Randomized Trial of a Vaccine Regimen to Prevent Chronic HCV Infection.

BACKGROUND: A safe and effective vaccine to prevent chronic hepatitis C virus (HCV) infection is a critical component of efforts to eliminate the disease. METHODS: In this phase 1-2 randomized, double-blind, placebo-controlled trial, we evaluated a recombinant chimpanzee adenovirus 3 vector priming vaccination followed by a recombinant modified vaccinia Ankara boost; both vaccines encode HCV nonstructural proteins. Adults who were considered to be at risk for HCV infection on the basis of a history of recent injection drug use were randomly assigned (in a 1:1 ratio) to receive vaccine or placebo on days 0 and 56. Vaccine-related serious adverse events, severe local or systemic adverse events, and laboratory adverse events were the primary safety end points. The primary efficacy end point was chronic HCV infection, defined as persistent viremia for 6 months. RESULTS: A total of 548 participants underwent randomization, with 274 assigned to each group. There was no significant difference in the incidence of chronic HCV infection between the groups. In the per-protocol population, chronic HCV infection developed in 14 participants in each group (hazard ratio [vaccine vs. placebo], 1.53; 95% confidence interval [CI], 0.66 to 3.55; vaccine efficacy, -53%; 95% CI, -255 to 34). In the modified intention-to-treat population, chronic HCV infection developed in 19 participants in the vaccine group and 17 in placebo group (hazard ratio, 1.66; 95% CI, 0.79 to 3.50; vaccine efficacy, -66%; 95% CI, -250 to 21). The geometric mean peak HCV RNA level after infection differed between the vaccine group and the placebo group (152.51×103 IU per milliliter and 1804.93×103 IU per milliliter, respectively). T-cell responses to HCV were detected in 78% of the participants in the vaccine group. The percentages of participants with serious adverse events were similar in the two groups. CONCLUSIONS: In this trial, the HCV vaccine regimen did not cause serious adverse events, produced HCV-specific T-cell responses, and lowered the peak HCV RNA level, but it did not prevent chronic HCV infection. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT01436357.).

Advancing translational research for colorectal immuno-oncology.

Colorectal cancer (CRC) is a common and deadly disease. Unfortunately, immune checkpoint inhibitors (ICIs) fail to elicit effective anti-tumour responses in the vast majority of CRC patients. Patients that are most likely to respond are those with DNA mismatch repair deficient (dMMR) and microsatellite instability (MSI) disease. However, reliable predictors of ICI response are lacking, even within the dMMR/MSI subtype. This, together with identification of novel mechanisms to increase response rates and prevent resistance, are ongoing and vitally important unmet needs. To address the current challenges with translation of early research findings into effective therapeutic strategies, this review summarises the present state of preclinical testing used to inform the development of immuno-regulatory treatment strategies for CRC. The shortfalls and advantages of commonly utilised mouse models of CRC, including chemically induced, transplant and transgenic approaches are highlighted. Appropriate use of existing models, incorporation of patient-derived data and development of cutting-edge models that recapitulate important features of human disease will be key to accelerating clinically relevant research in this area.

The Origin and Contribution of Cancer-Associated Fibroblasts in Colorectal Carcinogenesis.

BACKGROUND & AIMS: Cancer-associated fibroblasts (CAFs) play an important role in colorectal cancer (CRC) progression and predict poor prognosis in CRC patients. However, the cellular origins of CAFs remain unknown, making it challenging to therapeutically target these cells. Here, we aimed to identify the origins and contribution of colorectal CAFs associated with poor prognosis. METHODS: To elucidate CAF origins, we used a colitis-associated CRC mouse model in 5 different fate-mapping mouse lines with 5-bromodeoxyuridine dosing. RNA sequencing of fluorescence-activated cell sorting-purified CRC CAFs was performed to identify a potential therapeutic target in CAFs. To examine the prognostic significance of the stromal target, CRC patient RNA sequencing data and tissue microarray were used. CRC organoids were injected into the colons of knockout mice to assess the mechanism by which the stromal gene contributes to colorectal tumorigenesis. RESULTS: Our lineage-tracing studies revealed that in CRC, many ACTA2+ CAFs emerge through proliferation from intestinal pericryptal leptin receptor (Lepr)+ cells. These Lepr-lineage CAFs, in turn, express melanoma cell adhesion molecule (MCAM), a CRC stroma-specific marker that we identified with the use of RNA sequencing. High MCAM expression induced by transforming growth factor ß was inversely associated with patient survival in human CRC. In mice, stromal Mcam knockout attenuated orthotopically injected colorectal tumoroid growth and improved survival through decreased tumor-associated macrophage recruitment. Mechanistically, fibroblast MCAM interacted with interleukin-1 receptor 1 to augment nuclear factor κB-IL34/CCL8 signaling that promotes macrophage chemotaxis. CONCLUSIONS: In colorectal carcinogenesis, pericryptal Lepr-lineage cells proliferate to generate MCAM+ CAFs that shape the tumor-promoting immune microenvironment. Preventing the expansion/differentiation of Lepr-lineage CAFs or inhibiting MCAM activity could be effective therapeutic approaches for CRC.

Mitochondrial Phosphoenolpyruvate Carboxykinase Regulates Metabolic Adaptation and Enables Glucose-Independent Tumor Growth.

Cancer cells adapt metabolically to proliferate under nutrient limitation. Here we used combined transcriptional-metabolomic network analysis to identify metabolic pathways that support glucose-independent tumor cell proliferation. We found that glucose deprivation stimulated re-wiring of the tricarboxylic acid (TCA) cycle and early steps of gluconeogenesis to promote glucose-independent cell proliferation. Glucose limitation promoted the production of phosphoenolpyruvate (PEP) from glutamine via the activity of mitochondrial PEP-carboxykinase (PCK2). Under these conditions, glutamine-derived PEP was used to fuel biosynthetic pathways normally sustained by glucose, including serine and purine biosynthesis. PCK2 expression was required to maintain tumor cell proliferation under limited-glucose conditions in vitro and tumor growth in vivo. Elevated PCK2 expression is observed in several human tumor types and enriched in tumor tissue from non-small-cell lung cancer (NSCLC) patients. Our results define a role for PCK2 in cancer cell metabolic reprogramming that promotes glucose-independent cell growth and metabolic stress resistance in human tumors.

Treatment of Syphilis With Doxycycline in a Pregnant Woman Unable to Be Desensitized to Penicillin.

ABSTRACT: A pregnant woman with a non-IgE-mediated penicillin allergy was treated for syphilis with doxycycline with resolution of infection and no evidence of adverse outcome for mother or infant.

A Randomized, Placebo-Controlled, Respiratory Syncytial Virus Human Challenge Study of the Antiviral Efficacy, Safety, and Pharmacokinetics of RV521, an Inhibitor of the RSV-F Protein.

Effective treatments for respiratory syncytial virus (RSV) infection are lacking. Here, we report a human proof-of-concept study for RV521, a small-molecule antiviral inhibitor of the RSV-F protein. In this randomized, double-blind, placebo-controlled trial, healthy adults were challenged with RSV-A Memphis-37b. After infection was confirmed (or 5 days after challenge virus inoculation), subjects received RV521 (350 mg or 200 mg) or placebo orally every 12 h for 5 days. The primary endpoint was area under the curve (AUC) for viral load, as assessed by reverse transcriptase quantitative PCR (RT-qPCR) of nasal wash samples. The primary efficacy analysis set included subjects successfully infected with RSV who received ≥1 dose of study drug. A total of 66 subjects were enrolled (n = 22 per group); 53 were included in the primary analysis set (RV521 350 mg: n = 16; 200 mg: n = 18; placebo: n = 19). The mean AUC of RT-qPCR-assessed RSV viral load (log10 PFU equivalents [PFUe]/ml · h) was significantly lower with RV521 350 mg (185.26; standard error [SE], 31.17; P = 0.002) and 200 mg (224.35; SE, 37.60; P = 0.007) versus placebo (501.39; SE, 86.57). Disease severity improved with RV521 350 mg and 200 mg versus placebo (P = 0.002 and P = 0.009, respectively, for AUC total symptom score [score × hours]). Daily nasal mucus weight was significantly reduced (P = 0.010 and P = 0.038 for RV521 350 mg and 200 mg, respectively, versus placebo). All treatment-emergent adverse events were grade 1 or 2. No subjects discontinued due to adverse events. There was no evidence of clinically significant viral resistance, and only three variants were detected. RV521 effectively reduced RSV viral load and disease severity in humans and was well tolerated. (This study has been registered at ClinicalTrials.gov under registration no. NCT03258502.).

Isoform-specific AMPK association with TBC1D1 is reduced by a mutation associated with severe obesity.

AMP-activated protein kinase (AMPK) is a key regulator of cellular and systemic energy homeostasis which achieves this through the phosphorylation of a myriad of downstream targets. One target is TBC1D1 a Rab-GTPase-activating protein that regulates glucose uptake in muscle cells by integrating insulin signalling with that promoted by muscle contraction. Ser237 in TBC1D1 is a target for phosphorylation by AMPK, an event which may be important in regulating glucose uptake. Here, we show AMPK heterotrimers containing the α1, but not the α2, isoform of the catalytic subunit form an unusual and stable association with TBC1D1, but not its paralogue AS160. The interaction between the two proteins is direct, involves a dual interaction mechanism employing both phosphotyrosine-binding (PTB) domains of TBC1D1 and is increased by two different pharmacological activators of AMPK (AICAR and A769962). The interaction enhances the efficiency by which AMPK phosphorylates TBC1D1 on its key regulatory site, Ser237 Furthermore, the interaction is reduced by a naturally occurring R125W mutation in the PTB1 domain of TBC1D1, previously found to be associated with severe familial obesity in females, with a concomitant reduction in Ser237 phosphorylation. Our observations provide evidence for a functional difference between AMPK α-subunits and extend the repertoire of protein kinases that interact with substrates via stabilisation mechanisms that modify the efficacy of substrate phosphorylation.

Self-management approaches for osteoarthritis in the hand: a 2×2 factorial randomised trial.

BACKGROUND: Osteoarthritis is the leading cause of disability in older adults. Evidence of effectiveness for self-management of hand osteoarthritis is lacking. METHODS: In this randomised, factorial trial, we evaluated the effectiveness of joint protection versus no joint protection, and hand exercise versus no hand exercise in adults, 50 years of age or older, with hand osteoarthritis. Following a population survey (n=12 297), eligible individuals were randomly assigned (1:1:1:1) to: leaflet and advice; joint protection; hand exercise; joint protection plus hand exercise. Joint protection and hand exercises were delivered by nine occupational therapists, over four group sessions. The primary outcome was the OARSI/OMERACT responder criteria at 6 months. Outcomes were collected blind to allocation (3, 6, 12 m). Analysis was by intention to treat. RESULTS: Of 257 participants randomised (65:62:65:65) (mean age (SD) 66 years (9.1); female 66%) follow-up was 85% at 6 m (n=212). Baseline characteristics and loss to follow-up were similar between groups. There were no reported treatment side effects. At 6 m 33% assigned joint protection were responders compared with 21% with no joint protection (p=0.03). Of those assigned hand exercises, 28% were responders compared with 25% with no exercises (n.s.). Differences in secondary outcomes were not statistically significant, except for improvement in pain self-efficacy with joint protection (3 m p=0.002; 6 m p=0.001; 12 m p=0.03). CONCLUSIONS: These findings show that occupational therapists can support self-management in older adults with hand osteoarthritis, and that joint protection provides an effective intervention for medium term outcome. (Funded by the Arthritis Research UK ISRCTN 33870549).

The population prevalence of symptomatic radiographic foot osteoarthritis in community-dwelling older adults: cross-sectional findings from the clinical assessment study of the foot.

OBJECTIVES: To estimate the population prevalence of symptomatic radiographic osteoarthritis (OA) affecting the 1st metatarsophalangeal joint (MTPJ), 1st and 2nd cuneometatarsal joints (CMJs), navicular first cuneiform joint (NCJ) and talonavicular joint (TNJ) in community-dwelling older adults. METHODS: 9334 adults aged ≥50 years registered with four general practices were mailed a health survey. Responders reporting foot pain within the last 12 months were invited to undergo weight-bearing dorso-plantar and lateral radiographs of both feet. OA at the 1st MTPJ, 1st and 2nd CMJs, NCJ and TNJ was graded using a validated atlas. Population prevalence estimates for symptomatic radiographic foot OA overall and for each joint were calculated using multiple imputation and weighted logistic regression modelling to account for missing data and non-response. RESULTS: 5109 health surveys were received (adjusted response 56%). Radiographs were obtained on 557 participants. Overall population prevalence of symptomatic radiographic OA was 16.7% (95% CI 15.3% to 18.0%), 1st MTPJ 7.8% (6.7% to 8.9%), 1st CMJ 3.9% (2.9% to 4.9%), 2nd CMJ 6.8% (5.7% to 7.8%), NCJ 5.2% (4.0% to 6.4%) and TNJ 5.8% (4.8% to 6.9%). With the exception of the 1st CMJ, prevalence was greater in females than males, increased with age and was higher in lower socioeconomic classes. Three-quarters of those with symptomatic radiographic OA reported disabling foot symptoms. CONCLUSIONS: While cautious interpretation due to non-response is warranted, our study suggests that symptomatic radiographic foot OA affects one in six older adults and the majority report associated disability. Clinicians should consider OA as a possible cause of chronic foot pain in older people.

Maximising response from GPs to questionnaire surveys: do length or incentives make a difference?

BACKGROUND: General Practitioners (GPs) respond poorly to postal surveys. Consequently there is potential for reduced data quality and bias in the findings. In general population surveys, response to postal questionnaires may be improved by reducing their length and offering incentives. The aim of this study was to investigate whether questionnaire length and/or the offer of an incentive improves the response of GPs to a postal questionnaire survey. METHODS: A postal questionnaire survey was sent to 800 UK GPs randomly selected from Binley's database; a database containing contact details of professionals working in UK general practices. The random sample of GPs was assigned to one of four groups of 200, each receiving a different questionnaire, either a standard (eight sides of A4) or an abbreviated (four sides of A4) questionnaire, with or without the offer of an incentive (a prize draw entry for a £100 voucher) for completion. The effects of questionnaire length and offer of incentive on response were calculated. RESULTS: Of 800 mailed questionnaires, 19 GPs did not meet inclusion criteria and 172 (adjusted response 22.0%) completed questionnaires were received. Among the four groups, response ranged from 20.1% (standard questionnaire with no incentive and abbreviated questionnaire with incentive) through 21.8% (standard questionnaire with incentive), to 26.0% (abbreviated questionnaire with no incentive). There were no significant differences in response between the four groups (p = 0.447), between the groups receiving the standard versus the abbreviated questionnaire (% difference -2.1% (95% confidence interval (CI) -7.9, 3.7)) or the groups offered an incentive versus no incentive (% difference -2.1% (95% CI -7.9, 3.7). CONCLUSIONS: Strategies known to improve response to postal questionnaire surveys in the general population do not significantly improve the response to postal questionnaire surveys among GPs. Further refinements to these strategies, or more novel strategies, aimed at increasing response specifically among GPs need to be identified in order to maximise data quality and generalisability of research results.

Pain location matters: the impact of leg pain on health care use, work disability and quality of life in patients with low back pain.

PURPOSE: In low back pain (LBP) patients, those with radiating leg pain or sciatica have poorer pain and disability outcomes. Few studies have assessed the effect of leg pain on health care use and quality of life. METHODS: Prospective cohort study of 1,581 UK LBP primary care consulters. Back pain, employment, health care utilisation, and quality of life (EQ-5D) data were collected at baseline, 6 and 12 months. At baseline, patients were classified as reporting (1) LBP only, (2) LBP and leg pain above the knee only (LBP + AK) or (3) LBP and leg pain extending below the knee (LBP + BK). RESULTS: Self-reported leg pain was common; at baseline 645 (41 %) reported LBP only, 392 (25 %) reported LBP + AK and 544 (34 %) reported LBP + BK. Patients with LBP + BK, compared to those with LBP only, were significantly more likely to be unemployed, take time off work, consult their family doctor, receive physical therapy, or be referred to other health care practitioners. There were statistically significant decrements in EQ-5D scores for LBP + AK compared to LBP only, and for LBP + BK compared to LBP + AK (p ≤ 0.05 for all comparisons). CONCLUSIONS: Patients with self-reported leg pain below the knee utilise more health care are more likely to be unemployed and have poorer quality of life than those with LBP only 12 months following primary care consultation. The presence of leg pain warrants early identification in primary care to explore if targeted interventions can reduce the impact and consequences of leg pain.

Defining and mapping the person with osteoarthritis for population studies and public health.

OBJECTIVE: To determine population-based estimates for the prevalence of the person with OA, predicted to be the single greatest cause of disability in the general population by 2030, in order to inform the planning and commissioning of health, social care and prevention services. METHODS: A postal survey to all adults ≥50 years of age registered with eight general practices in the UK. Self-reported data on chronic joint pain in four body regions (hand, hip, knee, foot) and the disabling nature of the pain was collected to determine gender and age-group specific prevalence estimates of clinical OA in the joint region and in the person. Multiple imputation and weighted logistic regression was used to allow for missing data. RESULTS: A total of 26 705 mailed surveys resulted in 18 474 responses (adjusted response = 71.8%). Approximately half of the mailed population had OA in at least one of the four regions (53.23%, 95% CI 52.3, 54.1) and less than half of these had disabling OA (21.87%, 95% CI 21.2, 22.5). The more joint regions involved, the more likely that the OA was disabling. OA prevalence was higher in females and increased with age. Applied to the population of England, this yielded an estimated 3.5 million persons with disabling OA, including 1.45 million people between 50 and 65 years of age and 370 000 ≥85 years of age. CONCLUSIONS: A simple approach to defining the person with OA can contribute to population comparisons, public health projections and health care needs assessments.

Pain at multiple body sites and health-related quality of life in older adults: results from the North Staffordshire Osteoarthritis Project.

OBJECTIVES: Number of pain sites (NPS) is a potentially important marker of health-related quality of life (HRQoL) but remains unexplored in older people. This cross-sectional study investigated whether, in older people including the oldest old, NPS was independently associated with poorer mental and physical HRQoL and if the association was moderated by age. METHODS: A postal questionnaire sent to a population sample of adults aged ≥50 years in North Staffordshire, UK, included the 12-item Short Form Health Survey (SF-12) mental component summary (MCS) and physical component summary (PCS), a blank body pain manikin, socio-demographic, health behaviour and morbidity questions. Participants shaded sites of pain lasting ≥1 day in the past 4 weeks on the manikin. OA consultation data were obtained for participants consenting to medical records review. RESULTS: A total of 13 986 individuals (adjusted response 70.6%) completed a questionnaire, of which 12 408 provided complete pain data. The median NPS reported was 4 [interquartile range (IQR) 0-8]. General linear models showed that an increasing NPS was significantly associated with poorer MCS (ß = -0.43, 95% CI -0.46, -0.40) and PCS (ß = -0.87, 95% CI -0.90, -0.84). Adjustment for covariates attenuated the associations but they remained significant ( MCS: ß = -0.28, 95% CI -0.31, -0.24; PCS: ß = -0.63, 95% CI -0.66, -0.59). The association between NPS and MCS or PCS was moderated by age, but the strongest associations were not in the oldest old. CONCLUSION: NPS appears to be a potentially modifiable target for improving physical and mental HRQoL in older people. Future analyses should investigate the influence of NPS on HRQoL over time in older people.

Engineering tumor-colonizing E. coli Nissle 1917 for detection and treatment of colorectal neoplasia.

Bioengineered probiotics enable new opportunities to improve colorectal cancer (CRC) screening, prevention and treatment. Here, first, we demonstrate selective colonization of colorectal adenomas after oral delivery of probiotic E. coli Nissle 1917 (EcN) to a genetically-engineered murine model of CRC predisposition and orthotopic models of CRC. We next undertake an interventional, double-blind, dual-centre, prospective clinical trial, in which CRC patients take either placebo or EcN for two weeks prior to resection of neoplastic and adjacent normal colorectal tissue (ACTRN12619000210178). We detect enrichment of EcN in tumor samples over normal tissue from probiotic-treated patients (primary outcome of the trial). Next, we develop early CRC intervention strategies. To detect lesions, we engineer EcN to produce a small molecule, salicylate. Oral delivery of this strain results in increased levels of salicylate in the urine of adenoma-bearing mice, in comparison to healthy controls. To assess therapeutic potential, we engineer EcN to locally release a cytokine, GM-CSF, and blocking nanobodies against PD-L1 and CTLA-4 at the neoplastic site, and demonstrate that oral delivery of this strain reduces adenoma burden by ~50%. Together, these results support the use of EcN as an orally-deliverable platform to detect disease and treat CRC through the production of screening and therapeutic molecules.

Molecular Characterization of Testicular Mesothelioma and the Role of Asbestos as a Causative Factor.

CONTEXT.­: Mesothelioma of the tunica vaginalis testis (TVT) is an extremely rare form of mesothelioma. OBJECTIVE.­: To compare the clinical and molecular characteristics of mesothelioma of the TVT with those of mesothelioma at other more common sites, including the relationship with exposure to asbestos. DESIGN.­: We present clinical and pathological data for 9 cases of primary TVT mesothelioma. We performed whole-genome sequencing on 3 cases for the first time. RESULTS.­: The majority (7 of 9 cases) of TVT mesotheliomas were epithelioid, with the remaining 2 cases showing biphasic morphology. Morphology and immunohistochemical profiles were indistinguishable from mesothelioma elsewhere. Asbestos exposure was documented for 7 of the 9 cases, with no information for 2 cases. The 3 TVT mesothelioma cases that underwent whole-genome sequencing displayed a mutational profile similar to that of mesothelioma at other sites, including NF2 and TP53 mutations. CONCLUSIONS.­: The clinical and molecular profile of TVT mesothelioma is similar to that of mesothelioma elsewhere.

Engineered bacteria detect tumor DNA.

Synthetic biology has developed sophisticated cellular biosensors to detect and respond to human disease. However, biosensors have not yet been engineered to detect specific extracellular DNA sequences and mutations. Here, we engineered naturally competent Acinetobacter baylyi to detect donor DNA from the genomes of colorectal cancer (CRC) cells, organoids, and tumors. We characterized the functionality of the biosensors in vitro with coculture assays and then validated them in vivo with sensor bacteria delivered to mice harboring colorectal tumors. We observed horizontal gene transfer from the tumor to the sensor bacteria in our mouse model of CRC. This cellular assay for targeted, CRISPR-discriminated horizontal gene transfer (CATCH) enables the biodetection of specific cell-free DNA.

Colorectal cancer detection and treatment with engineered probiotics.

Bioengineered probiotics enable new opportunities to improve colorectal cancer (CRC) screening, prevention and treatment strategies. Here, we demonstrate the phenomenon of selective, long-term colonization of colorectal adenomas after oral delivery of probiotic E. coli Nissle 1917 (EcN) to a genetically-engineered murine model of CRC predisposition. We show that, after oral administration, adenomas can be monitored over time by recovering EcN from stool. We also demonstrate specific colonization of EcN to solitary neoplastic lesions in an orthotopic murine model of CRC. We then exploit this neoplasia-homing property of EcN to develop early CRC intervention strategies. To detect lesions, we engineer EcN to produce a small molecule, salicylate, and demonstrate that oral delivery of this strain results in significantly increased levels of salicylate in the urine of adenoma-bearing mice, in comparison to healthy controls. We also assess EcN engineered to locally release immunotherapeutics at the neoplastic site. Oral delivery to mice bearing adenomas, reduced adenoma burden by ∻50%, with notable differences in the spatial distribution of T cell populations within diseased and healthy intestinal tissue, suggesting local induction of robust anti-tumor immunity. Together, these results support the use of EcN as an orally-delivered platform to detect disease and treat CRC through its production of screening and therapeutic molecules.

Hand assessment in older adults with musculoskeletal hand problems: a reliability study.

BACKGROUND: Musculoskeletal hand pain is common in the general population. This study aims to investigate the inter- and intra-observer reliability of two trained observers conducting a simple clinical interview and physical examination for hand problems in older adults. The reliability of applying the American College of Rheumatology (ACR) criteria for hand osteoarthritis to community-dwelling older adults will also be investigated. METHODS: Fifty-five participants aged 50 years and over with a current self-reported hand problem and registered with one general practice were recruited from a previous health questionnaire study. Participants underwent a standardised, structured clinical interview and physical examination by two independent trained observers and again by one of these observers a month later. Agreement beyond chance was summarised using Kappa statistics and intra-class correlation coefficients. RESULTS: Median values for inter- and intra-observer reliability for clinical interview questions were found to be "substantial" and "moderate" respectively [median agreement beyond chance (Kappa) was 0.75 (range: -0.03, 0.93) for inter-observer ratings and 0.57 (range: -0.02, 1.00) for intra-observer ratings]. Inter- and intra-observer reliability for physical examination items was variable, with good reliability observed for some items, such as grip and pinch strength, and poor reliability observed for others, notably assessment of altered sensation, pain on resisted movement and judgements based on observation and palpation of individual features at single joints, such as bony enlargement, nodes and swelling. Moderate agreement was observed both between and within observers when applying the ACR criteria for hand osteoarthritis. CONCLUSION: Standardised, structured clinical interview is reliable for taking a history in community-dwelling older adults with self reported hand problems. Agreement between and within observers for physical examination items is variable. Low Kappa values may have resulted, in part, from a low prevalence of clinical signs and symptoms in the study participants. The decision to use clinical interview and hand assessment variables in clinical practice or further research in primary care should include consideration of clinical applicability and training alongside reliability. Further investigation is required to determine the relationship between these clinical questions and assessments and the clinical course of hand pain and hand problems in community-dwelling older adults.

Impairment-targeted exercises for older adults with knee pain: protocol for a proof-of-principle study.

BACKGROUND: Exercise therapy for knee pain and osteoarthritis remains a key element of conservative treatment, recommended in clinical guidelines. Yet systematic reviews point to only modest benefits from exercise interventions.One reason for this might be that clinical trials tend to use a one-size-fits-all approach to exercise, effectively disregarding the details of their participants' clinical presentations. This uncontrolled before-after study (TargET-Knee-Pain) aims to test the principle that exercises targeted at the specific physical impairments of older adults with knee pain may be able to significantly improve those impairments. It is a first step towards testing the effectiveness of this more individually-tailored approach. METHODS/DESIGN: We aim to recruit 60 participants from an existing observational cohort of community-dwelling older adults with knee pain. Participants will all have at least one of the three physical impairments of weak quadriceps, a reduced range of knee flexion and poor standing balance. Each participant will be asked to undertake a programme of exercises, targeted at their particular combination and degree of impairment(s), over the course of twelve weeks. The exercises will be taught and progressed by an experienced physiotherapist, with reference to a "menu" of agreed exercises for each of the impairments, over the course of six fortnightly home visits, alternating with six fortnightly telephone calls. Primary outcome measures will be isometric quadriceps strength, knee flexion range of motion, timed single-leg standing balance and the "Four Balance Test Scale" at 12 weeks. Key secondary outcome measures will be self-reported levels of pain, stiffness and difficulties with day-to-day functional tasks (WOMAC). Outcome measures will be taken at three time-points (baseline, six weeks and twelve weeks) by a study nurse blinded to the exercise status of the participants. DISCUSSION: This study (TargET-Knee-Pain) is the first step towards exploring whether an impairment-targeted approach to exercise prescription for older adults with knee pain may have sufficient efficacy to warrant further testing. If warranted, future randomised clinical trials may compare this approach with more traditional one-size-fits-all exercise approaches. TRIAL REGISTRATION: Current Controlled Trials ISRCTN61638364.