable factors of treatment burden including addressing the frequency of appointments, improving healthcare interactions and continuity of care, improving health literacy and information provision, and reducing polypharmacy. Some changes could be implemented at individual and system levels to reduce treatment burden for people with Parkinson's and their caregivers. Recognition of these by healthcare professionals and adopting a patient-centered approach may improve health outcomes in Parkinson's disease.

Exploring the prevalence and types of fall-risk-increasing drugs among older people with upper limb fractures.

OBJECTIVES: Medications and specifically fall-risk-increasing drugs (FRIDs) are associated with increased risk of falls: reducing their prescription may improve this risk. This study explored patient characteristics associated with FRID use, prevalence and type of FRIDs and changes in their prescriptions among older people with arm fractures over 6 months. METHODS: Observational prospective study in three fracture clinics in England. Patients aged ≥65 years with a single upper limb fragility fracture were recruited. The STOPPFall tool identified the number and type of FRIDs prescribed at baseline, 3- and 6-month follow-ups. Changes in FRID prescription were categorised as discontinued, new or exchanged. KEY FINDINGS: 100 patients (median age 73 years; 80% female) were recruited. At baseline, 73% used ≥1 FRID daily (median = 2), reducing to 64% and 59% at 3 and 6 months, respectively. Those with >1 FRID prescription had a significantly higher number of co-morbidities and medications and higher rates of male gender, polypharmacy, frailty and sarcopenia. The most frequently prescribed FRIDs were antihypertensives, opioids and antidepressants. Between 0 and 3 months, 44 (60%) participants had changes to FRID prescription: 20 discontinued (opioids and antihistamines), 13 started (antidepressants) and 11 exchanged for another. Similar trends were observed at 6 months. CONCLUSION: Use of FRIDs among older people with upper limb fragility fractures was high. Although overall use decreased over time, 59% were still on ≥1 FRID at the 6-month follow-up, with trends to stop opioids and start antidepressants. Older people presenting with upper limb fractures should be offered a structured medication review to identify FRIDs for targeted deprescribing.

Establishment and Characterization of Single and Triple-Agent Resistant Osteosarcoma Cell Lines.

Two human osteosarcoma cell lines (MG-63 and HOS-143B) are developed into drug-resistant models using a short-term drug exposure and recovery in drug-free media. Cisplatin, doxorubicin, and methotrexate are used as single agents and in triple combination. The highest level of resistance to cisplatin is observed in MG-63/CISR8, doxorubicin in HOS-143B/DOXR8, and methotrexate in HOS-143B/MTXR8. The MG-63/TRIR8 and HOS-143B/TRIR8 triple-resistance models show lower levels of resistance to combination treatment and are not resistant to the drugs individually. Apoptosis assays suggest that the resistance in MG-63/TRIR8 isfrom cisplatin and methotrexate and not doxorubicin. In contrast, the resistance in HOS-143B/TRIR8 is from doxorubicin and methotrexate instead of cisplatin. Upregulation of P-glycoprotein is seen in all resistant models except those developed with single-agent methotrexate. However, P-glycoprotein is not causing resistance in all cell lines as the inhibitor elacridar only reverses the resistance of doxorubicin on MG-63/DOXR8 and HOS-143B/TRIR8. The migration of the MG-63 resistant models is significantly increased, their invasion rate tends to increase, and RT-PCR shows a switch from epithelial to mesenchymal gene signaling. In contrast, a significant decrease in migration is seen in HOS-143B resistant models with their invasion rate tending to decrease and a switch from mesenchymal to epithelial gene signaling.

Mood and physical activity are associated with appetite in hospitalised older men and women.

BACKGROUND: The anorexia of ageing is important in the development of malnutrition, frailty and sarcopenia amongst the older population and is a particular problem for hospital inpatients. This study assessed appetite-related factors in a group of hospitalised older adults, to identify potential preventive strategies. DESIGN: Cross sectional observational study. SETTING: Eleven wards in one large hospital in England. SUBJECTS: Older inpatients aged ≥70 years, admitted non-electively. METHODS: Appetite was assessed using the four-item Simplified Nutritional Appetite Questionnaire (SNAQ). Associations between SNAQ score and appetite-related factors present in the dataset were assessed in continuous analyses, including habitual physical activity, mood, medication, cognition and living circumstances. RESULTS: 200 participants, mean age of 80.7 years (SD 6.9); 40% were women. Prevalence of poor appetite was 43%. In univariate analyses, lower medication count, higher habitual physical activity and better mood were associated with higher SNAQ scores during admission. In a multivariate analysis, independent associations of higher habitual physical activity and better mood with higher SNAQ scores during hospital admission remained. CONCLUSION: In this group of older adults, better mood and higher habitual physical activity were independently associated with better appetite during hospital admission. These are potentially modifiable factors and could be targets for future research into interventions for the anorexia of ageing in the hospitalised older population.

Effect of perindopril or leucine on physical performance in older people with sarcopenia: the LACE randomized controlled trial.

BACKGROUND: This trial aimed to determine the efficacy of leucine and/or perindopril in improving physical function in older people with sarcopenia. METHODS: Placebo-controlled, parallel group, double-blind, randomized two-by-two factorial trial. We recruited adults aged ≥ 70 years with sarcopenia, defined as low gait speed (<0.8 m/s on 4 m walk) and/or low handgrip strength (women < 20 kg, men < 30 kg) plus low muscle mass (using sex and body mass index category-specific thresholds derived from normative UK BioBank data) from 14 UK centres. Eligible participants were randomized to perindopril 4 mg or placebo, and to oral leucine powder 2.5 g or placebo thrice daily. The primary outcome was the between-group difference in the short physical performance battery (SPPB) score over 12-month follow-up by repeated-measures mixed models. Results were combined with existing systematic reviews using random-effects meta-analysis to derive summary estimates of treatment efficacy. RESULTS: We screened 320 people and randomized 145 participants compared with an original target of 440 participants. For perindopril [n = 73, mean age 79 (SD 6), female sex 39 (53%), mean SPPB 7.1 (SD 2.3)] versus no perindopril [n = 72, mean age 79 (SD 6), female sex 39 (54%), mean SPPB 6.9 (SD 2.4)], median adherence to perindopril was lower (76% vs. 96%; P < 0.001). Perindopril did not improve the primary outcome [adjusted treatment effect -0.1 points (95%CI -1.2 to 1.0), P = 0.89]. No significant treatment benefit was seen for any secondary outcome including muscle mass [adjusted treatment effect -0.4 kg (95%CI -1.1 to 0.3), P = 0.27]. More adverse events occurred in the perindopril group (218 vs. 165), but falls rates were similar. For leucine [n = 72, mean age 78 (SD 6), female sex 38 (53%), mean SPPB 7.0 (SD 2.1)] versus no leucine [n = 72, mean age 79 (SD 6), female sex 40 (55%), mean SPPB 7.0 (SD 2.5)], median adherence was the same in both groups (76% vs. 76%; P = 0.99). Leucine did not improve the primary outcome [adjusted treatment effect 0.1 point (95%CI -1.0 to 1.1), P = 0.90]. No significant treatment benefit was seen for any secondary outcome including muscle mass [adjusted treatment effect -0.3 kg (95%CI -1.0 to 0.4), P = 0.47]. Meta-analysis of angiotensin converting enzyme inhibitor/angiotensin receptor blocker trials showed no clinically important treatment effect for the SPPB [between-group difference -0.1 points (95%CI -0.4 to 0.2)]. CONCLUSIONS: Neither perindopril nor leucine improved physical performance or muscle mass in this trial; meta-analysis did not find evidence of efficacy of either ACE inhibitors or leucine as treatments to improve physical performance.

Epigenome-wide association study of sarcopenia: findings from the Hertfordshire Sarcopenia Study (HSS).

BACKGROUND: Sarcopenia is the age-related loss of muscle mass, strength, and function. Epigenetic processes such as DNA methylation, which integrate both genetic and environmental exposures, have been suggested to contribute to the development of sarcopenia. This study aimed to determine whether differences in the muscle methylome are associated with sarcopenia and its component measures: grip strength, appendicular lean mass index (ALMi), and gait speed. METHODS: Using the Infinium Human MethylationEPIC BeadChip, we measured DNA methylation in vastus lateralis muscle biopsies of 83 male participants (12 with sarcopenia) with a mean (standard deviation) age of 75.7 (3.6) years from the Hertfordshire Sarcopenia Study (HSS) and Hertfordshire Sarcopenia Study extension (HSSe) and examined associations with sarcopenia and its components. Pathway, histone mark, and transcription factor enrichment of the differentially methylated CpGs (dmCpGs) were determined, and sodium bisulfite pyrosequencing was used to validate the sarcopenia-associated dmCpGs. Human primary myoblasts (n = 6) isolated from vastus lateralis muscle biopsies from male individuals from HSSe were treated with the EZH2 inhibitor GSK343 to assess how perturbations in epigenetic processes may impact myoblast differentiation and fusion, measured by PAX7 and MYHC immunocytochemistry, and mitochondrial bioenergetics determined using the Seahorse XF96. RESULTS: Sarcopenia was associated with differential methylation at 176 dmCpGs (false discovery rate ≤ 0.05) and 141 differentially methylated regions (Stouffer ≤ 0.05). The sarcopenia-associated dmCpGs were enriched in genes associated with myotube fusion (P = 1.40E-03), oxidative phosphorylation (P = 2.78E-02), and voltage-gated calcium channels (P = 1.59E-04). ALMi was associated with 71 dmCpGs, grip strength with 49 dmCpGs, and gait speed with 23 dmCpGs (false discovery rate ≤ 0.05). There was significant overlap between the dmCpGs associated with sarcopenia and ALMi (P = 3.4E-35), sarcopenia and gait speed (P = 4.78E-03), and sarcopenia and grip strength (P = 7.55E-06). There was also an over-representation of the sarcopenia, ALMi, grip strength, and gait speed-associated dmCpGs with sites of H3K27 trimethylation (all P ≤ 0.05) and amongst EZH2 target genes (all P ≤ 0.05). Furthermore, treatment of human primary myoblasts with the EZH2 inhibitor GSK343 inhibitor led to an increase in PAX7 expression (P ≤ 0.05), decreased myotube fusion (P = 0.043), and an increase in ATP production (P = 0.008), with alterations in the DNA methylation of genes involved in oxidative phosphorylation and myogenesis. CONCLUSIONS: These findings show that differences in the muscle methylome are associated with sarcopenia and individual measures of muscle mass, strength, and function in older individuals. This suggests that changes in the epigenetic regulation of genes may contribute to impaired muscle function in later life.

A systematic review of the evidence for deprescribing interventions among older people living with frailty.

BACKGROUND: Older people living with frailty are often exposed to polypharmacy and potential harm from medications. Targeted deprescribing in this population represents an important component of optimizing medication. This systematic review aims to summarise the current evidence for deprescribing among older people living with frailty. METHODS: The literature was searched using Medline, Embase, CINAHL, PsycInfo, Web of Science, and the Cochrane library up to May 2020. Interventional studies with any design or setting were included if they reported deprescribing interventions among people aged 65+ who live with frailty identified using reliable measures. The primary outcome was safety of deprescribing; whereas secondary outcomes included clinical outcomes, medication-related outcomes, feasibility, acceptability and cost-related outcomes. Narrative synthesis was used to summarise findings and study quality was assessed using Joanna Briggs Institute checklists. RESULTS: Two thousand three hundred twenty-two articles were identified and six (two randomised controlled trials) were included with 657 participants in total (mean age range 79-87 years). Studies were heterogeneous in their designs, settings and outcomes. Deprescribing interventions were pharmacist-led (n = 3) or multidisciplinary team-led (n = 3). Frailty was identified using several measures and deprescribing was implemented using either explicit or implicit tools or both. Three studies reported safety outcomes and showed no significant changes in adverse events, hospitalisation or mortality rates. Three studies reported positive impact on clinical outcomes including depression, mental health status, function and frailty; with mixed findings on falls and cognition; and no significant impact on quality of life. All studies described medication-related outcomes and reported a reduction in potentially inappropriate medications and total number of medications per-patient. Feasibility of deprescribing was reported in four studies which showed that 72-91% of recommendations made were implemented. Two studies evaluated and reported the acceptability of their interventions and further two described cost saving. CONCLUSION: There is a paucity of research about the impact of deprescribing in older people living with frailty. However, included studies suggest that deprescribing could be safe, feasible, well tolerated and can lead to important benefits. Research should now focus on understanding the impact of deprescribing on frailty status in high risk populations. TRIAL REGISTRATION: The review was registered on the international prospective register of systematic reviews (PROSPERO) ID number: CRD42019153367 .

The composition of the gut microbiome differs among community dwelling older people with good and poor appetite.

BACKGROUND: Anorexia of ageing is common and important in the development of sarcopenia in older individuals. Links have been proposed between the gut microbiota and sarcopenia. Disordered gut function is also recognized in anorexia of ageing, but how this may relate to resident gut microbiota is unexplored. Understanding this relationship may provide a basis for novel interventions for anorexia of ageing and sarcopenia. This study explores compositional differences of the gut microbiota between community dwelling healthy older adults with good or poor appetite, and associated differences in sarcopenia. METHODS: We assessed appetite by the Simplified Nutritional Appetite Questionnaire (SNAQ) in members of the TwinsUK cohort aged ≥65 years. Using a pool of 776 individuals with existing microbiome data estimated from 16S rRNA sequencing data, we identified 102 cases (SNAQ score < 14) (95% female, mean age 68 years) matched to controls (SNAQ > 14) on body mass index, gender, age, diet, calorie consumption, frailty, antibiotic use, socio-economic status, and technical variables to minimize confounding microbiota associations. Species abundance and diversity, compositional differences, and paired differences in taxa abundance were compared between cases and controls. Additionally, we compared case and controls for sarcopenia as measured by muscle mass (appendicular lean mass/height2 ) and strength (chair stand time in seconds). RESULTS: Cases with poor appetite had reduced species richness and diversity of their gut microbiome (adjusted OBSERVED: beta = -0.2, P < 0.001; adjusted SHANNON: beta = -0.17, P = 0.0135), significant compositional differences (adjusted non-parametric multivariate analysis of variance, P = 0.0095), and significant differences in taxa abundance including reduction of genus Lachnospira (logFC = -1.015, q = 0.023). In all-female subgroup analysis, cases with poor appetite demonstrated reduction in muscle strength (11.03 s vs. 9.26 s, P = 0.02). CONCLUSIONS: This study is the first to observe differences in the composition of gut microbiota between healthy community dwelling older individuals with good and poor appetite. We found female individuals with reduced muscle strength had poor appetite compared with those with normal strength. These associations require further examination to understand causality and mechanisms of interaction, to inform potential strategies targeting the gut microbiota as a novel intervention for anorexia of ageing and sarcopenia.

Mapping human serum-induced gene networks as a basis for the creation of biomimetic periosteum for bone repair.

BACKGROUND: The periosteum is a highly vascularized, collagen-rich tissue that plays a crucial role in directing bone repair. This is orchestrated primarily by its resident progenitor cell population. Indeed, preservation of periosteum integrity is critical for bone healing. Cells extracted from the periosteum retain their osteochondrogenic properties and as such are a promising basis for tissue engineering strategies for the repair of bone defects. However, the culture expansion conditions and the way in which the cells are reintroduced to the defect site are critical aspects of successful translation. Indeed, expansion in human serum and implantation on biomimetic materials has previously been shown to improve in vivo bone formation. AIM: This study aimed to develop a protocol to allow for the expansion of human periosteum derived cells (hPDCs) in a biomimetic periosteal-like environment. METHODS: The expansion conditions were defined through the investigation of the bioactive cues involved in augmenting hPDC proliferative and multipotency characteristics, based on transcriptomic analysis of cells cultured in human serum. RESULTS: Master regulators of transcriptional networks were identified, and an optimized periosteum-derived growth factor cocktail (PD-GFC; containing ß-estradiol, FGF2, TNFα, TGFß, IGF-1 and PDGF-BB) was generated. Expansion of hPDCs in PD-GFC resulted in serum mimicry with regard to the cell morphology, proliferative capacity and chondrogenic differentiation. When incorporated into a three-dimensional collagen type 1 matrix and cultured in PD-GFC, the hPDCs migrated to the surface that represented the matrix topography of the periosteum cambium layer. Furthermore, gene expression analysis revealed a down-regulated WNT and TGFß signature and an up-regulation of CREB, which may indicate the hPDCs are recreating their progenitor cell signature. CONCLUSION: This study highlights the first stage in the development of a biomimetic periosteum, which may have applications in bone repair.

Barriers and facilitators to screening and treating malnutrition in older adults living in the community: a mixed-methods synthesis.

BACKGROUND: Malnutrition (specifically undernutrition) in older, community-dwelling adults reduces well-being and predisposes to disease. Implementation of screen-and-treat policies could help to systematically detect and treat at-risk and malnourished patients. We aimed to identify barriers and facilitators to implementing malnutrition screen and treat policies in primary/community care, which barriers have been addressed and which facilitators have been successfully incorporated in existing interventions. METHOD: A data-base search was conducted using MEDLINE, Embase, PsycINFO, DARE, CINAHL, Cochrane Central and Cochrane Database of Systematic Reviews from 2012 to June 2016 to identify relevant qualitative and quantitative literature from primary/community care. Studies were included if participants were older, community-dwelling adults (65+) or healthcare professionals who would screen and treat such patients. Barriers and facilitators were extracted and mapped onto intervention features to determine whether these had addressed barriers. RESULTS: Of a total of 2182 studies identified, 21 were included (6 qualitative, 12 quantitative and 3 mixed; 14 studies targeting patients and 7 targeting healthcare professionals). Facilitators addressing a wide range of barriers were identified, yet few interventions addressed psychosocial barriers to screen-and-treat policies for patients, such as loneliness and reluctance to be screened, or healthcare professionals' reservations about prescribing oral nutritional supplements. CONCLUSION: The studies reviewed identified several barriers and facilitators and addressed some of these in intervention design, although a prominent gap appeared to be psychosocial barriers. No single included study addressed all barriers or made use of all facilitators, although this appears to be possible. Interventions aiming to implement screen-and-treat approaches to malnutrition in primary care should consider barriers that both patients and healthcare professionals may face. REVIEW REGISTRATIONS: PROSPERO: CRD42017071398 . The review protocol was registered retrospectively.

Learning from older peoples' reasons for participating in demanding, intensive epidemiological studies: a qualitative study.

BACKGROUND: Recruitment rates of older people in epidemiological studies, although relatively higher than in clinical trials, have declined in recent years. This study aimed to explore motivating factors and concerns among older participants in an intensive epidemiological study (Hertfordshire Sarcopenia Study - HSS) and identify those that could aid future recruitment to epidemiological studies and clinical trials. METHODS: Participants of the HSS fasted overnight and travelled several hours each way to the research facility at an English hospital for extensive diet/lifestyle questionnaires and investigations to assess muscle including blood tests and a muscle biopsy. We conducted semi-structured interviews with 13 participants (ten women) at the research facility in May-October 2015. The interviews were audio-taped, transcribed verbatim, coded and analysed thematically by three researchers. RESULTS: We identified personal motives for participation (potential health benefit for self and family; curiosity; comparing own fitness to others; socialising). Altruistic motives (benefit for other people; belief in importance of research) were also important. Participants voiced a number of external motives related to the study uniqueness, organisation and safety record; family support; and just 'being asked'. Anxiety about the biopsy and travel distance were the only concerns and were alleviated by smooth and efficient running of the study. CONCLUSIONS: Personal and altruistic reasons were important motivators for these older people to participate in demanding, intensive research. They valued belonging to a birth cohort with previous research experience, but personal contact with the research team before and after consent provided reassurance, aided recruitment to HSS and could be readily replicated by other researchers. Any fears or concerns related to certain aspects of a demanding, intensive study should ideally be explored at an early visit to establish a good relationship with the research team.

Human Vastus Lateralis Skeletal Muscle Biopsy Using the Weil-Blakesley Conchotome.

Percutaneous muscle biopsy using the Weil-Blakesley conchotome is well established in both clinical and research practice. It is a safe, effective and well tolerated technique. The Weil-Blakesley conchotome has a sharp biting tip with a 4 - 6 mm wide hollow. It is inserted through a 5 - 10 mm skin incision and can be maneuvered for controlled tissue penetration. The tip is opened and closed within the tissue and then rotated through 90 -180° to cut the muscle. The amount of muscle obtained following repeated sampling can vary from 20 mg to 290 mg which can be processed for both histology and molecular studies. The wound needs to be kept dry and vigorous physical activity kept to a minimum for approximately 72 hr although normal levels of activity can restart immediately following the procedure. This procedure is safe and effective when close attention is paid to the selection of subjects, full asepsis and post procedure care.  Both right and left vastus lateralis are suitable for biopsy dependent on participant preference.

Outcomes after unplanned admission to hospital in older people: ill-defined conditions as potential indicators of the frailty trajectory.

OBJECTIVES: To describe outcomes after unplanned hospital admission in older people and to determine whether disease trajectories in those admitted with ill-defined conditions (symptoms and signs) are distinct from other diagnostic groups and consistent with known disease trajectories. DESIGN: Longitudinal follow-up after a retrospective cross-sectional study of emergency admissions to general internal and geriatric medicine units in one hospital. SETTING: Acute hospital in southern England. PARTICIPANTS: All people aged 65 and older with unplanned admissions to general internal and geriatric medicine inpatient units during 2002 (N = 5,312). MEASUREMENTS: Age, sex, comorbidity, presence of cognitive and mood disorders, residence, and primary diagnostic group at discharge. Outcomes were death up to 36 months from admission, any readmission, and readmission for ill-defined conditions up to 36 months after discharge. RESULTS: There were significant differences in death rates between the diagnostic groups, with mortality being highest in individuals with a primary diagnosis of cancer and lowest in the ill-defined conditions group. Nearly 83% of the ill-defined conditions group survived the follow-up period. Adjusted Cox proportional hazard models indicated that, when age, sex, comorbidity, residence, and cognitive and mood disorders were accounted for, the ill-defined condition group had a lower risk of death but a higher risk of subsequent readmissions for ill-defined conditions than any other group. Overall readmission risk was highest for individuals admitted for a respiratory condition but was similar in all other diagnostic groups. CONCLUSION: The lower mortality risk associated with ill-defined conditions is consistent with chronic rather than acute needs, but the pattern of mortality and readmission is more consistent with the frailty than the chronic organ system failure illness trajectory, suggesting that functional support needs may be more important in this group of individuals.

The effectiveness of implementing a care pathway for femoral neck fracture in older people: a prospective controlled before and after study.

OBJECTIVES: To investigate whether a care pathway for older hip fracture patients can reduce length of stay while maintaining the quality of clinical care. DESIGN: Prospective study of patients admitted 12 months before and after implementation of a care pathway for the management of femoral neck fracture. Audit data for corresponding time periods from nearby orthopaedic units was used to control for secular trends. SETTING: Teaching hospital. SUBJECTS: Patients aged 65 years and over with a femoral neck fracture. EXCLUSION CRITERIA: multiple fractures, fractures due to malignancy, re-fracture, total hip replacement, previously entered into the study, operation performed elsewhere. Three-hundred and ninety-five (99%) and 369 (97%) case records were available for full analysis. MAIN OUTCOME MEASURES: primary outcome: length of stay on the orthopaedic unit. SECONDARY OUTCOMES: ambulation at discharge, discharge destination, in-hospital complications, 30 day mortality, readmission within 30 days of discharge, post-operative days the patient first sat out of bed and walked. RESULTS: Mean length of stay increased by 6.5 days (95% confidence interval 3.5-9.5 days, P < 0.0005) in the second period with a significant improvement in ambulation on discharge (odds ratio 1.6, 95% confidence interval 1.0-2.6, P = 0.033) and a trend towards reduction in admission to long term care (odds ratio 0.6, 95% confidence interval 0.3-1.0, P = 0.058). CONCLUSIONS: This care pathway was associated with longer hospital stay and improved clinical outcomes. Care pathways for hip fracture patients can be a useful tool for raising care standards but may require additional resources.