Psychometric Properties of LUN-MS: A New Questionnaire to Identify the Unmet Needs of People With Multiple Sclerosis.

Background: We developed a 29-item Questionnaire, Long-term Unmet Needs in MS (LUN-MS) to identify the unmet needs of people with multiple sclerosis (pwMS). Objective: To assess acceptability, test-retest reliability, internal consistency, and validity of the LUN-MS. Methods: Participants completed the LUN-MS and MSIS-29 twice, four weeks apart. Acceptability was assessed by looking at the response rate in each time point. Reliability was calculated by comparing the response during the two time points using Cohen's weighted kappa. Using principal component analysis, the dimensionality of the questionnaire's items was reduced, to five domains and the internal consistency of each domain was assessed using Cronbach's alpha. Concurrent validity was tested by comparing the total LUN-MS score against MSIS-29 and EQ-5D-3L using Pearson's product-moment correlation coefficient. Results: Among 88 participants, rate of completion at time points-1 and 2 was 96 and 80% respectively. Test-retest reliability for individual items was between fair to near-perfect (weighted Cohen's kappa 0.39-0.81). The unmet needs could be divided into five internally consistent domains (Cronbach's alpha 0.83-0.74): neuropsychological, ambulation, physical, interpersonal relationship and informational. Concurrent validity with MSIS-29 (r = 0.705, P < .001) and EQ-5D-3L (r = 0.617, P < .001) were good. Conclusion: LUN-MS is a reliable, valid, and acceptable tool to identify the unmet needs of pwMS.

Effect of Remote Ischemic Conditioning on Heart Rate Responses to Walking in People with Multiple Sclerosis.

Background: Remote ischemic conditioning (RIC), exposure of body parts to brief periods of circulatory occlusion and reperfusion, has been shown to improve cardiovascular responses to exercise in healthy individuals but its effects in people with MS are unknown. Objective: This study aimed to assess the effect of RIC on heart rate responses to walking in people with MS. Design: Double blind randomized controlled trial. Setting: Multiple sclerosis clinic of tertiary care center teaching hospital in the United Kingdom. Methods: Three cycles of RIC were delivered by occluding the upper arm with a blood pressure cuff inflated to a pressure of 30 mmHg above the systolic blood pressure. In the sham group, the blood pressure cuff was inflated to 30 mmHg below diastolic blood pressure. Heart rate responses to the 6-minute walk test (6MWT), the tolerability of RIC using a numerical rating scale for discomfort (0-10), and adverse events were studied. Results: Seventy-five participants (RIC -38 and Sham-37) completed the study. RIC was well tolerated. Compared to sham, RIC significantly decreased the rise in heart rate (P = 0.04) and percentage of predicted maximum heart rate (P = 0.016) after the 6MWT. Conclusion: RIC was well tolerated and improved the heart rate response to walking in people with MS. Further studies on RIC in the management of MS are needed.

Fatigue in multiple sclerosis: A UK MS-register based study.

BACKGROUND: Fatigue is a widely experienced, incapacitating symptom of MS. It hinders daily functioning and has deleterious effects on quality of life. The UK MS Register is an online registry of over 20,000 participants with MS. The aim of this study was to estimate the prevalence, predictors, and impact of fatigue on people with MS using data from the UKMS register. METHODS: All participants who completed the Fatigue Severity Scale (FSS), WebEDSS, Hospital Anxiety and Depression Scale (HADS) within 28 days of each other were selected from the UK MS Register. Data on age, gender, duration and type of MS, use of disease modifying drugs and comorbidities were obtained from the UKMS register. We categorised people with FSS score of 5 or more as with fatigue and those with scores of 4 or less as without fatigue. Descriptive statistics and logistical and multiple regressions were used to explore predictors of fatigue and the effect of fatigue on mobility (MS Walking Scale), physical and psychological aspects of life (MS Impact Scale) and quality of life (European Quality of Life 5D-3 L). RESULTS: Amongst the 20,946 participants of the UK MS registry, 4620 completed FSS. Out of these, 775 (mean age= 54.71 years, SD= 10.90; mean duration of MS diagnosis =13.21 years, SD=9.75) had completed the FSS, Web EDSS and Hospital Anxiety and Depression Scale within 28 days of each other. 427 (55.1%) of pwMS had a FSS score >5 consistent with clinical fatigue. Logistic regression analysis showed that depression (p=<0.001), duration of MS (p = 0.017), secondary progressive MS (p = 0.001) and EDSS (p=<0.001) predicted fatigue. FSS scores had a significant negative impact on both psychological (p > 0.001) and physical (p > 0.001) domains of the MS Impact scale, MS walking scale (p = 0.003) and EQoL (p = 0.005). CONCLUSIONS: Fatigue was a common symptom amongst people with MS. Depression, longer duration of MS, secondary progressive MS, and high EDSS predicted fatigue. Fatigue had an adverse effect on physical activities, mobility, psychological wellbeing, and quality of life of people with MS.

How Diverse Is Medicinal Chemistry? Insights into Race, Ethnicity, Origin, Gender, and Geography.

A bibliometric study of authors across medicinal chemistry journals over 20 years reveals important trends. Most United States (US) based authors are assigned as racially/ethnically Asian or White; few are Black or Hispanic. More US coauthors have the same race/ethnicity as the corresponding author than expected. The percentage of female authors increased globally, but only slowly. Since 2010, the number of female and male authors declined by 9% and 30%, respectively. Geographically, most authors are male except in Italy where there is gender balance. Gender homophily is observed globally. Geographically, the discipline is now more widely practiced. Article output doubled from 2000 to 2010 with a large increase in articles from China. China excepted, output has since declined. The average number of authors per article rose by a third since 2000. The value of high diversity groups in education, research, and industry cannot be overstated. We recommend diversity is addressed by every medicinal chemist.

Upper limb entrapment neuropathies in multiple sclerosis.

INTRODUCTION: Entrapment neuropathies of upper limbs such as carpal tunnel and cubital tunnel syndromes are common in the general population. Identification of entrapment neuropathies of upper limbs in patients with multiple sclerosis can be clinically challenging as signs and symptoms could be attributed to multiple sclerosis. People at later stages of multiple sclerosis use mobility aids and wheelchairs. Weakness of hands in this cohort due to entrapment neuropathies could adversely affect their mobility and independence. METHODS: This was a retrospective review of records of patients with multiple sclerosis referred for clinical neurophysiological studies with clinical suspicion of upper limb entrapment neuropathies over a 10-year period. We collected demographic details, clinical features, clinical neurophysiological data and details of aids and appliances used for mobility. RESULTS: Among 71 patients, 38 (53.5%) patients had at least one entrapment neuropathy of upper limb confirmed by clinical neurophysiological studies. Twelve (31%) patients had median nerve entrapment, 20 (53%) had ulnar nerve entrapment and six (16%) had both. Risk of ulnar nerve entrapment was significantly higher in patients using a powered wheelchair (odds ratio 5.7, 95% confidence interval (1.7-18.7, p = 0.0037). DISCUSSION: Entrapment neuropathies should be considered in patients with multiple sclerosis reporting sensory and motor symptoms of hands.

Effect of remote ischaemic preconditioning on walking in people with multiple sclerosis: double-blind randomised controlled trial.

BACKGROUND: Remote ischaemic preconditioning (RIPC) is the exposure of body parts to brief periods of circulatory occlusion and reperfusion. Recent studies have also shown that RIPC can improve exercise performance in healthy individuals. OBJECTIVE: This study aimed to assess the effect of RIPC on walking in people with multiple sclerosis (MS). METHODS: This was a double-blind randomised controlled clinical trial. We used three cycles of RIPC delivered by occluding the upper arm with a blood pressure (BP) cuff inflated to a pressure of 30 mm Hg above the systolic BP. In patients in the sham intervention group, the BP cuff was inflated only to 30 mm Hg below diastolic BP. Outcome measures included the Six-Minute Walk Test (6MWT), gait speed, the Borg rate of perceived exertion (RPE) scale, the tolerability of the RIPC using a Numerical Rating Scale for discomfort from 0 to 10, and adverse events. We identified responders meeting the minimal clinically important difference (MCID) established in the literature in each group. RESULTS: Seventy-five participants completed the study (RIPC: 38 and Sham: 37). The distance walked during the 6MWT improved by 1.9% in the sham group and 5.7% in the RIPC group (p=0.012). The number of responders meeting MCID criteria in the RIPC group was significantly greater compared with the sham intervention group. No serious adverse events occurred. CONCLUSION: Single cycle of RIPC resulted in immediate improvement in walking distances during 6MWT in people with MS. TRIAL REGISTRATION NUMBERS: NCT03153553.

Magnetic resonance spectroscopy reveals mitochondrial dysfunction in amyotrophic lateral sclerosis.

Mitochondrial dysfunction is postulated to be central to amyotrophic lateral sclerosis (ALS) pathophysiology. Evidence comes primarily from disease models and conclusive data to support bioenergetic dysfunction in vivo in patients is currently lacking. This study is the first to assess mitochondrial dysfunction in brain and muscle in individuals living with ALS using 31P-magnetic resonance spectroscopy (MRS), the modality of choice to assess energy metabolism in vivo. We recruited 20 patients and 10 healthy age and gender-matched control subjects in this cross-sectional clinico-radiological study. 31P-MRS was acquired from cerebral motor regions and from tibialis anterior during rest and exercise. Bioenergetic parameter estimates were derived including: ATP, phosphocreatine, inorganic phosphate, adenosine diphosphate, Gibbs free energy of ATP hydrolysis (ΔGATP), phosphomonoesters, phosphodiesters, pH, free magnesium concentration, and muscle dynamic recovery constants. Linear regression was used to test for associations between brain data and clinical parameters (revised amyotrophic functional rating scale, slow vital capacity, and upper motor neuron score) and between muscle data and clinico-neurophysiological measures (motor unit number and size indices, force of contraction, and speed of walking). Evidence for primary dysfunction of mitochondrial oxidative phosphorylation was detected in the brainstem where ΔGATP and phosphocreatine were reduced. Alterations were also detected in skeletal muscle in patients where resting inorganic phosphate, pH, and phosphomonoesters were increased, whereas resting ΔGATP, magnesium, and dynamic phosphocreatine to inorganic phosphate recovery were decreased. Phosphocreatine in brainstem correlated with respiratory dysfunction and disability; in muscle, energy metabolites correlated with motor unit number index, muscle power, and speed of walking. This study provides in vivo evidence for bioenergetic dysfunction in ALS in brain and skeletal muscle, which appears clinically and electrophysiologically relevant. 31P-MRS represents a promising technique to assess the pathophysiology of mitochondrial function in vivo in ALS and a potential tool for future clinical trials targeting bioenergetic dysfunction.

Longitudinal multi-modal muscle-based biomarker assessment in motor neuron disease.

BACKGROUND: Clinical phenotypic heterogeneity represents a major barrier to trials in motor neuron disease (MND) and objective surrogate outcome measures are required, especially for slowly progressive patients. We assessed responsiveness of clinical, electrophysiological and radiological muscle-based assessments to detect MND-related progression. MATERIALS AND METHODS: A prospective, longitudinal cohort study of 29 MND patients and 22 healthy controls was performed. Clinical measures, electrophysiological motor unit number index/size (MUNIX/MUSIX) and relative T2- and diffusion-weighted whole-body muscle magnetic resonance (MR) were assessed three times over 12 months. Multi-variable regression models assessed between-group differences, clinico-electrophysiological associations, and longitudinal changes. Standardized response means (SRMs) assessed sensitivity to change over 12 months. RESULTS: MND patients exhibited 18% higher whole-body mean muscle relative T2-signal than controls (95% CI 7-29%, p < 0.01), maximal in leg muscles (left tibialis anterior 71% (95% CI 33-122%, p < 0.01). Clinical and electrophysiological associations were evident. By 12 months, 16 patients had died or could not continue. In the remainder, relative T2-signal increased over 12 months by 14-29% in right tibialis anterior, right quadriceps, bilateral hamstrings and gastrocnemius/soleus (p < 0.01), independent of onset-site, and paralleled progressive weakness and electrophysiological loss of motor units. Highest clinical, electrophysiological and radiological SRMs were found for revised ALS-functional rating scale scores (1.22), tibialis anterior MUNIX (1.59), and relative T2-weighted leg muscle MR (right hamstrings: 0.98), respectively. Diffusion MR detected minimal changes. CONCLUSION: MUNIX and relative T2-weighted MR represent objective surrogate markers of progressive denervation in MND. Radiological changes were maximal in leg muscles, irrespective of clinical onset-site.

Correction to: Longitudinal multi-modal muscle-based biomarker assessment in motor neuron disease.

The original version of this article unfortunately contained a mistake. The numbers in the Table 5 appear to have been reproduced wrongly as dates, rather than percentages.

Identification of Cardiac Magnetic Resonance Imaging Thresholds for Risk Stratification in Pulmonary Arterial Hypertension.

Rationale: Pulmonary arterial hypertension (PAH) is a life-shortening condition. The European Society of Cardiology and European Respiratory Society and the REVEAL (North American Registry to Evaluate Early and Long-Term PAH Disease Management) risk score calculator (REVEAL 2.0) identify thresholds to predict 1-year mortality.Objectives: This study evaluates whether cardiac magnetic resonance imaging (MRI) thresholds can be identified and used to aid risk stratification and facilitate decision-making.Methods: Consecutive patients with PAH (n = 438) undergoing cardiac MRI were identified from the ASPIRE (Assessing the Spectrum of Pulmonary Hypertension Identified at a Referral Center) MRI database. Thresholds were identified from a discovery cohort and evaluated in a test cohort.Measurements and Main Results: A percentage-predicted right ventricular end-systolic volume index threshold of 227% or a left ventricular end-diastolic volume index of 58 ml/m2 identified patients at low (<5%) and high (>10%) risk of 1-year mortality. These metrics respectively identified 63% and 34% of patients as low risk. Right ventricular ejection fraction >54%, 37-54%, and <37% identified 21%, 43%, and 36% of patients at low, intermediate, and high risk, respectively, of 1-year mortality. At follow-up cardiac MRI, patients who improved to or were maintained in a low-risk group had a 1-year mortality <5%. Percentage-predicted right ventricular end-systolic volume index independently predicted outcome and, when used in conjunction with the REVEAL 2.0 risk score calculator or a modified French Pulmonary Hypertension Registry approach, improved risk stratification for 1-year mortality.Conclusions: Cardiac MRI can be used to risk stratify patients with PAH using a threshold approach. Percentage-predicted right ventricular end-systolic volume index can identify a high percentage of patients at low-risk of 1-year mortality and, when used in conjunction with current risk stratification approaches, can improve risk stratification. This study supports further evaluation of cardiac MRI in risk stratification in PAH.

Reliability and acceptability of the Multiple Sclerosis Quality of Life-29 questionnaire in an English-speaking cohort.

BACKGROUND: Multiple Sclerosis Quality-of-Life Questionnaire-54 (MSQoL-54) is a disease-specific instrument for assessing health-related quality of life (HRQoL). Due to the number of items, the time taken to complete it is long. A shorter 29-item version, Multiple Sclerosis Quality-of-Life Questionnaire-29 (MSQoL-29) is yet to be evaluated in English. OBJECTIVE: To assess reliability and acceptability of English version of MSQoL-29. METHODS: Among 100 participants with MS who first completed both MSQoL-54 and MSQoL-29, 91 completed MSQoL-29 after 4-8 weeks. We looked for internal consistency (Cronbach's alpha), acceptability, reliability (intraclass correlation coefficients (ICCs)) and agreement (Bland-Altman plots). RESULTS: ICCs were strongly positive between MSQoL-54 and MSQoL-29 (Physical Health Composite (PHC) -ICC = 0.914, confidence interval (CI) = 0.872-0.942; Mental Health Composite (MHC) - ICC = 0.875, CI = 0.814-0.916) and between the two MSQoL-29 (PHC - ICC = 0.970, CI = 0.955-0.980; MHC - ICC = 0.937, CI = 0.904-0.958). On Bland-Altman plots, the MSQoL-29 scores of 95% of participants during two visits were within the limits of agreement (LOAs). Time taken to complete MSQoL-29 was 7.2 ± 2.9 minutes and MSQoL-54 was 19.79 ± 5.4 minutes (p = 0.0001). CONCLUSION: MSQoL-29 has good test-retest reliability in English-speaking population and was quicker to complete.

A Pilot Study Investigating a Novel Non-Linear Measure of Eyes Open versus Eyes Closed EEG Synchronization in People with Alzheimer's Disease and Healthy Controls

BACKGROUND: The incidence of Alzheimer disease (AD) is increasing with the ageing population. The development of low cost non-invasive diagnostic aids for AD is a research priority. This pilot study investigated whether an approach based on a novel dynamic quantitative parametric EEG method could detect abnormalities in people with AD. METHODS: 20 patients with probable AD, 20 matched healthy controls (HC) and 4 patients with probable fronto temporal dementia (FTD) were included. All had detailed neuropsychology along with structural, resting state fMRI and EEG. EEG data were analyzed using the Error Reduction Ratio-causality (ERR-causality) test that can capture both linear and nonlinear interactions between different EEG recording areas. The 95% confidence intervals of EEG levels of bi-centroparietal synchronization were estimated for eyes open (EO) and eyes closed (EC) states. RESULTS: In the EC state, AD patients and HC had very similar levels of bi-centro parietal synchronization; but in the EO resting state, patients with AD had significantly higher levels of synchronization (AD = 0.44; interquartile range (IQR) 0.41 vs. HC = 0.15; IQR 0.17, p < 0.0001). The EO/EC synchronization ratio, a measure of the dynamic changes between the two states, also showed significant differences between these two groups (AD ratio 0.78 versus HC ratio 0.37 p < 0.0001). EO synchronization was also significantly different between AD and FTD (FTD = 0.075; IQR 0.03, p < 0.0001). However, the EO/EC ratio was not informative in the FTD group due to very low levels of synchronization in both states (EO and EC). CONCLUSION: In this pilot work, resting state quantitative EEG shows significant differences between healthy controls and patients with AD. This approach has the potential to develop into a useful non-invasive and economical diagnostic aid in AD.

Study of Two Dose Regimens of Ticagrelor Compared With Clopidogrel in Patients Undergoing Percutaneous Coronary Intervention for Stable Coronary Artery Disease.

BACKGROUND: Ticagrelor has superior efficacy to clopidogrel in the management of acute coronary syndromes but has not been assessed in patients undergoing percutaneous coronary intervention for stable coronary artery disease. We compared the pharmacodynamic effects of ticagrelor and clopidogrel in this stable population. METHODS: One hundred eighty aspirin-treated stable coronary artery disease patients, who were planned to undergo elective percutaneous coronary intervention in a single center, were randomized 1:1:1 to either a standard clopidogrel regimen or 1 of 2 regimens of ticagrelor, either 90 mg (T90) or 60 mg twice daily (T60), both with a 180 mg loading dose. Cellular adenosine uptake was assessed, at the time of the procedure and pre- and postdose at 1 month, by adding adenosine 1 µmol/L to aliquots of anticoagulated whole blood and mixing with a stop solution at 0, 15, 30, and 60 seconds, then measuring residual plasma adenosine concentration by high-performance liquid chromatography. Systemic plasma adenosine concentration and platelet reactivity were assessed at the same timepoints. High-sensitivity troponin T was measured pre- and 18 to 24 hours postpercutaneous coronary intervention. RESULTS: One hundred seventy-four patients underwent an invasive procedure, of whom 162 received percutaneous coronary intervention (mean age 65 years, 18% female, 21% with diabetes mellitus). No effect on in vitro adenosine uptake was seen postdose at 1 month for either ticagrelor dose compared with clopidogrel (residual adenosine at 15 seconds, mean±SD: clopidogrel 0.274±0.101 µmol/L; T90 0.278±0.134 µmol/L; T60 0.288±0.149 µmol/L; P=0.37). Similarly, no effect of ticagrelor on in vitro adenosine uptake was seen at other timepoints, nor was plasma adenosine concentration affected (all P>0.1). Both maintenance doses of ticagrelor achieved more potent and consistent platelet inhibition than clopidogrel (VerifyNow P2Y12 reaction units, 1 month, mean±SD: predose, T60: 62±47, T90: 40±38, clopidogrel 181±44; postdose, T60: 34±30, T90: 24±21, clopidogrel 159±57; all P<0.0001 for ticagrelor versus clopidogrel). High platelet reactivity was markedly less with both T60 and T90 compared with clopidogrel (VerifyNow P2Y12 reaction units>208, 1 month postdose: 0%, 0%, and 21%, respectively). Median (interquartile range) high-sensitivity troponin T increased 16.9 (6.5-46.9) ng/L for clopidogrel, 22.4 (5.5-53.8) ng/L for T60, and 17.7 (8.1-43.5) ng/L for T90 (P=0.95). There was a trend toward less dyspnea with T60 versus T90 (7.1% versus 19.0%; P=0.09). CONCLUSIONS: Maintenance therapy with T60 or T90 had no detectable effect on cellular adenosine uptake at 1 month, nor was there any effect on systemic plasma adenosine levels. Both regimens of ticagrelor achieved greater and more consistent platelet inhibition than clopidogrel but did not appear to affect troponin release after percutaneous coronary intervention. CLINICAL TRIAL REGISTRATION: URL: https://www. CLINICALTRIALS: gov. Unique identifier: NCT02327624.

The cortical focus in childhood absence epilepsy; evidence from nonlinear analysis of scalp EEG recordings.

OBJECTIVE: To determine the origin and dynamic characteristics of the generalised hyper-synchronous spike and wave (SW) discharges in childhood absence epilepsy (CAE). METHODS: We applied nonlinear methods, the error reduction ratio (ERR) causality test and cross-frequency analysis, with a nonlinear autoregressive exogenous (NARX) model, to electroencephalograms (EEGs) from CAE, selected with stringent electro-clinical criteria (17 cases, 42 absences). We analysed the pre-ictal and ictal strength of association between homologous and heterologous EEG derivations and estimated the direction of synchronisation and corresponding time lags. RESULTS: A frontal/fronto-central onset of the absences is detected in 13 of the 17 cases with the highest ictal strength of association between homologous frontal followed by centro-temporal and fronto-central areas. Delays consistently in excess of 4 ms occur at the very onset between these regions, swiftly followed by the emergence of "isochronous" (0-2 ms) synchronisation but dynamic time lag changes occur during SW discharges. CONCLUSIONS: In absences an initial cortico-cortical spread leads to dynamic lag changes to include periods of isochronous interhemispheric synchronisation, which we hypothesize is mediated by the thalamus. SIGNIFICANCE: Absences from CAE show ictal epileptic network dynamics remarkably similar to those observed in WAG/Rij rats which guided the formulation of the cortical focus theory.

Imaging muscle as a potential biomarker of denervation in motor neuron disease.

OBJECTIVE: To assess clinical, electrophysiological and whole-body muscle MRI measurements of progression in patients with motor neuron disease (MND), as tools for future clinical trials, and to probe pathophysiological mechanisms in vivo. METHODS: A prospective, longitudinal, observational, clinicoelectrophysiological and radiological cohort study was performed. Twenty-nine patients with MND and 22 age-matched and gender-matched healthy controls were assessed with clinical measures, electrophysiological motor unit number index (MUNIX) and T2-weighted whole-body muscle MRI, at first clinical presentation and 4 months later. Between-group differences and associations were assessed using age-adjusted and gender-adjusted multivariable regression models. Within-subject longitudinal changes were assessed using paired t-tests. Patterns of disease spread were modelled using mixed-effects multivariable regression, assessing associations between muscle relative T2 signal and anatomical adjacency to site of clinical onset. RESULTS: Patients with MND had 30% higher relative T2 muscle signal than controls at baseline (all regions mean, 95% CI 15% to 45%, p<0.001). Higher T2 signal was associated with greater overall disability (coefficient -0.009, 95% CI -0.017 to -0.001, p=0.023) and with clinical weakness and lower MUNIX in multiple individual muscles. Relative T2 signal in bilateral tibialis anterior increased over 4 months in patients with MND (right: 10.2%, 95% CI 2.0% to 18.4%, p=0.017; left: 14.1%, 95% CI 3.4% to 24.9%, p=0.013). Anatomically, contiguous disease spread on MRI was not apparent in this model. CONCLUSIONS: Whole-body muscle MRI offers a new approach to objective assessment of denervation over short timescales in MND and enables investigation of patterns of disease spread in vivo. Muscles inaccessible to conventional clinical and electrophysiological assessment may be investigated using this methodology.

Incidence and reinfection rates of genital chlamydial infection among women aged 16-24 years attending general practice, family planning and genitourinary medicine clinics in England: a prospective cohort study by the Chlamydia Recall Study Advisory Group.

BACKGROUND: In England, screening for genital chlamydial infection has begun; however, screening frequency for women is not yet determined. AIM: To measure chlamydia incidence and reinfection rates among young women to suggest screening intervals. METHODS: An 18-month prospective cohort study of women aged 16-24 years recruited from general practices, family planning clinics and genitourinary medicine (GUM) clinics: baseline-negative women followed for incidence and baseline-positive women for reinfection; urine tested every 6 months via nucleic acid amplification; and behavioural data collected. Extra test and questionnaire completed 3 months after initial positive test. Factors associated with infection and reinfection investigated using Cox regression stratified by healthcare setting of recruitment. RESULTS: Chlamydia incidence was mean (95% CI) 4.9 (2.7 to 8.8) per 100 person-years (py) among women recruited from general practices, 6.4 (4.2 to 9.8) from family planning clinics and 10.6 (7.4 to 15.2) from GUM clinics. Incidence was associated with young age, history of chlamydial infection and acquisition of new sexual partners. If recently acquiring new partners, condom use at last sexual intercourse was independently associated with lower incidence. Chlamydia reinfection was mean (95% CI) 29.9 (19.7 to 45.4) per 100/person-year from general practices, 22.3 (15.6 to 31.8) from family planning clinics and 21.1 (14.3 to 30.9) from GUM clinics. Factors independently associated with higher reinfection rates were acquisition of new partners and failure to treat all partners. CONCLUSIONS: Sexual behaviours determined incidence and reinfection, regardless of healthcare setting. Our results suggest annual screening of women aged 16-24 years who are chlamydia negative, or sooner if partner change occurs. Rescreening chlamydia-positive women within 6 months of baseline infection may be sensible, especially if partner change occurs or all partners are not treated.

Evolution of short sequence repeats in Mycobacterium tuberculosis.

Whole genome comparison has revealed the presence of short sequence repeats (also called mycobacterial interspersed repeat units and variable number tandem repeat units) used for genotyping schemes. In this study, we have used deletion analysis, single nucleotide polymorphism data and spoligotype taken from published data from others to investigate the evolution of selected repeats that form the common denominators of the majority of established schemes. Analysis of the number of repeats per locus from over 400 isolates revealed that the general trend globally appears to be loss of repeats in modern strains compared with ancestral strains.

No time to wait: how many HIV-infected homosexual men are diagnosed late and consequently die? (England and Wales, 1993-2002).

OBJECTIVES: To present national trends of the estimated number and proportion of late HIV diagnoses and short-term mortality following diagnosis among men who have had sex with men (MSM). To determine separately risk factors for late diagnosis and short-term mortality. METHODS: Analysis of national HIV/AIDS case reports of new diagnoses linked to CD4 cell counts from the CD4 Surveillance Scheme. Inverse probability weighting adjusted for individuals with no CD4 cell count at diagnosis. Outcomes were late diagnosis (CD4 cell count <200 x 10(6) cells/l at diagnosis) and short-term mortality (death within 1 year of diagnosis). RESULTS: Of 14,158 new diagnoses, 31% were estimated as late diagnoses. Despite a decreasing trend (P trend <0.01) an estimated 430 (25%) MSM were still diagnosed late in 2001. Late diagnosis disproportionately affected individuals diagnosed outside London, of non-white ethnicity, and of older age. There were 710 (5.0% of 14 158) deaths within a year of HIV diagnosis. Estimated short-term mortality was 14% for MSM diagnosed late and 1% for other MSM (adjusted odds ratio, 10.8; 95% confidence interval, 7.7-15.9). Short-term mortality declined concurrently with availability of highly active antiretroviral therapy and was independently associated with age and diagnosis outside London but not ethnicity. CONCLUSIONS: The continued late diagnosis of one in four MSM means these individuals lose the option to start therapy early, miss opportunities to prevent further transmission and are approximately 10 times more likely to die within a year of diagnosis. Early diagnosis of all MSM in 2001 could have reduced short-term mortality by 84% and all mortality in that year by 22%.

Prevalent diagnosed HIV in England, Wales and Northern Ireland: adjusted totals 1996 to 2001 and extrapolations to 2004.

OBJECTIVE: To predict trends in diagnosed HIV prevalence by extrapolation to 2004 using data from the annual surveys of individuals receiving HIV-related care in England, Wales and Northern Ireland from 1996 to 2001. METHODS: Data from the annual surveys of prevalent HIV infections diagnosed (SOPHID) were adjusted for under-reporting and non-attendance and separately extrapolated for infections acquired homosexually, heterosexually and by other routes. The data were extrapolated using negative binomial and linear regression models based on the 1996 to 2001 annual surveys. RESULTS: The negative binomial model predicted an increase of 56% in diagnosed HIV prevalence in England, Wales and Northern Ireland between 2001 and 2004. The linear model predicted an increase of 25% for the same time period. The predicted increases are mostly driven by the large rise in the number of new diagnoses, in particular in individuals infected heterosexually. CONCLUSION: Increases in HIV prevalence in England, Wales and Northern Ireland have diverged from a linear trend. Negative binomial modelling of the data predicts that large rises in prevalence will continue during the early 2000s.