Acoustic Mist Ionization Platform for Direct and Contactless Ultrahigh-Throughput Mass Spectrometry Analysis of Liquid Samples.

Mass spectrometry (MS) has many advantages as a quantitative detection technology for applications within drug discovery. However, current methods of liquid sample introduction to a detector are slow and limit the use of mass spectrometry for kinetic and high-throughput applications. We present the development of an acoustic mist ionization (AMI) interface capable of contactless nanoliter-scale "infusion" of up to three individual samples per second into the mass detector. Installing simple plate handling automation allowed us to reach a throughput of 100 000 samples per day on a single mass spectrometer. We applied AMI-MS to identify inhibitors of a human histone deacetylase from AstraZeneca's collection of 2 million small molecules and measured their half-maximal inhibitory concentration. The speed, sensitivity, simplicity, robustness, and consumption of nanoliter volumes of sample suggest that this technology will have a major impact across many areas of basic and applied research.

Implementation of CT-P13 via a Managed Switch Programme in Crohn's Disease: 12-Month Real-World Outcomes.

BACKGROUND: Switching from Remicade to CT-P13 allows for significant cost savings and has been shown to be non-inferior to continued therapy with Remicade for the treatment of Crohn's disease. AIM: The aim of this work was to prospectively evaluate clinical outcomes in a cohort of patients with Crohn's disease switching from Remicade to CT-P13. METHODS: A prospective service evaluation was performed. The Harvey-Bradshaw index, CRP, faecal calprotectin and serum for infliximab/antibody levels were collected prior to patients' final Remicade infusion and at 6 and 12 months after switching to CT-P13 as part of routine clinical care. All adverse events during follow-up were also recorded. RESULTS: One hundred and ten patients on Remicade switched to CT-P13. No significant difference was observed between the Harvey-Bradshaw Index (p = 0.07), CRP (p = 0.13), faecal calprotectin (p = 0.25) or trough infliximab levels (p = 0.47) comparing before and at 6 and 12 months after the switch to CT-P13. Seven patients developed new infliximab antibodies after switching from Remicade to CT-P13. The majority of patients remained on CT-P13 at 12 months (84.5%) and the rate of adverse events and serious adverse events was 53.8 and 13.5 per 100 patient-years of follow-up, respectively. Switching to CT-P13 resulted in a cost saving of approximately 46.4%. CONCLUSION: The transition to CT-P13 from Remicade for the treatment of Crohn's disease is safe and has no negative effect on clinical outcomes at 12 months.

Development of a physical literacy model for older adults - a consensus process by the collaborative working group on physical literacy for older Canadians.

BACKGROUND: Arguably the uptake and usability of the physical activity (PA) guidelines for older adults has not been effective with only 12% of this population meeting the minimum guidelines to maintain health. Health promoters must consider innovative ways to increase PA adoption and long-term sustainability. Physical literacy (PL) is emerging as a promising strategy to increase lifelong PA participation in younger age-groups, yet there is relatively little evidence of PL being used to support older adults in achieving the PA guidelines. METHODS: An iterative and mixed-methods consensus development process was utilized over a series of six informed processes and meetings to develop a model of physical literacy for adults aged 65 years and older. RESULTS: A multi-disciplinary collaborative working group (n = 9) from diverse practice settings across Canada, and representative and reflective of the full range of key elements of PL, was assembled. Three consensus meetings and two Delphi surveys, using an international cohort of 65 expert researchers, practitioners, non-government organizations and older adults, was conducted. 45% responded on the first round and consensus was achieved; however, we elected to run a second survey to support our results. With 79% response rate, there was consensus to support the new PL model for older adults. CONCLUSION: Older adults are a unique group who have yet to be exposed to PL as a means to promote long-term PA participation. This new PL model uses an ecological approach to integrate PL into the lifestyles of most older adults. Understanding the interactions between components and elements that facilitate PL will ultimately provide a new and effective tool to target PA promotion and adherence for all older Canadians.

Handgrip Strength Related to Long-Term Electromyography: Application for Assessing Functional Decline in Parkinson Disease.

OBJECTIVE: To determine which clinical measures of physical function (ie, gait, balance, and grip strength) best represent long-term electromyography in persons with Parkinson disease (PD) compared with those without PD. DESIGN: Cross-sectional study. SETTING: Local community. PARTICIPANTS: A sample (N=37) of men and women with PD (n=23) and those without PD (n=14), living independently at home, older than 50 years of age, from the local community. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Measures of gait, balance, and grip strength were completed, and electromyography was examined in biceps brachii, triceps brachii, vastus lateralis, and biceps femoris during a 6.5-hour day. Muscle activity was quantified through burst in electromyography (>2% of the normalized maximum voluntary exertion with a continuous activity period of >0.1s). Stepwise multiple regression models were used to determine the proportion of variance in burst characteristics explained by clinical measures of physical function in PD. RESULTS: Grip strength was the best predictor of muscle activity in persons with PD (R2=.17-.33; P<.04), whereas gait characteristics explained muscle activity in healthy controls (R2=.40-.82; P<.04). CONCLUSIONS: Grip strength could serve as an effective clinical assessment tool to determine changes in muscle activity, which is a precursor to functional loss in persons with PD.

Exercise Modality Choices One Year After Intervention in Previously Inactive Older Men and Women.

A convenience sample of 176 healthy, community-dwelling, inactive older adults (mean age 70 ± 5 years; 62 males, 114 females) were tracked for one year. The purpose was to describe the exercise modality choices older adults make one year following participation in an exercise and education intervention. Telephone follow-up contacted 137 participants (78%, men = 50, women = 87) and 62% of the men and 69% of the women reported to be "currently exercising." Exercising independently was the most common type of exercise reported by 81% and 64% of men and women, respectively. Walking was the most commonly reported modality by both genders. The setting of exercise was most often reported to be at home or outside for both men and women. The main reason for continued participation at 12 months was for overall health (50% of men and 40% of women). Little variation was observed for exercise modality choice. Future interventions should consider a variety of exercise and physical activity opportunities for older adults.

Neutralising antibody responses against SARS-CoV-2 Omicron BA.4/5 and wild-type virus in patients with inflammatory bowel disease following three doses of COVID-19 vaccine (VIP): a prospective, multicentre, cohort study.

Background: Patients with inflammatory bowel disease (IBD) receiving anti-TNF and JAK-inhibitor therapy have attenuated responses to COVID-19 vaccination. We aimed to determine how IBD treatments affect neutralising antibody responses against the Omicron BA.4/5 variant. Methods: In this multicentre cohort study, we prospectively recruited 340 adults (69 healthy controls and 271 IBD) at nine UK hospitals between May 28, 2021 and March 29, 2022. The IBD study population was established (>12 weeks therapy) on either thiopurine (n = 63), infliximab (n = 45), thiopurine and infliximab combination therapy (n = 48), ustekinumab (n = 45), vedolizumab (n = 46) or tofacitinib (n = 24). Patients were excluded if they were being treated with any other immunosuppressive therapies. Participants had two doses of either ChAdOx1 nCoV-19 or BNT162b2 vaccines, followed by a third dose of either BNT162b2 or mRNA1273. Pseudo-neutralisation assays against SARS-CoV-2 wild-type and BA.4/5 were performed. The half maximal inhibitory concentration (NT50) of participant sera was calculated. The primary outcome was anti-SARS-CoV-2 neutralising response against wild-type virus and Omicron BA.4/5 variant after the second and third doses of anti-SARS-CoV-2 vaccine, stratified by immunosuppressive therapy, adjusting for prior infection, vaccine type, age, and interval between vaccination and blood collection. This study is registered with ISRCTN (No. 13495664). Findings: Both heterologous (first two doses adenovirus vaccine, third dose mRNA vaccine) and homologous (three doses mRNA vaccine) vaccination strategies significantly increased neutralising titres against both wild-type SARS-CoV-2 virus and the Omicron BA.4/5 variant in healthy participants and patients with IBD. Antibody titres against BA.4/5 were significantly lower than antibodies against wild-type virus in both healthy participants and patients with IBD (p < 0.0001). Multivariable models demonstrated that neutralising antibodies against BA.4/5 after three doses of vaccine were significantly lower in patients with IBD on infliximab (Geometric Mean Ratio (GMR) 0.19 [0.10, 0.36], p < 0.0001), infliximab and thiopurine combination (GMR 0.25 [0.13, 0.49], p < 0.0001) or tofacitinib (GMR 0.43 [0.20, 0.91], p = 0.028), but not in patients on thiopurine monotherapy, ustekinumab, or vedolizumab. Breakthrough infection was associated with lower neutralising antibodies against wild-type (p = 0.037) and BA.4/5 (p = 0.045). Interpretation: A third dose of a COVID-19 mRNA vaccine based on the wild-type spike glycoprotein significantly boosts neutralising antibody titres in patients with IBD. However, responses are lower against the Omicron variant BA.4/5, particularly in patients taking anti-TNF and JAK-inhibitor therapy. Breakthrough infections are associated with lower neutralising antibodies and immunosuppressed patients with IBD may receive additional benefit from bivalent vaccine boosters which target Omicron variants. Funding: Pfizer.

Antibody responses to Influenza vaccination are diminished in patients with inflammatory bowel disease on infliximab or tofacitinib.

BACKGROUND AND AIMS: We sought to determine whether six commonly used immunosuppressive regimens were associated with lower antibody responses after seasonal influenza vaccination in patients with IBD. METHODS: We conducted a prospective study including 213 IBD patients and 53 healthy controls; 165 who had received seasonal influenza vaccine and 101 who had not. IBD medications included infliximab, thiopurines, infliximab and thiopurine combination therapy, ustekinumab, vedolizumab or tofacitinib. The primary outcome was antibody responses against influenza/A H3N2 and A/H1N1, compared to controls, adjusting for age, prior vaccination and interval between vaccination and sampling. RESULTS: Lower antibody responses against influenza A/H3N2 were observed in patients on infliximab (Geometric Mean Ratio 0.35 [95% CI 0.20-0.60], p=0.0002), combination of infliximab and thiopurine therapy (0.46 [0.27-0.79], p=0.0050) and tofacitinib (0.28 [0.14-0.57], p=0.0005) compared to controls. Lower antibody responses against A/H1N1 were observed in patients on infliximab (0.29 [0.15-0.56], p=0.0003), combination of infliximab and thiopurine therapy (0.34 [0.17-0.66], p=0.0016), thiopurine monotherapy (0.46 [0.24-0.87], p=0.017) and tofacitinib (0.23 [0.10-0.56], p=0.0013). Ustekinumab and vedolizumab were not associated with reduced antibody responses against A/H3N2 or A/H1N1. Vaccination in the previous year was associated with higher antibody responses to A/H3N2. Vaccine-induced anti-SARS-CoV-2 antibody concentration weakly correlated with antibodies against H3N2 (r=0.27; p=0.0004) and H1N1 (r=0.33; p<0.0001). CONCLUSIONS: Vaccination in both the 2020-2021 and 2021-2022 seasons was associated with significantly higher antibody responses to influenza/A than no vaccination or vaccination in 2021-2022 alone. Infliximab and tofacitinib are associated with lower binding antibody responses to Influenza/A, similar to COVID-19 vaccine-induced antibody responses.

Using a single question to assess physical activity in older adults: a reliability and validity study.

BACKGROUND: Single-item physical activity questions provide a quick approximation of physical activity levels. While recall questionnaires provide a more detailed picture of an individual's level of physical activity, single-item questions may be more appropriate in certain situations. The aim of this study was to evaluate two single-item physical activity questions (one absolute question and one relative question) for test-retest reliability, convergent validity, and discriminant validity, in a sample of older adults. METHODS: Data was obtained from the Project to Prevent Falls in Veterans, a fall risk-factor screening and modification trial. One question measured absolute physical activity (seldom, moderately, vigorously active) and one measured relative physical activity (more, about as, less active than peers). Test-retest reliability was examined using weighted Kappa statistics (κ) in a sample of 43 subjects. Validity was assessed using correlation coefficients (r) in participants who received clinical assessments (n = 159). RESULTS: The absolute physical activity question was more reliable than the relative physical activity question (κ = 0.75 vs. κ = 0.56). Convergent validity, however, was stronger for the relative physical activity question (r = 0.28 to 0.57 vs. r = 0.10 to 0.33). Discriminant validity was similar for both questions. For the relative physical activity question, there was moderate agreement when this question was re-administered seven days later, fair to moderate/good associations when compared with indicators of physical function, and little to no associations when compared with measures hypothesized to be theoretically not related to physical activity. CONCLUSIONS: The relative physical activity question had the best combination of test-retest reliability, convergent validity and discriminant validity. In studies requiring a measure of physical activity, where physical activity is not the primary focus and more detailed measures are not feasible, a single question may be an acceptable alternative.

COVID-19 vaccine-induced antibody and T-cell responses in immunosuppressed patients with inflammatory bowel disease after the third vaccine dose (VIP): a multicentre, prospective, case-control study.

BACKGROUND: COVID-19 vaccine-induced antibody responses are reduced in patients with inflammatory bowel disease (IBD) taking anti-TNF or tofacitinib after two vaccine doses. We sought to assess whether immunosuppressive treatments were associated with reduced antibody and T-cell responses in patients with IBD after a third vaccine dose. METHODS: VIP was a multicentre, prospective, case-control study done in nine centres in the UK. We recruited immunosuppressed patients with IBD and non-immunosuppressed healthy individuals. All participants were aged 18 years or older. The healthy control group had no diagnosis of IBD and no current treatment with systemic immunosuppressive therapy for any other indication. The immunosuppressed patients with IBD had an established diagnosis of Crohn's disease, ulcerative colitis, or unclassified IBD using standard definitions of IBD, and were receiving established treatment with one of six immunosuppressive regimens for at least 12 weeks at the time of first dose of SARS-CoV-2 vaccination. All participants had to have received three doses of an approved COVID-19 vaccine. SARS-CoV-2 spike antibody binding and T-cell responses were measured in all participant groups. The primary outcome was anti-SARS-CoV-2 spike (S1 receptor binding domain [RBD]) antibody concentration 28-49 days after the third vaccine dose, adjusted by age, homologous versus heterologous vaccine schedule, and previous SARS-CoV-2 infection. The primary outcome was assessed in all participants with available data. FINDINGS: Between Oct 18, 2021, and March 29, 2022, 352 participants were included in the study (thiopurine n=65, infliximab n=46, thiopurine plus infliximab combination therapy n=49, ustekinumab n=44, vedolizumab n=50, tofacitinib n=26, and healthy controls n=72). Geometric mean anti-SARS-CoV-2 S1 RBD antibody concentrations increased in all groups following a third vaccine dose, but were significantly lower in patients treated with infliximab (2736·8 U/mL [geometric SD 4·3]; p<0·0001), infliximab plus thiopurine (1818·3 U/mL [6·7]; p<0·0001), and tofacitinib (8071·5 U/mL [3·1]; p=0·0018) compared with the healthy control group (16 774·2 U/mL [2·6]). There were no significant differences in anti-SARS-CoV-2 S1 RBD antibody concentrations between the healthy control group and patients treated with thiopurine (12 019·7 U/mL [2·2]; p=0·099), ustekinumab (11 089·3 U/mL [2·8]; p=0·060), or vedolizumab (13 564·9 U/mL [2·4]; p=0·27). In multivariable modelling, lower anti-SARS-CoV-2 S1 RBD antibody concentrations were independently associated with infliximab (geometric mean ratio 0·15 [95% CI 0·11-0·21]; p<0·0001), tofacitinib (0·52 [CI 0·31-0·87]; p=0·012), and thiopurine (0·69 [0·51-0·95]; p=0·021), but not with ustekinumab (0·64 [0·39-1·06]; p=0·083), or vedolizumab (0·84 [0·54-1·30]; p=0·43). Previous SARS-CoV-2 infection (1·58 [1·22-2·05]; p=0·0006) was independently associated with higher anti-SARS-CoV-2 S1 RBD antibody concentrations and older age (0·88 [0·80-0·97]; p=0·0073) was independently associated with lower anti-SARS-CoV-2 S1 RBD antibody concentrations. Antigen-specific T-cell responses were similar in all groups, except for recipients of tofacitinib without evidence of previous infection, where T-cell responses were significantly reduced relative to healthy controls (p=0·021). INTERPRETATION: A third dose of COVID-19 vaccine induced a boost in antibody binding in immunosuppressed patients with IBD, but these responses were reduced in patients taking infliximab, infliximab plus thiopurine, and tofacitinib. Tofacitinib was also associated with reduced T-cell responses. These findings support continued prioritisation of immunosuppressed groups for further vaccine booster dosing, particularly patients on anti-TNF and JAK inhibitors. FUNDING: Pfizer.

COVID-19 vaccine-induced antibody responses in immunosuppressed patients with inflammatory bowel disease (VIP): a multicentre, prospective, case-control study.

BACKGROUND: The effects that therapies for inflammatory bowel disease (IBD) have on immune responses to SARS-CoV-2 vaccination are not yet fully known. Therefore, we sought to determine whether COVID-19 vaccine-induced antibody responses were altered in patients with IBD on commonly used immunosuppressive drugs. METHODS: In this multicentre, prospective, case-control study (VIP), we recruited adults with IBD treated with one of six different immunosuppressive treatment regimens (thiopurines, infliximab, a thiopurine plus infliximab, ustekinumab, vedolizumab, or tofacitinib) and healthy control participants from nine centres in the UK. Eligible participants were aged 18 years or older and had received two doses of COVID-19 vaccines (either ChAdOx1 nCoV-19 [Oxford-AstraZeneca], BNT162b2 [Pfizer-BioNTech], or mRNA1273 [Moderna]) 6-12 weeks apart (according to scheduling adopted in the UK). We measured antibody responses 53-92 days after a second vaccine dose using the Roche Elecsys Anti-SARS-CoV-2 spike electrochemiluminescence immunoassay. The primary outcome was anti-SARS-CoV-2 spike protein antibody concentrations in participants without previous SARS-CoV-2 infection, adjusted by age and vaccine type, and was analysed by use of multivariable linear regression models. This study is registered in the ISRCTN Registry, ISRCTN13495664, and is ongoing. FINDINGS: Between May 31 and Nov 24, 2021, we recruited 483 participants, including patients with IBD being treated with thiopurines (n=78), infliximab (n=63), a thiopurine plus infliximab (n=72), ustekinumab (n=57), vedolizumab (n=62), or tofacitinib (n=30), and 121 healthy controls. We included 370 participants without evidence of previous infection in our primary analysis. Geometric mean anti-SARS-CoV-2 spike protein antibody concentrations were significantly lower in patients treated with infliximab (156·8 U/mL [geometric SD 5·7]; p<0·0001), infliximab plus thiopurine (111·1 U/mL [5·7]; p<0·0001), or tofacitinib (429·5 U/mL [3·1]; p=0·0012) compared with controls (1578·3 U/mL [3·7]). There were no significant differences in antibody concentrations between patients treated with thiopurine monotherapy (1019·8 U/mL [4·3]; p=0·74), ustekinumab (582·4 U/mL [4·6]; p=0·11), or vedolizumab (954·0 U/mL [4·1]; p=0·50) and healthy controls. In multivariable modelling, lower anti-SARS-CoV-2 spike protein antibody concentrations were independently associated with infliximab (geometric mean ratio 0·12, 95% CI 0·08-0·17; p<0·0001) and tofacitinib (0·43, 0·23-0·81; p=0·0095), but not with ustekinumab (0·69, 0·41-1·19; p=0·18), thiopurines (0·89, 0·64-1·24; p=0·50), or vedolizumab (1·16, 0·74-1·83; p=0·51). mRNA vaccines (3·68, 2·80-4·84; p<0·0001; vs adenovirus vector vaccines) were independently associated with higher antibody concentrations and older age per decade (0·79, 0·72-0·87; p<0·0001) with lower antibody concentrations. INTERPRETATION: For patients with IBD, the immunogenicity of COVID-19 vaccines varies according to immunosuppressive drug exposure, and is attenuated in recipients of infliximab, infliximab plus thiopurines, and tofacitinib. Scheduling of third primary, or booster, doses could be personalised on the basis of an individual's treatment, and patients taking anti-tumour necrosis factor and tofacitinib should be prioritised. FUNDING: Pfizer.

Introduction of an enhanced recovery programme for total shoulder arthroplasty: report of a novel pathway.

BACKGROUND: Enhanced recovery (ER) programmes are well established in hip and knee arthroplasty, but are not yet commonplace for total shoulder arthroplasty (TSA). This study analyses the effect of implementing an ER programme with TSA, on length of stay (LOS), functional outcome and patient satisfaction. LOCAL PROBLEM: No established programme applying ER to the specifics of upper-limb arthroplasty existed at our unit. METHODS: A three-cycle plan-do-study-act quality improvement methodology was applied, involving development of our multifactorial programme, a pilot phase and wider roll-out. A consecutive series of patients who underwent TSA and were enrolled in an ER programme were compared with a matched control group of consecutive patients who underwent TSA in the year before the programme started. For all patients, LOS as well as mean Oxford Shoulder Score (OSS) and Constant Score (CS) were quantified and patient satisfaction assessed. INTERVENTIONS: A dedicated multidisciplinary team led preoperative class involving patient education, advice and occupational therapy assessment. A standardised perioperative anaesthetic regime based on regional anaesthetic techniques with preoperative analgesic and nutritional loading was introduced. Postoperative rehabilitation was also standardised with slings for comfort only and early safe-zone mobilisation. New patient information was developed. RESULTS: 71 patients were included in matched cohorts. Mean LOS was reduced from 2.4 nights to 1.9 nights. The single night stay rate improved from 40% to 49%. Across the ER cohort, 15 less nights were required to complete same volume of surgeries as in the non-ER cohort.Parity in OSS and CS measured at 3 and 12 months after surgery were observed in both cohorts.Satisfaction was already high before ER but scores stayed the same or improved across all areas surveyed.Absolute complication rates of 9.9% in the non-ER group and 7% in the ER group were recorded. CONCLUSION: Our ER programme benefited patients and the Trust by reducing time in hospital and improving patient satisfaction without an adverse effect on complication rate.

Dopamine D(1) receptor binding in the anterior cingulate cortex of patients with obsessive-compulsive disorder.

Functional neuroimaging studies in patients with obsessive-compulsive disorder (OCD) suggest there is a hyperactivation of the anterior cingulate cortex (ACC) during provocation of symptoms and conflict-inhibition tasks. Since dopamine, acting through D(1) receptors is suggested to modulate ACC activity, we hypothesised that there would be an altered D(1) binding potential (BP) in the ACC of OCD patients. Using [(11)C]-SCH23390 and positron emission tomography, we report significantly reduced D(1) BP in seven drug-free OCD patients compared with matched healthy controls. These findings suggest mesocortical dopamine inputs via D(1) receptors may play a role in the aetiology of OCD.

Higher anti-tumor necrosis factor levels are associated with perianal fistula healing and fistula closure in Crohn's disease.

OBJECTIVE: Limited data are available regarding the relationship between anti-tumor necrosis factor (TNF) drug/antibody levels and perianal fistula outcomes in Crohn's disease. The aims of this study were to assess the relationship between maintenance anti-TNF levels and perianal fistula outcomes. METHODS: This was a retrospective cross-sectional study of patients receiving maintenance adalimumab or infliximab therapy (minimum 24 weeks) for the treatment of Crohn's disease with associated perianal fistulas, who had anti-TNF drug/antibody levels (trough for infliximab) measured within 4 weeks of clinical assessment. The primary outcome was the association of anti-TNF levels with perianal fistula healing defined as the absence of drainage. The secondary outcome was the association of anti-TNF levels with complete perianal fistula closure. RESULTS: A total of 64 patients (adalimumab, n = 35; infliximab, n = 29) were included. Patients with fistula healing had higher levels of anti-TNF vs. those without fistula healing (adalimumab: 12.6 vs. 2.7 µg/mL, P < 0.01; infliximab: 8.1 vs. 3.2 µg/mL, P < 0.01). Patients with fistula closure also had significantly higher anti-TNF levels vs. those without fistula closure (adalimumab: 14.8 vs. 5.7 µg/mL, P < 0.01; infliximab: 8.2 vs. 3.2 µg/mL, P < 0.01). For adalimumab, receiver operator characteristic analysis identified an optimum level of >6.8 µg/mL and >9.8 µg/mL for fistula healing and closure, respectively. For infliximab, receiver operator characteristic analysis identified an optimum trough level of >7.1 µg/mL for both fistula healing and closure. CONCLUSION: Higher maintenance anti-TNF levels are associated with perianal fistula healing and closure in Crohn's disease.

Association of trough vedolizumab levels with clinical, biological and endoscopic outcomes during maintenance therapy in inflammatory bowel disease.

OBJECTIVE: To establish the relationship between trough vedolizumab levels and outcomes during maintenance therapy. DESIGN: Cross-sectional service evaluation was performed on patients with inflammatory bowel disease (IBD) receiving maintenance vedolizumab therapy (minimum of 12 weeks following induction). Prior to infusion, data on clinical activity (Harvey-Bradshaw Index or partial Mayo score), trough C-reactive protein (CRP)/vedolizumab levels and faecal calprotectin were collected. Endoscopic data (±8 weeks from vedolizumab level testing) were obtained by review of medical records. Vedolizumab levels were processed using the Immundiagnostik monitor ELISA. SETTING: The Edinburgh IBD Unit, Western General Hospital (tertiary IBD referral centre). PATIENTS: Seventy-three patients (30 ulcerative colitis and 43 Crohn's disease) were identified who fulfilled inclusion criteria and had vedolizumab levels matched with clinical activity scores, CRP and faecal calprotectin. Of these, 40 patients also had matched endoscopic data. MAIN OUTCOME MEASURES: The association of trough vedolizumab levels with clinical remission (Harvey-Bradshaw Index <5 or partial Mayo <2), biologic remission (faecal calprotectin <250 µg/g+CRP <5 mg/L) and endoscopic remission (Mayo score 0/no inflammation and ulceration on colonoscopy). RESULTS: The median trough vedolizumab levels were similar between patients in and not in clinical remission (10.6 vs 9.9 µg/mL, p=0.54); biologic remission (10.6 vs 9.8 µg/mL, p=0.35) and endoscopic remission (8.1 vs 10.2 µg/mL, p=0.21). Quartile analysis revealed no significant increase in the proportion of patients in clinical remission, biologic remission or endoscopic remission with increasing trough vedolizumab levels (p<0.05). CONCLUSIONS: In this cohort, trough vedolizumab levels were not associated with clinical, biological or endoscopic outcomes during maintenance therapy.

Higher Adalimumab Drug Levels During Maintenance Therapy for Crohn's Disease Are Associated With Biologic Remission.

BACKGROUND: Adalimumab is an established treatment for Crohn's disease. Limited data are available regarding the relationship between adalimumab drug levels and serum/fecal markers of gut inflammation. We therefore aimed to characterize the relationship between adalimumab levels and biologic remission during maintenance therapy. METHODS: A single-center prospective cross-sectional study was undertaken on Crohn's disease patients who had received adalimumab therapy for a minimum of 12 weeks after induction. Data on clinical activity (Harvey-Bradshaw Index), C-reactive protein (CRP), adalimumab drug and antibody levels, and fecal calprotectin were collected. Biologic remission was defined as a CRP <5 mg/L and fecal calprotectin <250 µg/g. Adalimumab drug and antibody levels were processed using the Immundiagnostik monitor enzyme-linked immunosorbent assay. RESULTS: One hundred fifty-two patients had drug and antibody samples matched with CRP and fecal calprotectin. Patients in biologic remission had significantly higher adalimumab levels compared with others (12.0 µg/mL vs 8.0 µg/mL, P < 0.0001). Receiver operating characteristic curve analysis demonstrated an optimal adalimumab level of >8.5 µg/mL (sensitivity, 82.2%; specificity, 55.7%; likelihood ratio, 1.9) for predicting biologic remission. Multivariable logistic regression revealed that adalimumab levels >8.5 µg/mL were independently associated with biologic remission (odds ratio, 5.27; 95% confidence interval, 2.43-11.44; P < 0.0001). CONCLUSIONS: Higher adalimumab levels are associated with biologic remission. An optimal level of >8.5 µg/mL was identified.

Injurious falls are associated with lower household but higher recreational physical activities in community-dwelling older male veterans.

BACKGROUND: Physical activity (PA) and exercise have numerous beneficial effects in older adults. The effect of sustaining an injury from a fall on subsequent PA levels has received little research attention, even though about a quarter of older adults who fall sustain a serious injury. Even less is known about the effect of injurious falls on different PA categorizations. OBJECTIVE: To examine the role of injurious falls on subsequent household and recreational PA levels in older community-dwelling males who were all Canadian veterans of World War II and the Korean War. METHODS: Data from a fall risk-factor modification trial were used for the present study. Falls and related injuries were ascertained prospectively using fall calendars. A brief, valid and reliable PA interview for older adults (Phone-FITT) measured household and recreational PA approximately 1 year later. Covariates were measured as part of the screening questionnaire administered at the start of the study. Multiple linear regression models were computed using household and recreational PA as dependent variables. RESULTS: The present study included 200 males with a mean age 81 years (SD = 3.8). Half of the participants fell at least once and about one third reported at least one injury resulting from a fall. Multivariable analyses indicated that household PA scores were 3.1 points lower (95% CI = -5.8 to -0.3, p = 0.03) and recreational PA scores were 3.4 points higher (95% CI = 0.1 to 6.7, p = 0.04) among persons who had one or more falls leading to injury compared to those who did not fall or had one or more falls without injury. Analyses were adjusted for age, baseline PA, self-rated health, foot problems, balance problems, inability to stand without using armrests, vision and memory. CONCLUSION: Categorization of PA type (household vs. recreational) suggests distinct differences in PA response following an injurious fall. Use of an overall PA measure would obscure this finding. Following further research, the results from this study may help in the design of preventive strategies to maximize physical activity in those who have sustained an injurious fall.

Martin Vigorimeter assesses muscle fatigability in older adults better than the Jamar Dynamometer.

INTRODUCTION: Muscle fatigability can be measured based on sustained handgrip performance, but different grip strength devices exist and their relationship to frailty remains unclear. We aimed to compare muscle fatigability obtained by Martin Vigorimeter and Jamar Dynamometer in older women across levels of frailty. METHOD: 53 community-dwelling women living in Greece (63-100 y), categorized according to tertiles on the Frailty Index score (FI) as: low-frail (FI < 0.19), intermediate-frail (FI 0.19-0.36), and high-frail (FI > 0.36). Fatigue resistance (FR, time for maximal grip strength to decrease to 50% during sustained contraction) was measured with both Martin Vigorimeter and Jamar Dynamometer, and grip work (GW, reflecting the area under the time-force curve) was calculated. RESULTS: FR, when measured with the Martin Vigorimeter, was approximately double in low-frail (44.3 ±â€¯24.6 s) compared to high-frail participants (23.9 ±â€¯12.7 s, p = 0.011), whereas FR was similar across frailty groups when measured with the Jamar Dynamometer. In logistic regression models, FR (OR = 0.94 [0.90-0.99]) and GW (OR = 0.90 [0.82-0.99]) were significantly related to high frailty when measured with the Martin Vigorimeter but not when measured with Jamar Dynamometer. There is a significantly proportional difference in FR measured with both devices (R2 = 0.364, p < 0.001), highlighting that the longer the participant could sustain the FR test, the higher the difference in FR measured with both devices. CONCLUSION: Our results suggest that the Martin Vigorimeter is a more appropriate handgrip device compared with the Jamar Dynamometer to assess muscle fatigability for older women across levels of frailty. When measured with the Martin Vigorimeter, high-frail participants show twice the level of fatigability compared to low-frail, whereas no difference was observed when using the Jamar Dynamometer. Older participants might stop the FR test prematurely when using the Jamar Dynamometer, before muscle fatigue is reached, indicating that the Jamar Dynamometer is unable to identify those participants with higher levels of muscle endurance. Martin Vigorimeter assessed muscle fatigability might be a good additional marker to include in frailty tools.

Validity and reliability of an iPhone App to assess time, velocity and leg power during a sit-to-stand functional performance test.

The purposes of this study were: (i) Analyze the concurrent validity and reliability of an iPhone App for measuring time, velocity and power during a single sit-to-stand (STS) test compared with measurements recorded from a force plate; and (ii) Evaluate the relationship between the iPhone App measures with age and functional performance. Forty-eight healthy individuals (age range: 26-81 years) were recruited. All participants completed a STS test on a force plate with the movement recorded on an iPhone 6 at 240 frames-per-second. Functional ability was also measured using isometric handgrip strength and self-paced walking time tests. Intraclass correlation coefficients (ICC), Pearson's correlation coefficient, Cronbach's alpha (α) and Bland-Altman plots with 95% confidence intervals (CI) were used to test validity and reliability between instruments. The results showed a good agreement between all STS measurement variables; time (ICC=0.864, 95%CI=0.77-0.92; α=0.926), velocity (ICC=0.912, 95%CI=0.85-0.95; α=0.953) and power (ICC=0.846, 95%CI=0.74-0.91; α=0.917) with no systematic bias between instruments for any variable analyzed. STS time, velocity and power derived from the iPhone App show moderate to strong associations with age (|r|=0.63-0.83) and handgrip strength (|r|=0.4-0.64) but not the walking test. The results of this study identify that this iPhone App is reliable for measuring STS and the derived values of time, velocity and power shows strong associations with age and handgrip strength.

Ageing and physical activity: evidence to develop exercise recommendations for older adults.

An abundance of epidemiological research confirms the benefits of physical activity in reducing risk of various age-related morbidities and all-cause mortality. Analysis of the literature focusing on key exercise variables (e.g., intensity, type, and volume) suggests that the requisite beneficial amount of activity is that which engenders improved cardiorespiratory fitness, strength, power, and, indirectly, balance. Age-related declines in these components are such that physical limitations impinge on functional activities of daily living. However, an exercise programme can minimize declines, thus preventing older adults (age 65+ years) from crossing functional thresholds of inability. Cross-sectional and longitudinal data demonstrate that cardiorespiratory fitness is associated with functional capacity and independence; strength and, importantly, power are related to performance and activities of daily living; and balance-mobility in combination with power are important factors in preventing falls. Exercise interventions have documented that older adults can adapt physiologically to exercise training, with gains in functional capacities. The few studies that have explored minimal or optimal activity requirements suggest that a threshold (intensity) within the moderately vigorous domain is needed to achieve and preserve related health benefits. Thus, physical activity and (or) exercise prescriptions should emphasize activities of the specificity and type to improve components related to the maintenance of functional capacity and independence; these will also delay morbidity and mortality. An appropriate recommendation for older adults includes moderately vigorous cardiorespiratory activities (e.g., brisk walking), strength and (or) power training for maintenance of muscle mass and specific muscle-group performance, as well as "balance-mobility practice" and flexibility (stretching) exercise as needed.

Exercise prescription to reverse frailty.

Frailty is a clinical geriatric syndrome caused by physiological deficits across multiple systems. These deficits make it challenging to sustain homeostasis required for the demands of everyday life. Exercise is likely the best therapy to reverse frailty status. Literature to date suggests that pre-frail older adults, those with 1-2 deficits on the Cardiovascular Health Study-Frailty Phenotype (CHS-frailty phenotype), should exercise 2-3 times a week, for 45-60 min. Aerobic, resistance, flexibility, and balance training components should be incorporated but resistance and balance activities should be emphasized. On the other hand, frail (CHS-frailty phenotype ≥ 3 physical deficits) older adults should exercise 3 times per week, for 30-45 min for each session with an emphasis on aerobic training. During aerobic, balance, and flexibility training, both frail and pre-frail older adults should work at an intensity equivalent to a rating of perceived exertion of 3-4 ("somewhat hard") on the Borg CR10 scale. Resistance-training intensity should be based on a percentage of 1-repetition estimated maximum (1RM). Program onset should occur at 55% of 1RM (endurance) and progress to higher intensities of 80% of 1RM (strength) to maximize functional gains. Exercise is the medicine to reverse or mitigate frailty, preserve quality of life, and restore independent functioning in older adults at risk of frailty.