Barriers and facilitators to participation in exercise prehabilitation before cancer surgery for older adults with frailty: a qualitative study.

BACKGROUND: Older adults with frailty are at an increased risk of adverse outcomes after surgery. Exercise before surgery (exercise prehabilitation) may reduce adverse events and improve recovery after surgery. However, adherence with exercise therapy is often low, especially in older populations. The purpose of this study was to qualitatively assess the barriers and facilitators to participating in exercise prehabilitation from the perspective of older people with frailty participating in the intervention arm of a randomized trial. METHODS: This was a research ethics approved, nested descriptive qualitative study within a randomized controlled trial of home-based exercise prehabilitation vs. standard care with older patients (≥ 60 years) having elective cancer surgery, and who were living with frailty (Clinical Frailty Scale ≥ 4). The intervention was a home-based prehabilitation program for at least 3 weeks before surgery that involved aerobic activity, strength and stretching, and nutritional advice. After completing the prehabilitation program, participants were asked to partake in a semi-structured interview informed by the Theoretical Domains Framework (TDF). Qualitative analysis was guided by the TDF. RESULTS: Fifteen qualitative interviews were completed. Facilitators included: 1) the program being manageable and suitable to older adults with frailty, 2) adequate resources to support engagement, 3) support from others, 4) a sense of control, intrinsic value, noticing progress and improving health outcomes and 5) the program was enjoyable and facilitated by previous experience. Barriers included: 1) pre-existing conditions, fatigue and baseline fitness, 2) weather, and 3) guilt and frustration when unable to exercise. A need for individualization and variety was offered as a suggestion by participants and was therefore described as both a barrier and facilitator. CONCLUSIONS: Home-based exercise prehabilitation is feasible and acceptable to older people with frailty preparing for cancer surgery. Participants identified that a home-based program was manageable, easy to follow with helpful resources, included valuable support from the research team, and they reported self-perceived health benefits and a sense of control over their health. Future studies and implementation should consider increased personalization based on health and fitness, psychosocial support and modifications to aerobic exercises in response to adverse weather conditions.

Home-based prehabilitation with exercise to improve postoperative recovery for older adults with frailty having cancer surgery: the PREHAB randomised clinical trial.

BACKGROUND: Frailty is a state of vulnerability as a result of decreased reserves. Prehabilitation may increase reserve and improve postoperative outcomes. Our objective was to determine if home-based prehabilitation improves postoperative functional recovery in older adults with frailty having cancer surgery. METHODS: This double blind randomised trial enrolled people ≥60 yr having elective cancer surgery and ≥3 weeks from enrolment to surgery as eligible. Participation in a remotely supported, home-based exercise prehabilitation program plus nutritional guidance was compared with standard care plus written advice on age-appropriate activity and nutrition. The primary outcome was 6-min walk test (6MWT) distance at the first postoperative clinic visit. Secondary outcomes included physical performance, quality of life, disability, length of stay, non-home discharge, and 30-day readmission. RESULTS: Of 543 patients assessed, 254 were eligible and 204 (80%) were randomised (102 per arm); 182 (94 intervention and 88 control) had surgery and were analysed. Mean age was 74 yr and 57% were female. Mean duration of participation was 5 weeks, mean adherence was 61% (range 0%-100%). We found no significant difference in 6MWT at follow-up (+14 m, 95% confidence interval -26-55 m, P=0.486), or for secondary outcomes. Analyses using a prespecified adherence definition of ≥80% supported improvements in 6MWT distance, complication count, and disability. CONCLUSIONS: A home-based prehabilitation program did not significantly improve postoperative recovery or other outcomes in older adults with frailty having cancer surgery. Program adherence may be a key mediator of prehabilitation efficacy. CLINICAL TRIAL REGISTRATION: NCT02934230.

Peripheral Nerve Blocks and Potentially Attributable Adverse Events in Older People with Hip Fracture: A Retrospective Population-based Cohort Study.

BACKGROUND: Peripheral nerve blocks are being used with increasing frequency for management of hip fracture-related pain. Despite converging evidence that nerve blocks may be beneficial, safety data are lacking. This study hypothesized that peripheral nerve block receipt would not be associated with adverse events potentially attributable to nerve blocks, as well as overall patient safety incidents while in hospital. METHODS: This was a preregistered, retrospective population-based cohort study using linked administrative data. This study identified all hip fracture admissions in people 50 yr of age or older and identified all nerve blocks (although we were unable to ascertain the specific anatomic location or type of block), potentially attributable adverse events (composite of seizures, fall-related injuries, cardiac arrest, nerve injury), and any patient safety events using validated codes. The study also estimated the unadjusted and adjusted association of nerve blocks with adverse events; adjusted absolute risk differences were also calculated. RESULTS: In total, 91,563 hip fracture patients from 2009 to 2017 were identified; 15,631 (17.1%) received a nerve block, and 5,321 (5.8%; 95% CI, 5.7 to 6.0%) patients experienced a potentially nerve block-attributable adverse event: 866 (5.5%) in patients with a block and 4,455 (5.9%) without a block. Before and after adjustment, nerve blocks were not associated with potentially attributable adverse events (adjusted odds ratio, 1.05; 95% CI, 0.97 to 1.15; and adjusted risk difference, 0.3%, 95% CI, -0.1 to 0.8). CONCLUSIONS: The data suggest that nerve blocks in hip fracture patients are not associated with higher rates of potentially nerve block-attributable adverse events, although these findings may be influenced by limitations in routinely collected administrative data.

Comparison of Clerkship Directors' Expectations of Physical Examination Skills with Point-of-care Ultrasound Skills Using the RIME Framework.

Background: The expectations of point-of-care ultrasound (PoCUS) in undergraduate clerkship at the University of Ottawa has not been described. We compared clerkship directors' expectations of physical examination skills with PoCUS skills, before and after completing the clerkship rotation. Methods: A pilot-tested, expert developed, bilingual on-line survey consisting of 15 questions was sent to all clerkship directors (23) in December 2019. The survey included questions regarding the expectations of medical students with respect to physical examination and PoCUS using the RIME Framework: none, reporter, interpreter, manager, educator. Results: The response rate was 60.9% (14/23). With regards to physical exam skills, 82.8% of directors had no expectations or expected students to be reporters when starting clerkship. At graduation, 77.5% of directors expected students to be interpreters, managers, or educators. For PoCUS, 100.0% of directors had no expectations or expected students to be reporters when starting clerkship. At clerkship completion, 33.0% of directors felt that students should be interpreters or managers for PoCUS skills. Conclusions: Clerkship directors have low expectations of PoCUS skills for entering and graduating clerks when compared with their physical examination skills despite formal pre-clerkship PoCUS objectives. Enhanced communication and targeted education of directors could improve the PoCUS curriculum.

The Canadian Medical Student Ultrasound Curriculum: A Statement From the Canadian Ultrasound Consensus for Undergraduate Medical Education Group.

OBJECTIVES: This study sought to establish by expert review a consensus-based, focused ultrasound curriculum, consisting of a foundational set of focused ultrasound skills that all Canadian medical students would be expected to attain at the end of the medical school program. METHODS: An expert panel of 21 point-of-care ultrasound and educational leaders representing 15 of 17 (88%) Canadian medical schools was formed and participated in a modified Delphi consensus method. Experts anonymously rated 195 curricular elements on their appropriateness to include in a medical school curriculum using a 5-point Likert scale. The group defined consensus as 70% or more experts agreeing to include or exclude an element. We determined a priori that no more than 3 rounds of voting would be performed. RESULTS: Of the 195 curricular elements considered in the first round of voting, the group reached consensus to include 78 and exclude 24. In the second round, consensus was reached to include 4 and exclude 63 elements. In our final round, with 1 additional item added to the survey, the group reached consensus to include an additional 3 and exclude 8 elements. A total of 85 curricular elements reached consensus to be included, with 95 to be excluded. Sixteen elements did not reach consensus to be included or excluded. CONCLUSIONS: By expert opinion-based consensus, the Canadian Ultrasound Consensus for Undergraduate Medical Education Group recommends that 85 curricular elements be considered for inclusion for teaching in the Canadian medical school focused ultrasound curricula.

PREHAB study: a protocol for a prospective randomised clinical trial of exercise therapy for people living with frailty having cancer surgery.

INTRODUCTION: Exercise prehabilitation may improve outcomes after surgery. Frailty is a key predictor of adverse postoperative outcomes in older people; the multidimensional nature of frailty makes this a population who may derive substantial benefit from exercise prehabilitation. The objective of this trial is to test the efficacy of exercise prehabilitation to improve postoperative functional outcomes for people living with frailty having cancer surgery with curative intent. METHODS AND ANALYSIS: We will conduct a single-centre, parallel-arm randomised controlled trial of home-based exercise prehabilitation versus standard care among consenting patients >60 years having elective cancer surgery (intra-abdominal and intrathoracic) and who are frail (Clinical Frailty Scale >4). The intervention consists of > 3 weeks of exercise prehabilitation (strength, aerobic and stretching). The primary outcome is the 6 min walk test at the first postoperative clinic visit. Secondary outcomes include the short physical performance battery, health-related quality of life, disability-free survival, complications and health resource utilisation. The primary outcome will be analysed by intention to treat using analysis of covariance. Outcomes up to 1 year after surgery will be ascertained through linkage to administrative data. ETHICS AND DISSEMINATION: Ethical approval has been granted by our ethics review board (Protocol Approval #2016009-01H). Results will be disseminated through presentation at scientific conferences, through peer-reviewed publication, stakeholder organisations and engagement of social and traditional media. TRIAL REGISTRATION NUMBER: NCT02934230; Pre-results.

Driving and Dementia: Workshop Module on Communicating Cessation to Drive.

BACKGROUND: For persons with dementia (PWD), driving becomes very dangerous. Physicians in Canada are legally responsible to report unfit drivers and then must disclose that decision to their patients. That difficult discussion is fraught with challenges: physicians want to maintain a healthy relationship; patients often lack insight into their cognitive loss and have very strong emotional reactions to the loss of their driving privileges. All of which may stifle the exchange of accurate information. The goal of this project was to develop a multimedia module that would provide strategies and support for health professionals having these difficult conversations. METHODS: Literature search was conducted of Embase and OVID MedLine on available driving and dementia tools, and on websites of online tools for communication strategies on driving cessation. A workshop module was developed with background material, communication strategies, links to resources and two videos demonstrating the "bad" then the "good" ways of managing this emotionally charged discussion. RESULTS: When the module was tested with internal medicine trainees, results demonstrated that confidence increased significantly (p < .001), and comfort and willingness in discussing the subject improved. CONCLUSION: This project demonstrated the positive impact of the module on improving health professionals' attitude and readiness to communicate driving cessation to PWD.

Patient function and caregiver burden after ambulatory surgery: a cohort study of patients older than 65.

PURPOSE: The primary objective of this prospective cohort study was to assess the impact of ambulatory surgery on patient function one week and one month following surgery among surgical patients ≥ 65 yr of age. Secondary objectives were to determine whether changes in patient function were correlated with increased burden of care in the patient's primary caregiver and with patient assessments of postoperative pain and quality of life. METHODS: Following Research Ethics Board approval, patients aged ≥ 65 yr undergoing elective ambulatory surgery and their caregivers were recruited. Patients completed the système de mesure de l'autonomie fonctionnelle (SMAF) and the Brief Pain Inventory. Primary caregivers completed the Zarit Burden Interview (ZBI). All measurements were obtained preoperatively and on postoperative days (POD) 7 and 30. RESULTS: Patient function decreased on POD 7 and had not returned to baseline on POD 30 (mean change in SMAF 6.9; 95% confidence interval (CI) 5.3 to 8.4 on POD 7 and mean change in SMAF 2.6; 95% CI 1.3 to 4.0 on POD 30). Interval changes in caregiver burden were not significant (mean change in ZBI -0.4; 95% CI -1.8 to 0.96 on POD 7 and mean change in ZBI -0.6; 95% CI -2.1 to 0.8 on POD 30). Decreased patient function was associated with increased caregiver burden at all time points (P < 0.001). Decreased caregiver function at baseline was also associated with higher ZBI (linear association 0.71; P = 0.02). CONCLUSIONS: Patients exhibited reduced function seven days following ambulatory surgery. Patient function largely recovered by POD 30. Caregiver burden was variable and influenced by both patient and caregiver function. This trial was registered with Clinical Trials.gov (NCT01382251).

Telemedicine in a rural memory disorder clinic-remote management of patients with dementia.

BACKGROUND: There are many reasons to develop telemedicine clinics for assessment and management of dementia. Time constraints, location, and poor weather conditions can all impact on the ability of patients and providers to attend rural clinics. The utility of telemedicine in the diagnosis of dementia and subsequent follow-up appears promising in the literature, as it provides a viable means of assessing cognition in patients in remote areas with limited access to medical specialists. METHODS #ENTITYSTARTX00026; RESULTS: This study explored the feasibility of introducing a telemedicine memory disorder follow-up clinic in a rural community. The evaluation of 32 clinic sessions found high levels of satisfaction, with over 90% of physicians and patients indicating that they'd be willing to use video conferencing again. Physicians overwhelmingly felt the sessions provided enough information to assist in clinical decision-making (96%), and patients and CCAC Case Managers/Geriatric Assessors felt able to present the same information by video conferencing as in person (92% for both groups). The telemedicine clinic provided a number of favourable results such as: timely access to specialist care in the patient's own community; fewer cancelled clinics; enhanced care transitions between the follow-up clinic and primary care with the support of a case manager/geriatric assessor; and enhanced follow-up for a complex patient population. In addition, the telemedicine initiative freed up spaces for "in-person" clinics. This allowed them to focus on new patient assessments. CONCLUSIONS: The high satisfaction rates amongst all key stakeholders affirm that telemedicine is a viable option and worth continued efforts at shaping and developing, particularly in regions where local physician specialists are a scare resource.

The anti-cancer IgM monoclonal antibody PAT-SM6 binds with high avidity to the unfolded protein response regulator GRP78.

The monoclonal IgM antibody PAT-SM6 derived from human tumours induces apoptosis in tumour cells and is considered a potential anti-cancer agent. A primary target for PAT-SM6 is the unfolded protein response regulator GRP78, over-expressed externally on the cell surface of tumour cells. Small angle X-ray scattering (SAXS) studies of human GRP78 showed a two-domain dumbbell-shaped monomer, while SAXS analysis of PAT-SM6 revealed a saucer-shaped structure accommodating five-fold symmetry, consistent with previous studies of related proteins. Sedimentation velocity analysis of GRP78 and PAT-SM6 mixtures indicated weak complex formation characterized by dissociation constants in the high micromolar concentration range. In contrast, enzyme-linked immunosorbant assays (ELISAs) showed strong and specific interactions between PAT-SM6 and immobilized GRP78. The apparent binding constant estimated from a PAT-SM6 saturation curve correlated strongly with the concentration of GRP78 used to coat the microtiter tray. Experiments using polyclonal antiGRP78 IgG antibodies or a monoclonal IgG derivative of PAT-SM6 did not show a similar dependence. Competition experiments with soluble GRP78 indicated more effective inhibition of PAT-SM6 binding at low GRP78 coating concentrations. These observations suggest an avidity-based binding mechanism that depends on the multi-point attachment of PAT-SM6 to GRP78 clustered on the surface of the tray. Analysis of ELISA data at high GRP78 coating concentrations yielded an apparent dissociation constant of approximately 4 nM. We propose that the biological action of PAT-SM6 in tumour cell apoptosis may depend on the multivalent nature of PAT-SM6 and the high avidity of its interaction with multiple GRP78 molecules clustered on the tumour cell surface.

Induction of in vitro and in vivo NK cell cytotoxicity using high-avidity immunoligands targeting prostate-specific membrane antigen in prostate carcinoma.

Cancer that might develop as host natural killer (NK) cells fail to detect ligands for their activating NK receptors. Immunoligands represent promising immunotherapeutic tools to overcome this deficit. These are fusion proteins containing a single-chain antibody fragment (scFv) to target an available tumor antigen and ULBP2 to activate host NK cells by targeting the activatory receptor NKG2D. Prostate-specific membrane antigen (PSMA) is an integral non-shed type 2 membrane protein that is highly and specifically expressed on prostate epithelial cells and strongly upregulated in prostate cancer. Here, we compare the impact of various anti-PSMA immunoligand formats on the therapeutic efficacy against prostate carcinoma cells by activating NK cells via NKG2D. Shortening of the linker separating the heavy and light chain antibody domain leads to the formation of dimers, trimers, and higher molecular mass oligomers. NK cells are most efficiently activated by multimeric immunoligands, thus showing an altered cytokine release pattern. The high avidity format is also superior in in vitro NK-mediated tumor cell targeting as shown in cytotoxicity assays. Finally, the efficacy of a multimeric immunoligand is shown in a prostate carcinoma mouse xenograft model showing a strong activity against advanced established tumors.

Comparison of student examiner to faculty examiner scoring and feedback in an OSCE.

OBJECTIVES: to help reduce pressure on faculty staff, medical students have been used as raters in objective structured clinical examinations (OSCEs). There are few studies regarding their ability to complete checklists and global rating scales, and a paucity of data on their ability to provide feedback to junior colleagues. The objectives of this study were: (i) to compare expert faculty examiner (FE) and student-examiner (SE) assessment of students' (candidates') performances on a formative OSCE; (ii) to assess SE feedback provided to candidates, and (iii) to seek opinion regarding acceptability from all participants. METHODS: year 2 medical students (candidates, n = 66) participated in a nine-station formative OSCE. Year 4 students (n = 27) acted as SEs and teaching doctors (n = 27) served as FEs. In each station, SEs and FEs independently scored the candidates using checklists and global rating scales. The SEs provided feedback to candidates after each encounter. The FEs evaluated SEs on the feedback provided using a standardised rating scale (1 = strongly disagree, 5 = strongly agree) for several categories, according to whether the feedback was: balanced; specific; accurate; appropriate; professional, and similar to feedback the FE would have provided. All participants completed questionnaires exploring perceptions and acceptability. RESULTS: there was a high correlation on the checklist items between raters on each station, ranging from 0.56 to 0.86. Correlations on the global rating for each station ranged from 0.23 to 0.78. Faculty examiners rated SE feedback highly, with mean scores ranging from 4.02 to 4.44 for all categories. There was a high degree of acceptability on the part of candidates and examiners. CONCLUSIONS: student-examiners appear to be a viable alternative to FEs in a formative OSCE in terms of their ability to both complete checklists and provide feedback.

Therapeutic advances in rheumatology with the use of recombinant proteins.

Antibody engineering and protein design have led to the creation of a new era of targeted anti-inflammatory therapies in rheumatology. Recombinant DNA technologies have enabled the selection and humanization of specific antibody fragments in order to develop therapeutic reagents of any specificity that can be 'armed' to deliver effective anti-inflammatory 'payloads'. Antibodies and antibody-like proteins provide the opportunity to block key soluble mediators of inflammation in their milieu, or alternatively to block intracellular inflammation-triggering pathways by binding to an upstream cell-surface receptor. These designer proteins can be tuned for desired pharmacokinetic and pharmacodynamic effects, and represent tools for specific therapeutic intervention by delivering precisely the required immunosuppressive effect. The extent of desired and undesired effects of a particular biologic therapy, however, can be broader than initially predicted and require careful evaluation during clinical trials. This Review highlights advances in recombinant technologies for the development of novel biologic therapies in rheumatology.

Tumor targeting by a multivalent single-chain Fv (scFv) anti-Lewis Y antibody construct.

The use of single-chain variable fragment (scFv) constructs has been investigated in cancer radioimmunotherapy (RIT) and radioimmunodetection, as these molecules permit rapid tumor penetration and clearance from the serum relative to whole IgG. Multimerization of scFv constructs has demonstrated improvements in functional affinity (i.e., avidity) and maximal tumor uptake. In this paper, we report the first biodistribution and pharmacokinetics studies of a noncovalent, direct-linked scFv (V(L)-0-V(H)) trimeric/tetrameric "multimer" of the anti-Lewis Y monoclonal antibody, hu3S193. The in vitro binding and in vivo biodistribution of the hu3S193 multimer was characterized alongside the hu3S193 F(ab')(2) following radiolabeling with the Indium-111 ((111)In) radioisotope. Immunoreactivities of the radiolabeled multimer and F(ab')(2) were 73% and 53.2%, and binding affinities (K(a)) were 1.58 x 10(7) M(1) and 4.31 x 10(6) M (1) for the multimer and F(ab')(2), respectively. Maximal tumor uptake in Le(y)-positive MCF-7 breast cancer xenografted BALB/c nude mice was 12.6 +/- 2.5 percent injected dose/per gram (%ID/g) at 6 hours postinjection for the multimer and 15.7 +/- 2.1 %ID/g at 24 hours postinjection for the F(ab')(2). However, limited in vitro stability and high renal localization of radiolabeled constructs were observed, which, despite the observed tumor targeting of the hu3S193 multimer, most likely preclude its use in RIT and imaging modalities.

Lab-on-a-chip in vitro compartmentalization technologies for protein studies.

In vitro compartmentalization (IVC) is a powerful tool for studying protein-protein reactions, due to its high capacity and the versatility of droplet technologies. IVC bridges the gap between chemistry and biology as it enables the incorporation of unnatural amino acids with modifications into biological systems, through protein transcription and translation reactions, in a cell-like microdrop environment. The quest for the ultimate chip for protein studies using IVC is the drive for the development of various microfluidic droplet technologies to enable these unusual biochemical reactions to occur. These techniques have been shown to generate precise microdrops with a controlled size. Various chemical and physical phenomena have been utilized for on-chip manipulation to allow the droplets to be generated, fused, and split. Coupled with detection techniques, droplets can be sorted and selected. These capabilities allow directed protein evolution to be carried out on a microchip. With further technological development of the detection module, factors such as addressable storage, transport and interfacing technologies, could be integrated and thus provide platforms for protein studies with high efficiency and accuracy that conventional laboratories cannot achieve.

Ribosome display and selection of human anti-cD22 scFvs derived from an acute lymphocytic leukemia patient.

Novel in vitro methods for the display of antibody libraries against disease-related antigens have led to the development of powerful protein-based biotherapeutics. Eukaryotic ternary ribosome complexes can be used to display human single chain antibodies (scFvs) to isolate specific binding reagents to these antigens. Here, we present the isolation of human scFv against the immunotherapeutic target antigen CD22 from a patient-derived human scFv library using ribosome display technology. The ribosome complexes were enriched against the extra-cellular domain of human CD22 conjugated to magnetic beads. Isolated constructs were further affinity-matured and specific binding activity was demonstrated by surface plasmon resonance and validated using in vitro cell assays. The isolated human anti-CD22 scFvs can provide a basis for the development of new immunotherapeutic strategies in CD22-expressing malignant diseases.

Selection of human anti-CD28 scFvs from a T-NHL related scFv library using ribosome display.

Engineered antibodies have become an invaluable source of biopharmaceuticals against a wide range of diseases. About 200 antibody-based biologicals have been tested in clinical trials. Single chain variable fragments of antibodies (scFvs) provide binding specificity and offer an increased ease of in vitro display selection. Here, we present the generation of a human scFv library from peripheral blood lymphocyte RNA of a patient with relapsed T-cell non-Hodgkin lymphoma (T-NHL) who experienced a rare case of "spontaneous" remission. Antibodies against human T-cell antigen CD28, a co-stimulatory protein that influences the immune response by amplification of the transcriptional effects of T-cell receptors, might have contributed to the patient's remission. The scFv library was panned against CD28 using ribosome display and further subjected to affinity maturation. Isolated scFv were assessed for binding specificity and affinity and may provide the basis for the development of novel immunotherapeutic strategies. This work demonstrates the selection of a fully human antibody fragment from a patient-derived gene pool by in vitro ribosome display technology.

DNA hypomethylation and human diseases.

Changes in human DNA methylation patterns are an important feature of cancer development and progression and a potential role in other conditions such as atherosclerosis and autoimmune diseases (e.g., multiple sclerosis and lupus) is being recognised. The cancer genome is frequently characterised by hypermethylation of specific genes concurrently with an overall decrease in the level of 5 methyl cytosine. This hypomethylation of the genome largely affects the intergenic and intronic regions of the DNA, particularly repeat sequences and transposable elements, and is believed to result in chromosomal instability and increased mutation events. This review examines our understanding of the patterns of cancer-associated hypomethylation, and how recent advances in understanding of chromatin biology may help elucidate the mechanisms underlying repeat sequence demethylation. It also considers how global demethylation of repeat sequences including transposable elements and the site-specific hypomethylation of certain genes might contribute to the deleterious effects that ultimately result in the initiation and progression of cancer and other diseases. The use of hypomethylation of interspersed repeat sequences and genes as potential biomarkers in the early detection of tumors and their prognostic use in monitoring disease progression are also examined.