CD3 downregulation identifies high-avidity human CD8 T cells.

CD8 T cells recognize infected and cancerous cells via their T-cell receptor (TCR), which binds peptide-MHC complexes on the target cell. The affinity of the interaction between the TCR and peptide-MHC contributes to the antigen sensitivity, or functional avidity, of the CD8 T cell. In response to peptide-MHC stimulation, the TCR-CD3 complex and CD8 co-receptor are downmodulated. We quantified CD3 and CD8 downmodulation following stimulation of human CD8 T cells with CMV, EBV, and HIV peptides spanning eight MHC restrictions, observing a strong correlation between the levels of CD3 and CD8 downmodulation and functional avidity, regardless of peptide viral origin. In TCR-transduced T cells targeting a tumor-associated antigen, changes in TCR-peptide affinity were sufficient to modify CD3 and CD8 downmodulation. Correlation analysis and generalized linear modeling indicated that CD3 downmodulation was the stronger correlate of avidity. CD3 downmodulation, simply measured using flow cytometry, can be used to identify high-avidity CD8 T cells in a clinical context.

Using care and support planning to implement routine falls prevention and management for people living with frailty: A qualitative evaluation.

BACKGROUND: Frailty is a key issue in current healthcare delivery and falls is an important component. Care and support planning (CSP) is an established approach to managing long term conditions (LTCs) and has potential to provide more person-centred care for those at risk of falling. This qualitative evaluation aimed to understand the barriers and success criteria involved in incorporating falls assessment and management into the CSP process. METHODS: CSP for falls prevention was implemented in eight general practices in the North of England. Six of the eight practices participated in the qualitative evaluation. Seven group interviews were undertaken with staff (n = 31) that included practice nurses, health care assistants, nurses, and administrative staff (n = 2-8 per group). Observations of the falls and CSP training provided additional data. Interviews covered experiences and potential impacts of training, and processes of implementation of the programme, and were informed by normalisation process theory. Thematic analysis was undertaken using a team-based approach. RESULTS: Although successfully implemented across the practices, how established CSP was and therefore 'organisational readiness' was an overarching theme that illustrated differences in how easily sites were able to implement the additional elements for frailty. The challenges, successes and impacts of implementation are demonstrated through this theme and four further themes: training resources and learning; positive impacts of the programme (including enabling easier conversations around 'frailty'); integrating work processes/work with patients; and dealing with uncertainty and complexity. CONCLUSIONS: Care and Support Planning services designed to target frailty and falls is feasible and can successfully be delivered in the primary care setting, if key enablers are promoted and challenges to implementation addressed from planning through to integration in practice.

A rare case of lues maligna in an HIV-negative woman.

We describe an HIV-negative 43-year-old woman presenting with a diffuse ulceronodular eruption and positive serological tests for syphilis consistent with lues maligna. Lues maligna is a severe and rare variant of secondary syphilis characterized by prodromal constitutional symptoms followed by the formation of multiple well-circumscribed nodules with ulceration and crust. This case depicts a particularly rare presentation as lues maligna usually involves HIV-positive men. The clinical presentation of lues maligna can pose a diagnostic challenge, with infections, sarcoidosis, and cutaneous lymphoma as just a few entities in its broad differential diagnosis. However, with a high index of suspicion, clinicians can diagnose and treat this entity earlier and reduce morbidity.

Fall prevention interventions in primary care to reduce fractures and falls in people aged 70 years and over: the PreFIT three-arm cluster RCT.

BACKGROUND: Falls and fractures are a major problem. OBJECTIVES: To investigate the clinical effectiveness and cost-effectiveness of alternative falls prevention interventions. DESIGN: Three-arm, pragmatic, cluster randomised controlled trial with parallel economic analysis. The unit of randomisation was the general practice. SETTING: Primary care. PARTICIPANTS: People aged ≥ 70 years. INTERVENTIONS: All practices posted an advice leaflet to each participant. Practices randomised to active intervention arms (exercise and multifactorial falls prevention) screened participants for falls risk using a postal questionnaire. Active treatments were delivered to participants at higher risk of falling. MAIN OUTCOME MEASURES: The primary outcome was fracture rate over 18 months, captured from Hospital Episode Statistics, general practice records and self-report. Secondary outcomes were falls rate, health-related quality of life, mortality, frailty and health service resource use. Economic evaluation was expressed in terms of incremental cost per quality-adjusted life-year and incremental net monetary benefit. RESULTS: Between 2011 and 2014, we randomised 63 general practices (9803 participants): 21 practices (3223 participants) to advice only, 21 practices (3279 participants) to exercise and 21 practices (3301 participants) to multifactorial falls prevention. In the active intervention arms, 5779 out of 6580 (87.8%) participants responded to the postal fall risk screener, of whom 2153 (37.3%) were classed as being at higher risk of falling and invited for treatment. The rate of intervention uptake was 65% (697 out of 1079) in the exercise arm and 71% (762 out of 1074) in the multifactorial falls prevention arm. Overall, 379 out of 9803 (3.9%) participants sustained a fracture. There was no difference in the fracture rate between the advice and exercise arms (rate ratio 1.20, 95% confidence interval 0.91 to 1.59) or between the advice and multifactorial falls prevention arms (rate ratio 1.30, 95% confidence interval 0.99 to 1.71). There was no difference in falls rate over 18 months (exercise arm: rate ratio 0.99, 95% confidence interval 0.86 to 1.14; multifactorial falls prevention arm: rate ratio 1.13, 95% confidence interval 0.98 to 1.30). A lower rate of falls was observed in the exercise arm at 8 months (rate ratio 0.78, 95% confidence interval 0.64 to 0.96), but not at other time points. There were 289 (2.9%) deaths, with no differences by treatment arm. There was no evidence of effects in prespecified subgroup comparisons, nor in nested intention-to-treat analyses that considered only those at higher risk of falling. Exercise provided the highest expected quality-adjusted life-years (1.120), followed by advice and multifactorial falls prevention, with 1.106 and 1.114 quality-adjusted life-years, respectively. NHS costs associated with exercise (£3720) were lower than the costs of advice (£3737) or of multifactorial falls prevention (£3941). Although incremental differences between treatment arms were small, exercise dominated advice, which in turn dominated multifactorial falls prevention. The incremental net monetary benefit of exercise relative to treatment valued at £30,000 per quality-adjusted life-year is modest, at £191, and for multifactorial falls prevention is £613. Exercise is the most cost-effective treatment. No serious adverse events were reported. LIMITATIONS: The rate of fractures was lower than anticipated. CONCLUSIONS: Screen-and-treat falls prevention strategies in primary care did not reduce fractures. Exercise resulted in a short-term reduction in falls and was cost-effective. FUTURE WORK: Exercise is the most promising intervention for primary care. Work is needed to ensure adequate uptake and sustained effects. TRIAL REGISTRATION: Current Controlled Trials ISRCTN71002650. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 34. See the NIHR Journals Library website for further project information.

WHAT IS THE PROBLEM?: Falls are a major problem for older people. Current practice is to give people advice leaflets. Another approach is exercise, especially balance and strength training. A third alternative is to invite older people to attend a falls assessment with a health-care professional, either a doctor or a trained nurse. This usually involves a careful check of prescribed tablets, blood pressure, eyesight and other problems that might cause falls. WHAT DID WE DO?: We compared three strategies. We recruited 9803 people aged 70­101 years from 63 general practices across England. We randomly allocated practices in clusters into three treatment groups. The participants in one group were given a Staying Steady advice leaflet (Age UK. Staying Steady. London: Age UK; 2009). Participants in the second group received the same leaflet and were assessed to see if they were at higher risk of falling. Those participants identified as being at higher risk (about 1000 people) were invited to take part in an exercise programme, supported by an exercise therapist. These people did balance and strength training at home for up to 6 months. In the third group, we again identified participants who were at higher risk of falling (about 1000 people) and invited them for a detailed falls assessment with a trained nurse or doctor. This last group of participants were referred for other treatments if any health problems were found. In all groups we counted fractures and falls and measured changes in quality of life, frailty and the cost of the treatments over 18 months of follow-up. WHAT DID WE FIND OUT?: We found no difference in the number of fractures over 18 months between the different treatments. The exercise programme reduced falls in the short term but not over the longer term. The exercise programme was cheaper and led to a slightly better overall quality of life.

Group clinic for chemoprevention of squamous cell carcinoma: a pilot study.

Topical 5-fluorouracil (5-FU) is a valuable treatment of actinic keratosis (AK), but its use is limited by bothersome side effects. To evaluate patient satisfaction with a regimen of 5-FU for AK in group clinics, we offered participation in shared medical appointments (SMAs) to dermatology clinic patients diagnosed with AK at the Providence VA Medical Center in Rhode Island. Approximately 3 to 4 patients attended each pair of sessions spaced 2 weeks apart. At each visit, photographs and feedback were obtained; at the second visit, clinicians graded the patients' reactions to 5-FU according to a validated numeric scale. Of the 14 study patients who attended the second SMA, 10 stated that they completed 2 weeks of 5-FU therapy, and the other 4 stated that they completed at least 11 days. The validated scale used during the second visit to grade the patients' 5-FU reactions confirmed that all 14 patients demonstrated at least 1 expected adverse skin reaction. Feedback about the group setting was uniformly positive, with specific appreciation for the educational aspects, normalization of the treatment process, and opportunities to ask questions. The group clinic setting for 5-FU was well received and is a promising model for delivering this important treatment.

Validation of the Three-Item Skindex-Mini Among Hidradenitis Suppurativa Patients With Diverse Racial Backgrounds.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease that severely impairs patients' quality of life (QoL). Instruments such as the 10-item Dermatology Life Quality Index and 16-item Skindex-16 have been used to assess QoL in HS; however, it is unknown whether the shorter 3-item Skindex-mini can also provide an accurate assessment of skin-related QoL in patients with HS. OBJECTIVES: The aim was to assess how well the Skindex-16 correlates with its shorter adaptation, the Skindex-mini, in capturing QoL among patients with HS. METHODS: This retrospective cross-sectional study included all HS patients seen in the HS Clinic at The Emory Clinic between January 1, 2019, and August 16, 2019. We compared the correlation between the symptom, emotion, and function domains of the Skindex-16 and Skindex-mini using Pearson correlation coefficients (CC). Secondary outcome measures included individual survey item analysis, ItchyQuant scores, and numeric rating scale of pain. RESULTS: We identified 108 encounters among 75 unique hidradenitis suppurativa patients (43 black/African American, 18 white, 5 Asian/Pacific Islander, 3 Latino, 4 Other, 2 unknown). Pearson CC between the Skindex-16 and Skindex-mini domain scores for all encounters were 0.770 (P < .001), 0.787 (P < .001), and 0.801 (P < .001) for the symptom, emotion, and function domains, respectively. The mean pain and ItchyQuant scores were 4.14 (SD 3.31) and 3.55 (SD 3.34), respectively. CONCLUSIONS: The Skindex-mini correlated highly with the Skindex-16 in a racially diverse group of patients with HS. The Skindex-mini is a streamlined QoL instrument that could be practically implemented into routine clinical care among diverse patients presenting to dermatology.

The importance of different frailty domains in a population based sample in England.

BACKGROUND: The aim was to estimate the prevalence of frailty and relative contribution of physical/balance, nutritive, cognitive and sensory frailty to important adverse health states (falls, physical activity levels, outdoor mobility, problems in self-care or usual activities, and lack of energy or accomplishment) in an English cohort by age and sex. METHODS: Analysis of baseline data from a cohort of 9803 community-dwelling participants in a clinical trial. The sample was drawn from a random selection of all people aged 70 or more registered with 63 general practices across England. Data were collected by postal questionnaire. Frailty was measured with the Strawbridge questionnaire. We used cross sectional, multivariate logistic regression to estimate the association between frailty domains and known correlates and adjusted for age. Some models were stratified by sex. RESULTS: Mean age of participants was 78 years (sd 5.7), range 70 to 101 and 47.5% (4653/9803) were men. The prevalence of overall frailty was 20.7% (2005/9671) and there was no difference in prevalence by sex (Odds Ratio 0.98; 95% Confidence Interval 0.89 to 1.08). Sensory frailty was the most common and this was reported by more men (1823/4586) than women (1469/5056; Odds Ratio for sensory frailty 0.62, 95% Confidence Interval 0.57 to 0.68). Men were less likely than women to have physical or nutritive frailty. Physical frailty had the strongest independent associations with adverse health states. However, sensory frailty was independently associated with falls, less frequent walking, problems in self-care and usual activities, lack of energy and accomplishment. CONCLUSIONS: Physical frailty was more strongly associated with adverse health states, but sensory frailty was much more common. The health gain from intervention for sensory frailty in England is likely to be substantial, particularly for older men. Sensory frailty should be explored further as an important target of intervention to improve health outcomes for older people both at clinical and population level. TRIAL REGISTRATION: ISRCTN71002650.

Comparing Topical Treatments for Basal Cell Carcinoma.

Superficial basal cell carcinoma is a type of keratinocyte carcinoma that has increasing incidence and substantial morbidity. Jansen et al. report on a randomized trial with 5 years of follow-up that found imiquimod to be more effective than 5-fluorouracil or methyl aminolevulinate photodynamic therapy in preventing superficial basal cell carcinoma recurrence. However, the toxicity and cost of topical treatments, as well as patient preferences, need to be evaluated when making treatment decisions in clinical practice.

Chemoprevention of Basal and Squamous Cell Carcinoma With a Single Course of Fluorouracil, 5%, Cream: A Randomized Clinical Trial.

Importance: Keratinocyte carcinoma (ie, cutaneous basal and squamous cell carcinoma) is the most common cancer in the United States. Objective: To determine whether topical fluorouracil could prevent surgically treated keratinocyte carcinoma. Design, Setting, and Participants: The Veterans Affairs Keratinocyte Carcinoma Chemoprevention Trial was a randomized, double-blind, placebo-controlled trial of topical fluorouracil for chemoprevention of keratinocyte carcinoma. Participants were recruited from May 2009 to September 2011 from 12 Veterans Affairs medical centers and followed until June 30, 2013. Participants were veterans (n = 932) with a history of at least 2 keratinocyte carcinomas in the past 5 years; almost all were white males and the median age was 70 years. Interventions: Application of fluorouracil, 5%, (n = 468) or vehicle control cream (n = 464) to the face and ears twice daily for 2 to 4 weeks upon randomization. Main Outcomes and Measures: Surgically treated keratinocyte, basal cell, and squamous cell carcinoma risk on the face and ears in the first year after enrollment; and time to first surgically treated keratinocyte, basal cell, and squamous cell carcinoma. The a priori hypothesis was that fluorouracil would be effective in preventing these cancers. Results: Of 932 participants (916 men [98%]; 926 white [99%]; median age, 70 years), 299 developed a basal cell carcinoma end point (95 in year 1) and 108 developed a squamous cell carcinoma end point (25 in year 1) over 4 years (median follow-up, 2.8 years). Over the entire study, there was no difference between treatment groups in time to first keratinocyte, basal cell, or squamous cell carcinoma. During the first year, however, 5 participants (1%) in the fluorouracil group developed a squamous cell carcinoma vs 20 (4%) in the control group, a 75% (95% CI, 35%-91%) risk reduction (P = .002). The 11% reduction in basal cell carcinoma risk during year 1 (45 [10%] in the fluorouracil group vs 50 [11%] in the control group) was not statistically significant (95% CI, 39% reduction to 31% increase), nor was there a significant effect on keratinocyte carcinoma risk. However, a reduction in keratinocyte carcinomas treated with Mohs surgery was observed. Conclusions and Relevance: A conventional course of fluorouracil to the face and ears substantially reduces surgery for squamous cell carcinoma for 1 year without significantly affecting the corresponding risk for basal cell carcinoma. Trial Registration: clinicaltrials.gov Identifier: NCT00847912.

Racial disparities in the impact of chronic pruritus: A cross-sectional study on quality of life and resource utilization in United States veterans.

BACKGROUND: Chronic pruritus has a lifetime prevalence of up to 26% in the worldwide population. Research has shown that the incidence and quality of life (QoL) impact of chronic pruritus varies by race. OBJECTIVE: We sought to explore the effects of race on specific pruritus-related QoL factors and resource utilization. METHODS: We performed a cross-sectional, national telephone survey of 6000 US veterans randomly sampled from the Veterans Hospital Patient Database. We administered surveys to assess QoL impact and resource utilization of chronic pruritus. RESULTS: Nonwhites overall reported higher levels of burning and scarring with their pruritus. African Americans had a significantly greater emotional impact and use of special soaps, lotions, and clothes. African Americans were also more likely to visit their primary care provider for pruritus (P = .03), yet had similar numbers of specialty care visits. LIMITATIONS: Because our sample was drawn from a veteran population, generalizability may be limited. CONCLUSION: The data indicate a racial disparity in specific QoL impact and resource utilization from pruritus. These findings merit further exploration into explanations, such as access, communication, trust of the medical system, and biologic differences.

Phenformin Enhances the Efficacy of ERK Inhibition in NF1-Mutant Melanoma.

Inactivation of the tumor suppressor neurofibromin 1 (NF1) presents a newly characterized melanoma subtype, for which currently no targeted therapies are clinically available. Preclinical studies suggest that extracellular signal-regulated kinase (ERK) inhibitors are likely to provide benefit, albeit with limited efficacy as a single agent; therefore, there is a need for rationally designed combination therapies. Here, we evaluate the combination of the ERK inhibitor SCH772984 and the biguanide phenformin. A combination of both compounds showed potent synergy in cell viability assays and cooperatively induced apoptosis. Treatment with both drugs was required to fully suppress mechanistic target of rapamycin signaling, a known effector of NF1 loss. Mechanistically, SCH772984 increased the oxygen consumption rate, indicating that these cells relied more on oxidative phosphorylation upon treatment. Consistently, SCH772984 increased expression of the mitochondrial transcriptional coactivator peroxisome proliferator-activated receptor gamma, coactivator 1-α. In contrast, cotreatment with phenformin, an inhibitor of complex I of the respiratory chain, decreased the oxygen consumption rate. SCH772984 also promoted the expansion of the H3K4 demethylase KDM5B (also known as JARID1B)-positive subpopulation of melanoma cells, which are slow-cycling and treatment-resistant. Importantly, phenformin suppressed this KDM5B-positive population, which reduced the emergence of SCH772984-resistant clones in long-term cultures. Our results warrant the clinical investigation of this combination therapy in patients with NF1 mutant melanoma.

The metabolic/pH sensor soluble adenylyl cyclase is a tumor suppressor protein.

cAMP signaling pathways can both stimulate and inhibit the development of cancer; however, the sources of cAMP important for tumorigenesis remain poorly understood. Soluble adenylyl cyclase (sAC) is a non-canonical, evolutionarily conserved, nutrient- and pH-sensing source of cAMP. sAC has been implicated in the metastatic potential of certain cancers, and it is differentially localized in human cancers as compared to benign tissues. We now show that sAC expression is reduced in many human cancers. Loss of sAC increases cellular transformation in vitro and malignant progression in vivo. These data identify the metabolic/pH sensor soluble adenylyl cyclase as a previously unappreciated tumor suppressor protein.

Factors associated with returning to HIV care after a gap in care in New York State.

BACKGROUND: Retention in HIV care has important implications. Few studies examining retention include comprehensive and heterogeneous populations, and few examine factors associated with returning to care after gaps in care. We identified reasons for gaps in care and factors associated with returning to care. METHODS: We extracted medical record and state-wide reporting data from 1865 patients with 1 HIV visit to a New York facility in 2008 and subsequent 6-month gap in care. Using mixed effect logistic regression, we examined sociodemographic, clinical, and facility characteristics associated with returning to care. RESULTS: Most patients were men (63.2%), black (51.4%), had Medicaid (53.9%). Many had CD4 counts >500 cells per cubic millimeter (34.4%) and undetectable viral loads (45.0%). Most (55.9%) had unknown reasons for gaps in care; of those with known reasons, reasons varied considerably. After a gap, 54.6% returned to care. Patients who did (vs. did not) return to care were more likely to have stable housing, longer duration of HIV, high CD4 count, suppressed viral load, antiretroviral medications, and had facilities attempt to contact them. Those who returned to care were less likely to be uninsured and have mental health problems or substance use histories. CONCLUSION: Over half of our sample of patients in New York with 1 HIV visit and subsequent 6-month gap in care returned to care; no major reasons for gaps emerged. Nevertheless, our findings emphasize that stabilizing patients' psychosocial factors and contacting patients after a gap in care are key strategies to retain HIV-positive patients in care in New York.

A study of orthostatic hypotension in late-life depression.

OBJECTIVE: Studies examining vascular risk factors in depression report conflicting evidence but have not assessed orthostatic hypotension, a recently recognized risk factor for white matter hyperintensities. METHOD: The authors used noninvasive phasic orthostatic blood pressure monitoring to assess orthostatic hypotension in 17 subjects with late-life major depression and 17 comparison subjects. All received a neuropsychiatric assessment and standardized cardiovascular assessment. RESULTS: The authors found a higher proportion of subjects met standard criteria for orthostatic hypotension in the depressed group (94% versus 65%, X = 4.5, df = 1, p = 0.034), and the degree of systolic blood pressure drop on standing was highly significantly greater in this group (t = 4.02, df = 32, p <0.001; mean drop of 46 mm Hg). Depressed subjects also experienced more clinical symptoms consistent with orthostatic hypotension. CONCLUSIONS: Our findings suggest orthostatic hypotension may be an important factor in explaining the absence of an excess of clinically determined vascular risk factors in late-life depression.

Strategies to prevent falls and fractures in hospitals and care homes and effect of cognitive impairment: systematic review and meta-analyses.

OBJECTIVES: To evaluate the evidence for strategies to prevent falls or fractures in residents in care homes and hospital inpatients and to investigate the effect of dementia and cognitive impairment. DESIGN: Systematic review and meta-analyses of studies grouped by intervention and setting (hospital or care home). Meta-regression to investigate the effects of dementia and of study quality and design. DATA SOURCES: Medline, CINAHL, Embase, PsychInfo, Cochrane Database, Clinical Trials Register, and hand searching of references from reviews and guidelines to January 2005. RESULTS: 1207 references were identified, including 115 systematic reviews, expert reviews, or guidelines. Of the 92 full papers inspected, 43 were included. Meta-analysis for multifaceted interventions in hospital (13 studies) showed a rate ratio of 0.82 (95% confidence interval 0.68 to 0.997) for falls but no significant effect on the number of fallers or fractures. For hip protectors in care homes (11 studies) the rate ratio for hip fractures was 0.67 (0.46 to 0.98), but there was no significant effect on falls and not enough studies on fallers. For all other interventions (multifaceted interventions in care homes; removal of physical restraints in either setting; fall alarm devices in either setting; exercise in care homes; calcium/vitamin D in care homes; changes in the physical environment in either setting; medication review in hospital) meta-analysis was either unsuitable because of insufficient studies or showed no significant effect on falls, fallers, or fractures, despite strongly positive results in some individual studies. Meta-regression showed no significant association between effect size and prevalence of dementia or cognitive impairment. CONCLUSION: There is some evidence that multifaceted interventions in hospital reduce the number of falls and that use of hip protectors in care homes prevents hip fractures. There is insufficient evidence, however, for the effectiveness of other single interventions in hospitals or care homes or multifaceted interventions in care homes.

Multifactorial intervention after a fall in older people with cognitive impairment and dementia presenting to the accident and emergency department: randomised controlled trial.

OBJECTIVE: To determine the effectiveness of multifactorial intervention after a fall in older patients with cognitive impairment and dementia attending the accident and emergency department. DESIGN: Randomised controlled trial. PARTICIPANTS: 274 cognitively impaired older people (aged 65 or over) presenting to the accident and emergency department after a fall: 130 were randomised to assessment and intervention and 144 were randomised to assessment followed by conventional care (control group). SETTING: Two accident and emergency departments, Newcastle upon Tyne. MAIN OUTCOME MEASURES: Primary outcome was number of participants who fell in year after intervention. Secondary outcomes were number of falls (corrected for diary returns), time to first fall, injury rates, fall related attendances at accident and emergency department, fall related hospital admissions, and mortality. RESULTS: Intention to treat analysis showed no significant difference between intervention and control groups in proportion of patients who fell during 1 year's follow up (74% (96/130) and 80% (115/144), relative risk ratio 0.92, 95% confidence interval 0.81 to 1.05). No significant differences were found between groups for secondary outcome measures. CONCLUSIONS: Multifactorial intervention was not effective in preventing falls in older people with cognitive impairment and dementia presenting to the accident and emergency department after a fall.

Presence of a carotid bruit in adults with unexplained or recurrent falls: implications for carotid sinus massage.

BACKGROUND: Carotid sinus hypersensitivity is a common cardiovascular cause of unexplained or recurrent falls in older adults. Effective treatment is available once carotid sinus hypersensitivity is identified. Carotid sinus massage is the only practical method for achieving a diagnosis. Carotid sinus massage is contraindicated if a carotid bruit is present. OBJECTIVE: To determine the prevalence of carotid sinus hypersensitivity in adults presenting with unexplained or recurrent falls and a carotid bruit. DESIGN: Prospective consecutive cohort study. SETTING: Accident and Emergency department and regional syncope and falls facility. SUBJECTS: Accident and Emergency patients aged 50 years or over with unexplained or recurrent falls and a carotid bruit. INTERVENTION: 1) Carotid doppler ultrasound to identify significant stenosis (> or = 50%). 2) Carotid sinus massage (with electrocardiographic and phasic blood pressure monitoring) was performed supine and possibly upright. METHODS: Consecutive adults with unexplained or recurrent falls were screened for carotid bruits. Those with a carotid bruit were referred for carotid Doppler ultrasound and stratified for further investigation depending on presence and degree of underlying carotid artery stenosis. Carotid sinus massage was performed at least supine in those with up to moderate stenosis (50-69%) in either internal or common carotid artery. MAIN OUTCOME MEASURE: Diagnosis of carotid sinus hypersensitivity. RESULTS: We identified 1682 subjects with unexplained or recurrent falls of whom 179 (11%) had a carotid bruit, 167 underwent ultrasound, 31% had a stenosis > or = 50% (20% > or = 70%) in either internal or common carotid artery. A bruit was associated with significant ipsilateral stenosis in 25% and contralateral silent stenosis in a further 5%. Carotid sinus massage was performed in 121 subjects who were suitable (15 with moderate carotid artery stenosis). Carotid sinus hypersensitivity was found in 41 (34%) subjects (4 with moderate stenosis). No serious complications occurred following carotid sinus massage. CONCLUSIONS: Carotid sinus hypersensitivity is a possible attributable cause of symptoms in a third of subjects with unexplained or recurrent falls and carotid bruits. Only a small number have severe carotid artery stenosis. Ultrasound will identify high-risk subjects and facilitate accurate diagnosis with carotid sinus massage in the majority.