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1.  Cardiovascular and inflammatory effects of simvastatin therapy in patients with COPD: a randomized controlled trial 
There is excess cardiovascular mortality in patients with chronic obstructive pulmonary disease. Aortic stiffness, an independent predictor of cardiovascular risk, and systemic and airway inflammation are increased in patients with the disease. Statins modulate aortic stiffness and have anti-inflammatory properties. A proof-of-principle, double-blind, randomized trial determined if 6 weeks of simvastatin 20 mg once daily reduced aortic stiffness and systemic and airway inflammation in patients with chronic obstructive pulmonary disease.
Stable patients (n=70) were randomized to simvastatin (active) or placebo. Pre-treatment and post-treatment aortic stiffness, blood pressure, spirometry, and circulating and airway inflammatory mediators and lipids were measured. A predefined subgroup analysis was performed where baseline aortic pulse wave velocity (PWV) was >10 m/sec.
Total cholesterol dropped in the active group. There was no significant change in aortic PWV between the active group and the placebo group (−0.7 m/sec, P=0.24). In those with aortic stiffness >10 m/sec (n=22), aortic PWV improved in the active group compared with the placebo group (−2.8 m/sec, P=0.03). Neither systemic nor airway inflammatory markers changed.
There was a nonsignificant improvement in aortic PWV in those taking simvastatin 20 mg compared with placebo, but in those with higher baseline aortic stiffness (a higher risk group) a significant and clinically relevant reduction in PWV was shown.
PMCID: PMC4321645
chronic obstructive pulmonary disease; arterial stiffness; statins
2.  Periodontal Disease and Late-Onset Aortic Prosthetic Vascular Graft Infection 
Prosthetic vascular graft infection (PVGI) is a rare but significant complication of arterial reconstructive surgery. Although the relative risk is low, the clinical consequences can be catastrophic. Microbiological data on causative bacteria are limited. We present four cases of late-onset PVGI. Using a culture-independent nucleic acid amplification method for analysis of intraoperative samples, the presence of bacteria highly suggestive of an oral source was reported. Examination by an oral health specialist confirmed the presence of chronic periodontal disease. We hypothesize that chronic oral infection may be a previously unreported risk factor for the development of late-onset PVGI.
PMCID: PMC4320805
3.  Equity and seeking treatment for young children with fever in Nigeria: a cross-sectional study in Cross River and Bauchi States 
Poor children have a higher risk of contracting malaria and may be less likely to receive effective treatment. Malaria is an important cause of morbidity and mortality in Nigerian children and many cases of childhood fever are due to malaria. This study examined socioeconomic factors related to taking children with fever for treatment in formal health facilities.
A household survey conducted in Bauchi and Cross River states of Nigeria asked parents where they sought treatment for their children aged 0–47 months with severe fever in the last month and collected information about household socio-economic status. Fieldworkers also recorded whether there was a health facility in the community. We used treatment of severe fever in a health facility to indicate likely effective treatment for malaria. Multivariate analysis in each state examined associations with treatment of childhood fever in a health facility.
43% weighted (%wt) of 10,862 children had severe fever in the last month in Cross River, and 45%wt of 11,053 children in Bauchi. Of these, less than half (31%wt Cross River, 44%wt Bauchi) were taken to a formal health facility for treatment. Children were more likely to be taken to a health facility if there was one in the community (OR 2.31 [95% CI 1.57–3.39] in Cross River, OR 1.33 [95% CI 1.0–1.7] in Bauchi). Children with fever lasting less than five days were less likely to be taken for treatment than those with more prolonged fever, regardless of whether there was such a facility in their community. Educated mothers were more likely to take children with fever to a formal health facility. In communities with a health facility in Cross River, children from less-poor households were more likely to go to the facility (OR 1.30; 95% CI 1.07-1.58).
There is inequity of access to effective malaria treatment for children with fever in the two states, even when there is a formal health facility in the community. Understanding the details of inequity of access in the two states could help the state governments to plan interventions to increase access equitably. Increasing geographic access to health facilities is needed but will not be enough.
Electronic supplementary material
The online version of this article (doi:10.1186/2049-9957-4-1) contains supplementary material, which is available to authorized users.
PMCID: PMC4322819  PMID: 25671126
Severe fever; Malaria; Equity; Access to care; Nigeria
4.  Why children are not vaccinated against measles: a cross-sectional study in two Nigerian States 
Archives of Public Health  2014;72(1):48.
Childhood vaccination rates in Nigeria are among the lowest in the world and this affects morbidity and mortality rates. A 2011 mixed methods study in two states in Nigeria examined coverage of measles vaccination and reasons for not vaccinating children.
A household survey covered a stratified random cluster sample of 180 enumeration areas in Bauchi and Cross River States. Cluster-adjusted bivariate and then multivariate analysis examined associations between measles vaccination and potential determinants among children aged 12-23 months, including household socio-economic status, parental knowledge and attitudes about vaccination, and access to vaccination services. Focus groups of parents in the same sites subsequently discussed the survey findings and gave reasons for non-vaccination. A knowledge to action strategy shared findings with stakeholders, including state government, local governments and communities, to stimulate evidence-based actions to increase vaccination rates.
Interviewers collected data on 2,836 children aged 12-23 months in Cross River and 2,421 children in Bauchi. Mothers reported 81.8% of children in Cross River and 42.0% in Bauchi had received measles vaccine. In both states, children were more likely to receive measles vaccine if their mothers thought immunisation worthwhile, if immunisation was discussed in the home, if their mothers had more education, and if they had a birth certificate. In Bauchi, maternal awareness about immunization, mothers’ involvement in deciding about immunization, and fathers’ education increased the chances of vaccination. In Cross River, children from communities with a government immunisation facility were more likely to have received measles vaccine. Focus groups revealed lack of knowledge and negative attitudes about vaccination, and complaints about having to pay for vaccination. Health planners in both states used the findings to support efforts to increase vaccination rates.
Measles vaccination remains sub-optimal, particularly in Bauchi. Efforts to counter negative perceptions about vaccination and to ensure vaccinations are actually provided free may help to increase vaccination rates. Parents need to be made aware that vaccination should be free, including for children without a birth certificate, and vaccination could be an opportunity for issuing birth certificates. The study provides pointers for state level planning to increase vaccination rates.
PMCID: PMC4322649  PMID: 25671115
Vaccination; Measles; Immunisation; Children; MDG4; Nigeria
5.  Seeking evidence to support efforts to increase use of antenatal care: a cross-sectional study in two states of Nigeria 
Antenatal care (ANC) attendance is a strong predictor of maternal outcomes. In Nigeria, government health planners at state level and below have limited access to population-based estimates of ANC coverage and factors associated with its use. A mixed methods study examined factors associated with the use of government ANC services in two states of Nigeria, and shared the findings with stakeholders.
A quantitative household survey in Bauchi and Cross River states of Nigeria collected data from women aged 15–49 years on ANC use during their last completed pregnancy and potentially associated factors including socio-economic conditions, exposure to domestic violence and local availability of services. Bivariate and multivariate analysis examined associations with having at least four government ANC visits. We collected qualitative data from 180 focus groups of women who discussed the survey findings and recommended solutions. We shared the findings with state, Local Government Authority, and community stakeholders to support evidence-based planning.
40% of 7870 women in Bauchi and 46% of 7759 in Cross River had at least four government ANC visits. Women's education, urban residence, information from heath workers, help from family members, and household owning motorized transport were associated with ANC use in both states. Additional factors for women in Cross River included age above 18 years, being married or cohabiting, being less poor (having enough food during the last week), not experiencing intimate partner violence during the last year, and education of the household head. Factors for women in Bauchi were presence of government ANC services within their community and more than two previous pregnancies. Focus groups cited costly, poor quality, and inaccessible government services, and uncooperative partners as reasons for not attending ANC. Government and other stakeholders planned evidence-based interventions to increase ANC uptake.
Use of ANC services remains low in both states. The factors related to use of ANC services are consistent with those reported previously. Efforts to increase uptake of ANC should focus particularly on poor and uneducated women. Local solutions generated by discussion of the evidence with stakeholders could be more effective and sustainable than externally driven interventions.
PMCID: PMC4245780  PMID: 25410003
Antenatal care; Government; Determinants; Cross-sectional; Multivariate; Nigeria
8.  Socio-economic determinants of ownership and use of treated bed nets in Nigeria: results from a cross-sectional study in Cross River and Bauchi States in 2011 
Malaria Journal  2014;13(1):316.
Poor people bear a disproportionate burden of malaria and prevention measures may not reach them well. A study carried out to examine the socio-economic factors associated with ownership and use of treated bed nets in Cross River and Bauchi States of Nigeria took place soon after campaigns to distribute treated bed nets.
A cross-sectional household survey about childhood illnesses among mothers of children less than four years of age and focus group discussions in 90 communities in each of the two states asked about household ownership of treated bed nets and their use for children under four years old. Bivariate and multivariate analyses examined associations between socio-economic and other variables and these outcomes in each state.
Some 72% of 7,685 households in Cross River and 87% of 5,535 households in Bauchi State had at least one treated bed net. In Cross River, urban households were more likely to possess bed nets, as were less-poor households (enough food in the last week), those with a male head, and those from communities with a formal health facility. In Bauchi, less-poor households and those with a more educated head were more likely to possess nets. In households with nets, only about half of children under four years old always slept under a net: 54% of 11,267 in Cross River and 57% of 11,277 in Bauchi. Factors associated with use of nets for young children in Cross River were less-poor households, fewer young children in the household, more education of the father, antenatal care of the mother, and younger age of the child, while in Bauchi the factors were a mother with more education and antenatal care, and younger age of the child. Some focus groups complained of distribution difficulties, and many described misconceptions about adverse effects of nets as an important reason for not using them.
Despite a recent campaign to distribute treated bed nets, disadvantaged households were less likely to possess them and to use them for young children. Efforts are needed to reach these households and to dispel fears about dangers of using treated nets.
PMCID: PMC4143556  PMID: 25124831
Malaria; Bed nets; Nigeria; Equity; Ownership; Use
9.  Orbitofrontal Dopamine Depletion Upregulates Caudate Dopamine and Alters Behavior via Changes in Reinforcement Sensitivity 
The Journal of Neuroscience  2014;34(22):7663-7676.
Schizophrenia is associated with upregulation of dopamine (DA) release in the caudate nucleus. The caudate has dense connections with the orbitofrontal cortex (OFC) via the frontostriatal loops, and both areas exhibit pathophysiological change in schizophrenia. Despite evidence that abnormalities in dopaminergic neurotransmission and prefrontal cortex function co-occur in schizophrenia, the influence of OFC DA on caudate DA and reinforcement processing is poorly understood. To test the hypothesis that OFC dopaminergic dysfunction disrupts caudate dopamine function, we selectively depleted dopamine from the OFC of marmoset monkeys and measured striatal extracellular dopamine levels (using microdialysis) and dopamine D2/D3 receptor binding (using positron emission tomography), while modeling reinforcement-related behavior in a discrimination learning paradigm. OFC dopamine depletion caused an increase in tonic dopamine levels in the caudate nucleus and a corresponding reduction in D2/D3 receptor binding. Computational modeling of behavior showed that the lesion increased response exploration, reducing the tendency to persist with a recently chosen response side. This effect is akin to increased response switching previously seen in schizophrenia and was correlated with striatal but not OFC D2/D3 receptor binding. These results demonstrate that OFC dopamine depletion is sufficient to induce striatal hyperdopaminergia and changes in reinforcement learning relevant to schizophrenia.
PMCID: PMC4035526  PMID: 24872570
behavior; caudate nucleus; dopamine; orbitofrontal cortex; PET; schizophrenia
10.  A functional Kv1.2-hERG chimaeric channel expressed in Pichia pastoris 
Scientific Reports  2014;4:4201.
Members of the six-transmembrane segment family of ion channels share a common structural design. However, there are sequence differences between the members that confer distinct biophysical properties on individual channels. Currently, we do not have 3D structures for all members of the family to help explain the molecular basis for the differences in their biophysical properties and pharmacology. This is due to low-level expression of many members in native or heterologous systems. One exception is rat Kv1.2 which has been overexpressed in Pichia pastoris and crystallised. Here, we tested chimaeras of rat Kv1.2 with the hERG channel for function in Xenopus oocytes and for overexpression in Pichia. Chimaera containing the S1–S6 transmembrane region of HERG showed functional and pharmacological properties similar to hERG and could be overexpressed and purified from Pichia. Our results demonstrate that rat Kv1.2 could serve as a surrogate to express difficult-to-overexpress members of the six-transmembrane segment channel family.
PMCID: PMC3935203  PMID: 24569544
11.  Rationale and study design of the Prospective comparison of Angiotensin Receptor neprilysin inhibitor with Angiotensin receptor blocker MEasuring arterial sTiffness in the eldERly (PARAMETER) study 
BMJ Open  2014;4(2):e004254.
Hypertension in elderly people is characterised by elevated systolic blood pressure (SBP) and increased pulse pressure (PP), which indicate large artery ageing and stiffness. LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor (ARNI), is being developed to treat hypertension and heart failure. The Prospective comparison of Angiotensin Receptor neprilysin inhibitor with Angiotensin receptor blocker MEasuring arterial sTiffness in the eldERly (PARAMETER) study will assess the efficacy of LCZ696 versus olmesartan on aortic stiffness and central aortic haemodynamics.
Methods and analysis
In this 52-week multicentre study, patients with hypertension aged ≥60 years with a mean sitting (ms) SBP ≥150 to <180 and a PP>60 mm Hg will be randomised to once daily LCZ696 200 mg or olmesartan 20 mg for 4 weeks, followed by a forced-titration to double the initial doses for the next 8 weeks. At 12–24 weeks, if the BP target has not been attained (msSBP <140  and ms diastolic BP <90 mm Hg), amlodipine (2.5–5 mg) and subsequently hydrochlorothiazide (6.25–25 mg) can be added. The primary and secondary endpoints are changes from baseline in central aortic systolic pressure (CASP) and central aortic PP (CAPP) at week 12, respectively. Other secondary endpoints are the changes in CASP and CAPP at week 52. A sample size of 432 randomised patients is estimated to ensure a power of 90% to assess the superiority of LCZ696 over olmesartan at week 12 in the change from baseline of mean CASP, assuming an SD of 19 mm Hg, the difference of 6.5 mm Hg and a 15% dropout rate. The primary variable will be analysed using a two-way analysis of covariance.
Ethics and dissemination
The study was initiated in December 2012 and final results are expected in 2015. The results of this study will impact the design of future phase III studies assessing cardiovascular protection.
Clinical trials identifier
EUDract number 2012-002899-14 and NCT01692301.
PMCID: PMC3918996  PMID: 24496699
12.  Effect of A Reduction in glomerular filtration rate after NEphrectomy on arterial STiffness and central hemodynamics: Rationale and design of the EARNEST study☆ 
American Heart Journal  2014;167(2):141-149.e2.
There is strong evidence of an association between chronic kidney disease (CKD) and cardiovascular disease. To date, however, proof that a reduction in glomerular filtration rate (GFR) is a causative factor in cardiovascular disease is lacking. Kidney donors comprise a highly screened population without risk factors such as diabetes and inflammation, which invariably confound the association between CKD and cardiovascular disease. There is strong evidence that increased arterial stiffness and left ventricular hypertrophy and fibrosis, rather than atherosclerotic disease, mediate the adverse cardiovascular effects of CKD. The expanding practice of live kidney donation provides a unique opportunity to study the cardiovascular effects of an isolated reduction in GFR in a prospective fashion. At the same time, the proposed study will address ongoing safety concerns that persist because most longitudinal outcome studies have been undertaken at single centers and compared donor cohorts with an inappropriately selected control group.
The reduction in GFR accompanying uninephrectomy causes (1) a pressure-independent increase in aortic stiffness (aortic pulse wave velocity) and (2) an increase in peripheral and central blood pressure.
This is a prospective, multicenter, longitudinal, parallel group study of 440 living kidney donors and 440 healthy controls. All controls will be eligible for living kidney donation using current UK transplant criteria. Investigations will be performed at baseline and repeated at 12 months in the first instance. These include measurement of arterial stiffness using applanation tonometry to determine pulse wave velocity and pulse wave analysis, office blood pressure, 24-hour ambulatory blood pressure monitoring, and a series of biomarkers for cardiovascular and bone mineral disease.
These data will prove valuable by characterizing the direction of causality between cardiovascular and renal disease. This should help inform whether targeting reduced GFR alongside more traditional cardiovascular risk factors is warranted. In addition, this study will contribute important safety data on living kidney donors by providing a longitudinal assessment of well-validated surrogate markers of cardiovascular disease, namely, blood pressure and arterial stiffness. If any adverse effects are detected, these may be potentially reversed with the early introduction of targeted therapy. This should ensure that kidney donors do not come to long-term harm and thereby preserve the ongoing expansion of the living donor transplant program (NCT01769924).
PMCID: PMC3904213  PMID: 24439974
13.  Determinants of arterial stiffness in COPD 
Cardiovascular morbidity and mortality is high in patients with chronic obstructive pulmonary disease (COPD) and arterial stiffness is a potentially modifiable risk factor with added predictive value beyond that obtained from traditional risk factors. Arterial stiffness has been the target of pharmacologic and exercise interventions in patients with COPD, but the effects appear limited to those patients with more significant elevations in arterial stiffness. We aimed to identify predictors of increased arterial stiffness in a cohort with moderate to severe COPD.
Aortic pulse wave velocity (aPWV) was measured in subjects with moderate to severe COPD enrolled in a multicenter randomized controlled trial. Subjects were categorized into quartiles based on aPWV values and factors affecting high arterial stiffness were assessed. Multivariate models were created to identify independent predictors of high aPWV, and cardiovascular disease (CVD).
153 patients were included. Mean age was 63.2 (SD 8.2) years and mean FEV1 was 55.4 (SD 15.2) % predicted. Compared to the quartile with the lowest aPWV, subjects in the highest quartile were older, had higher systolic blood pressure (SBP), were more likely to be current smokers, and had greater burden of thoracic aortic calcification. On multivariate analyses, age (adjusted OR 1.14, 95%CI 1.05 to 1.25, p = 0.003) and SBP (adjusted OR 1.06, 95% CI 1.02 to 1.09, p = 0.001) were independent predictors of elevated aPWV. Body mass index, therapy with cholesterol lowering medications and coronary calcification were independent predictors of CVD.
Elevated arterial stiffness in patients with COPD can be predicted using age, blood pressure and thoracic aortic calcification. This will help identify subjects for enrollment in clinical trials using aPWV for assessing the impact of COPD therapies on CV outcomes.
Trial registration NCT00857766
PMCID: PMC3890490  PMID: 24387157
COPD; Arterial stiffness; Arterial calcification; Cardiovascular
14.  Individual differences in behavioral and cardiovascular reactivity to emotive stimuli and their relationship to cognitive flexibility in a primate model of trait anxiety 
High trait anxiety is a risk factor for the development of anxiety disorders. Like the disorders themselves high trait anxiety has marked phenotypic variation at the level of symptomatology and neural circuits, suggesting that there may be different symptoms and distinct neural circuits associated with risk for these disorders. To address these issues, it is essential to develop reliable animal models of trait anxiety in a non-human primate whose brain bears structural and functional similarity to humans. The present study investigated individual variation in responsivity to fearful and anxiety provoking stimuli in the common marmoset monkey. Seven out of 27 animals failed to display discriminative, conditioned cardiovascular and behavioral responses on an auditory fear discrimination task, similar to that seen in high anxious humans and rodents. Their heightened emotionality to a rubber snake was consistent with the hypothesis that they were high in trait-like anxiety. Evidence for phenotypic variation in the high anxiety group was provided by the finding that discrimination failure was predicted early in conditioning by either hyper-vigilant scanning to the cues or a reduction in blood pressure to the context, i.e., test apparatus. Given that high trait anxiety in humans can be associated with altered prefrontal cognitive functioning and previously we implicated the marmoset anterior orbitofrontal (antOFC) and ventrolateral prefrontal cortex (vlPFC) in negative emotion regulation, we also tested the marmosets on two tests of cognitive flexibility differentially dependent on these two regions. While the high anxious group did not differ overall in their perseverative performance, the two distinct phenotypes were differentially correlated with reduced perseverative responding on the OFC- and vlPFC-dependent flexibility tests. Together, this study provides a new model of trait anxiety in marmosets amenable to analysis of phenotypic variation and neural circuitry.
PMCID: PMC4006051  PMID: 24795587
trait anxiety; fear generalization; marmoset; cognitive flexibility; prefrontal cortex; biomarkers
15.  Occult Bacteraemia and Aortic Graft Infection: A Wolf in Sheep's Clothing 
We report a case of late-onset aortic prosthetic vascular graft infection. We stress the importance of maintaining a high index of suspicion for any patient presenting with fever on the background of in situ prosthetic material. We present the difficulties in managing these extremely complicated, often life and limb threatening infections and suggest that a multidisciplinary team approach, involving specialist centre referral, may be key to success. We highlight the difficulties in diagnosing late-onset PVGI, where presentation can be subacute with subtle signs and confusing microbiology. In this case the presentation was pyrexia of unknown origin with multiple positive blood cultures isolating a variety of gut-associated organisms; a wolf in sheep's clothing.
PMCID: PMC3893841  PMID: 24490098
16.  Identification of a Plasmodium falciparum Phospholipid Transfer Protein*  
The Journal of Biological Chemistry  2013;288(44):31971-31983.
Background: PFA0210c is an exported Plasmodium falciparum protein.
Results: PFA0210c is a phospholipid transfer protein with similarities to proteins of the family of START domain-containing proteins and can transfer various phospholipids between membranes in vitro.
Conclusion: PFA0210c and its orthologs are phospholipid transfer proteins with a broad specificity.
Significance: Identification of the function of conserved Plasmodium proteins allows deeper insight into the basis of pathogenesis.
Infection of erythrocytes by the human malaria parasite Plasmodium falciparum results in dramatic modifications to the host cell, including changes to its antigenic and transport properties and the de novo formation of membranous compartments within the erythrocyte cytosol. These parasite-induced structures are implicated in the transport of nutrients, metabolic products, and parasite proteins, as well as in parasite virulence. However, very few of the parasite effector proteins that underlie remodeling of the host erythrocyte are functionally characterized. Using bioinformatic examination and modeling, we have found that the exported P. falciparum protein PFA0210c belongs to the START domain family, members of which mediate transfer of phospholipids, ceramide, or fatty acids between membranes. In vitro phospholipid transfer assays using recombinant PFA0210 confirmed that it can transfer phosphatidylcholine, phosphatidylinositol, phosphatidylethanolamine, and sphingomyelin between phospholipid vesicles. Furthermore, assays using HL60 cells containing radiolabeled phospholipids indicated that orthologs of PFA0210c can also transfer phosphatidylcholine, phosphatidylinositol, and phosphatidylethanolamine. Biochemical and immunochemical analysis showed that PFA0210c associates with membranes in infected erythrocytes at mature stages of intracellular parasite growth. Localization studies in live parasites revealed that the protein is present in the parasitophorous vacuole during growth and is later recruited to organelles in the parasite. Together these data suggest that PFA0210c plays a role in the formation of the membranous structures and nutrient phospholipid transfer in the malaria-parasitized erythrocyte.
PMCID: PMC3814793  PMID: 24043620
Lipid Transport; Malaria; Parasitology; Phospholipid; Plasmodium; Phospholipid Transfer
17.  HIV prevention in favour of the choice-disabled in southern Africa: study protocol for a randomised controlled trial 
Trials  2013;14:274.
Most HIV prevention strategies assume beneficiaries can act on their prevention decisions. But some people are unable to do so. They are ‘choice-disabled’. Economic and educational interventions can reduce sexual violence, but there is less evidence that they can reduce HIV. There is little research on complex interventions in HIV prevention, yet all countries in southern Africa implement combination prevention programmes.
The primary objective is to reduce HIV infections among women aged 15 to 29 years. Secondary objectives are reduction in gender violence and improvement in HIV-related knowledge, attitudes and practices among youth aged 15 to 29 years.
A random sample of 77 census enumeration areas in three countries (Botswana, Namibia and Swaziland) was allocated randomly to three interventions, alone or in combination, in a factorial design stratified by country, HIV rates (above or below average for country), and urban/rural location. A baseline survey of youth aged 15 to 29 years provided cluster specific rates of HIV. All clusters continue existing prevention efforts and have a baseline and follow-up survey. Cluster is the unit of allocation, intervention and analysis, using generalised estimating equations, on an intention-to-treat basis.
One intervention discusses evidence about choice disability with local HIV prevention services, to help them to serve the choice-disabled. Another discusses an eight-episode audio-docudrama with community groups, of all ages and both sexes, to generate endogenous strategies to reduce gender violence and develop an enabling environment. A third supports groups of women aged 18 to 25 years to build self-esteem and life skills and to set up small enterprises to generate income.
A survey in all clusters after 3 years will measure outcomes, with interviewers unaware of group assignment of the clusters. The primary outcome is HIV infection in women aged 15 to 29 years. Secondary outcomes in youth aged 15 to 29 years are gender violence and protective knowledge, attitudes, subjective norms, intention to change, agency, discussion of prevention and practices related to HIV and gender violence.
Trial registration
Trial registration number: ISRCTN28557578
PMCID: PMC3765989  PMID: 23987126
HIV prevention; Gender violence; Southern Africa; Cluster randomised controlled trial
18.  Target renal damage: the microvascular associations of increased aortic stiffness in patients with COPD 
Respiratory Research  2013;14(1):31.
Although renal impairment has been described in COPD, there is opportunity to evaluate further to determine nature and consider optimal management. Increased aortic stiffness, as seen in COPD, leads to reduced buffering of pulsatile flow. We hypothesised that urinary albumin creatinine ratio (UACR) would reflect glomerular damage related to aortic stiffness.
Patients with COPD and controls underwent spirometry, blood pressure, arterial stiffness - aortic pulse wave velocity (PWV) and provided a spot urine sample for UACR, with other renal biomarkers measured.
The UACR was increased in patients (n = 52): 0.80 mg/mmol compared to controls (n = 34): 0.46 mg/mmol, p < 0.05. Aortic PWV was related to log10 UACR in all subjects (r = 0.426, p < 0.001) and COPD patients alone. Aortic PWV was a significant variable for UACR with oxygen saturations, after accounting for potential confounders. Eight subjects (7 patients) reached a defined clinical microalbuminuria threshold, with aortic PWV greater in these patients compared to those patients without, although albuminuria is a continuum. Proximal tubular damage biomarkers, unlike the glomerular marker, were not different between patients and controls.
There is glomerular damage in patients with COPD evidenced by increased UACR, related to increased aortic stiffness. Besides the macrovascular prognostic implications of increased aortic stiffness, the microvascular state in COPD management should be considered.
PMCID: PMC3599353  PMID: 23497267
Arterial stiffness; Biomarkers; Haemodynamics; Kidney; Renal; Microvascular
19.  Common Genetic Variation in the 3-BCL11B Gene Desert Is Associated With Carotid-Femoral Pulse Wave Velocity and Excess Cardiovascular Disease Risk The AortaGen Consortium 
Mitchell, Gary F. | Verwoert, Germaine C. | Tarasov, Kirill V. | Isaacs, Aaron | Smith, Albert V. | Yasmin | Rietzschel, Ernst R. | Tanaka, Toshiko | Liu, Yongmei | Parsa, Afshin | Najjar, Samer S. | O’Shaughnessy, Kevin M. | Sigurdsson, Sigurdur | De Buyzere, Marc L. | Larson, Martin G. | Sie, Mark P.S. | Andrews, Jeanette S. | Post, Wendy S. | Mattace-Raso, Francesco U.S. | McEniery, Carmel M. | Eiriksdottir, Gudny | Segers, Patrick | Vasan, Ramachandran S. | van Rijn, Marie Josee E. | Howard, Timothy D. | McArdle, Patrick F. | Dehghan, Abbas | Jewell, Elizabeth | Newhouse, Stephen J. | Bekaert, Sofie | Hamburg, Naomi M. | Newman, Anne B. | Hofman, Albert | Scuteri, Angelo | De Bacquer, Dirk | Ikram, Mohammad Arfan | Psaty, Bruce | Fuchsberger, Christian | Olden, Matthias | Wain, Louise V. | Elliott, Paul | Smith, Nicholas L. | Felix, Janine F. | Erdmann, Jeanette | Vita, Joseph A. | Sutton-Tyrrell, Kim | Sijbrands, Eric J.G. | Sanna, Serena | Launer, Lenore J. | De Meyer, Tim | Johnson, Andrew D. | Schut, Anna F.C. | Herrington, David M. | Rivadeneira, Fernando | Uda, Manuela | Wilkinson, Ian B. | Aspelund, Thor | Gillebert, Thierry C. | Van Bortel, Luc | Benjamin, Emelia J. | Oostra, Ben A. | Ding, Jingzhong | Gibson, Quince | Uitterlinden, André G. | Abecasis, Gonçalo R. | Cockcroft, John R. | Gudnason, Vilmundur | De Backer, Guy G. | Ferrucci, Luigi | Harris, Tamara B. | Shuldiner, Alan R. | van Duijn, Cornelia M. | Levy, Daniel | Lakatta, Edward G. | Witteman, Jacqueline C.M.
Carotid-femoral pulse wave velocity (CFPWV) is a heritable measure of aortic stiffness that is strongly associated with increased risk for major cardiovascular disease events.
Methods and Results
We conducted a meta-analysis of genome-wide association data in 9 community-based European ancestry cohorts consisting of 20,634 participants. Results were replicated in 2 additional European ancestry cohorts involving 5,306 participants. Based on a preliminary analysis of 6 cohorts, we identified a locus on chromosome 14 in the 3′-BCL11B gene desert that is associated with CFPWV (rs7152623, minor allele frequency = 0.42, beta=−0.075±0.012 SD/allele, P = 2.8 x 10−10; replication beta=−0.086±0.020 SD/allele, P = 1.4 x 10−6). Combined results for rs7152623 from 11 cohorts gave beta=−0.076±0.010 SD/allele, P=3.1x10−15. The association persisted when adjusted for mean arterial pressure (beta=−0.060±0.009 SD/allele, P = 1.0 x 10−11). Results were consistent in younger (<55 years, 6 cohorts, N=13,914, beta=−0.081±0.014 SD/allele, P = 2.3 x 10−9) and older (9 cohorts, N=12,026, beta=−0.061±0.014 SD/allele, P=9.4x10−6) participants. In separate meta-analyses, the locus was associated with increased risk for coronary artery disease (hazard ratio [HR]=1.05, confidence interval [CI]=1.02 to 1.08, P=0.0013) and heart failure (HR=1.10, CI=1.03 to 1.16, P=0.004).
Common genetic variation in a locus in the BCL11B gene desert that is thought to harbor one or more gene enhancers is associated with higher CFPWV and increased risk for cardiovascular disease. Elucidation of the role this novel locus plays in aortic stiffness may facilitate development of therapeutic interventions that limit aortic stiffening and related cardiovascular disease events.
PMCID: PMC3288392  PMID: 22068335
aorta; arterial stiffness; pulse wave velocity; genetics; cardiovascular disease
20.  The EPICure Study: Association between Hemodynamics and Lung Function at 11 Years after Extremely Preterm Birth 
The Journal of Pediatrics  2012;161(4):595-601.e2.
To investigate the relationship between disturbed lung function and large-artery hemodynamics in school-age children born extremely preterm (EP) (at 25 completed weeks of gestation or less).
Study design
This was a cross-sectional study of participants from the EPICure study, now aged 11 years (n = 66), and 86 age- and sex-matched term-born classmates. Spirometry parameters (including forced expiratory volume in 1 second), blood pressure, and augmentation index (AIx, a composite of arterial stiffness and global wave reflections) were measured.
Compared with their classmates, the EP children had significantly impaired lung function, particularly those with neonatal bronchopulmonary dysplasia. Peripheral blood pressure did not differ significantly between the 2 groups, but AIx values were on average 5% higher (95% CI, 2%-8%) in the preterm infants, remaining significant after adjustment for potential confounders. Neonatal bronchopulmonary dysplasia status was not related to AIx. Lung function and maternal smoking were independently associated with AIx; AIx increased by 2.7% per z-score reduction in baseline forced expiratory volume in 1 second and by 4.9% in those whose mothers smoked during pregnancy.
The independent association between impaired lung function and cardiovascular physiology in early adolescence implies higher cardiovascular risk for children born EP, and suggests that prevention of chronic neonatal lung disease may be a priority in reducing later cardiovascular risk in preterm infants.
PMCID: PMC3657191  PMID: 22575246
AIx, Augmentation index; BP, Blood pressure; BPD, Bronchopulmonary dysplasia; COPD, Chronic obstructive pulmonary disease; EP, Extremely preterm; FEF25-75, Forced mid-expiratory flow; FEV1, Forced expiratory volume in 1 second; FVC, Forced vital capacity; MAP, Mean arterial pressure
21.  Arterial stiffness 
JRSM Cardiovascular Disease  2012;1(6):cvd.2012.012024.
Measurements of biomechanical properties of arteries have become an important surrogate outcome used in epidemiological and interventional cardiovascular research. Structural and functional differences of vessels in the arterial tree result in a dampening of pulsatility and smoothing of blood flow as it progresses to capillary level. A loss of arterial elastic properties results a range of linked pathophysiological changes within the circulation including increased pulse pressure, left ventricular hypertrophy, subendocardial ischaemia, vessel endothelial dysfunction and cardiac fibrosis. With increased arterial stiffness, the microvasculature of brain and kidneys are exposed to wider pressure fluctuations and may lead to increased risk of stroke and renal failure. Stiffening of the aorta, as measured by the gold-standard technique of aortic Pulse Wave Velocity (aPWV), is independently associated with adverse cardiovascular outcomes across many different patient groups and in the general population. Therefore, use of aPWV has been proposed for early detection of vascular damage and individual cardiovascular risk evaluation and it seems certain that measurement of arterial stiffness will become increasingly important in future clinical care. In this review we will consider some of the pathophysiological processes that result from arterial stiffening, how it is measured and factors that may drive it as well as potential avenues for therapy. In the face of an ageing population where mortality from atheromatous cardiovascular disease is falling, pathology associated with arterial stiffening will assume ever greater importance. Therefore, understanding these concepts for all clinicians involved in care of patients with cardiovascular disease will become vital.
PMCID: PMC3738364  PMID: 24175072
22.  Normal expiratory flow rate and lung volumes in patients with combined emphysema and interstitial lung disease: A case series and literature review 
Pulmonary function tests in patients with idiopathic pulmonary fibrosis characteristically show a restrictive pattern including small lung volumes and increased expiratory flow rates resulting from a reduction in pulmonary compliance due to diffuse fibrosis. Conversely, an obstructive pattern with hyperinflation results in emphysema by loss of elastic recoil, expiratory collapse of the peripheral airways and air trapping. When the diseases coexist, pulmonary volumes are compensated, and a smaller than expected reduction or even normal lung volumes can be found. The present report describes 10 patients with progressive breathlessness, three of whom experienced severe limitation in their quality of life. All patients showed lung interstitial involvement and emphysema on computed tomography scan of the chest. The 10 patients showed normal spirometry and lung volumes with severe compromise of gas exchange. Normal lung volumes do not exclude diagnosis of idiopathic pulmonary fibrosis in patients with concomitant emphysema. The relatively preserved lung volumes may underestimate the severity of idiopathic pulmonary fibrosis and attenuate its effects on lung function parameters.
PMCID: PMC3267611  PMID: 21969934
Emphysema; Expiratory flow rates; Intersitial lung disease; Lung volumes
23.  Male circumcision, attitudes to HIV prevention and HIV status: A cross-sectional study in Botswana, Namibia and Swaziland 
AIDS Care  2011;24(3-4):301-309.
In efficacy trials male circumcision (MC) protected men against HIV infection. Planners need information relevant to MC programmes in practice. In 2008, we interviewed 2915 men and 4549 women aged 15–29 years in representative cluster samples in Botswana, Namibia and Swaziland, asking about socio-economic characteristics, knowledge and attitudes about HIV and MC and MC history. We tested finger prick blood samples for HIV. We calculated weighted frequencies of MC knowledge and attitudes, and MC history and HIV status. Multivariate analysis examined associations between MC and other variables and HIV status. In Botswana, 11% of young men reported MC, 28% in Namibia and 8% in Swaziland; mostly (75% in Botswana, 94% – mostly Herero – in Namibia and 68% in Swaziland) as infants or children. Overall, 6.5% were HIV positive (8.3% Botswana, 2.6% Namibia and 9.1% Swaziland). Taking other variables into account, circumcised men were as likely as uncircumcised men to be HIV positive. Nearly half of the uncircumcised young men planned to be circumcised; two-thirds of young men and women planned to have their sons circumcised. Some respondents had inaccurate beliefs and unhelpful views about MC and HIV, with variation between countries. Between 9 and 15% believed a circumcised man is fully protected against HIV; 20–26% believed men need not be tested for HIV before MC; 14–26% believed HIV-positive men who are circumcised cannot transmit the virus; and 8–34% thought it was “okay for a circumcised man to expect sex without a condom”. Inaccurate perceptions about protection from MC could lead to risk compensation and reduce women's ability to negotiate safer sex. More efforts are needed to raise awareness about the limitations of MC protection, especially for women, and to study the interactions between MC roll out programmes and primary HIV prevention programmes.
PMCID: PMC3379742  PMID: 21933035
male circumcision (MC); HIV status; HIV attitudes; Southern Africa
24.  Ethnic Differences in Arterial Wave Reflections and Normative Equations for Augmentation Index 
Hypertension  2011;57(6):1108-1116.
Data regarding ethnic differences in wave reflections, which markedly affect the central pressure profile, are very limited. Furthermore, because age, heart rate and body height are strong determinants of augmentation index, relating single measurements to normative data (in which augmentation index values correspond to average population values of its determinants) is challenging. We studied subject-level data from 10,550 adults enrolled in large population-based studies. In a healthy reference sample (n=3,497), we assessed ethnic differences in augmentation index (ratio of second/first systolic peaks) and generated equations for adjusted z-scores, allowing for a standardized comparison between individual augmentation index measurements and the normative population mean from subjects of the same age, gender, ethnic population, body height and heart rate. After adjustment for age, body height, heart rate and mean arterial pressure, African blacks (women:154%; men:138%) and Andean-Hispanics (women:152%; men:133%) demonstrated higher central (aortic) augmentation index values than British whites (women:140%; men:128%); whereas American Indians (women:133%; men:122%) demonstrated lower augmentation index (all P<0.0001), without significant differences between Chinese and British whites. Similar results were found for radial augmentation index. Non-linear ethnic/gender-specific equations for z-scores were successfully generated to adjust individual augmentation index values for age, body height and heart rate. Marked ethnic differences in augmentation index exist, which may contribute to ethnic differences in hypertensive organ damage. Our study provides normative data that can be used to complement the interpretation of individual hemodynamic assessments among men and women of various ethnic populations, after removing the effect of various physiologic determinants.
PMCID: PMC3151727  PMID: 21536986
wave reflections; augmentation index; ethnicity
25.  Prevalence and risk factors for forced or coerced sex among school-going youth: national cross-sectional studies in 10 southern African countries in 2003 and 2007 
BMJ Open  2012;2(2):e000754.
To study prevalence at two time points and risk factors for experience of forced or coerced sex among school-going youth in 10 southern African countries.
Cross-sectional surveys, by facilitated self-administered questionnaire, of in-school youth in 2003 and 2007.
Schools serving representative communities in eight countries (Botswana, Lesotho, Malawi, Mozambique, Namibia, Swaziland, Zambia and Zimbabwe) in 2003 and with Tanzania and South Africa added in 2007.
Students aged 11–16 years present in the school classes.
Main outcome measures
Experience of forced or coerced sex, perpetration of forced sex.
In 2007, 19.6% (4432/25 840) of female students and 21.1% (4080/21 613) of male students aged 11–16 years reported they had experienced forced or coerced sex. Rates among 16-year-olds were 28.8% in females and 25.4% in males. Comparing the same schools in eight countries, in an analysis age standardised on the 2007 Botswana male sample, there was no significant decrease between 2003 and 2007 among females in any country and inconsistent changes among males. In multilevel analysis using generalised linear mixed model, individual-level risk factors for forced sex among female students were age over 13 years and insufficient food in the household; school-level factors were a lower proportion of students knowing about child rights and higher proportions experiencing or perpetrating forced sex; and community-level factors were a higher proportion of adults in favour of transactional sex and a higher rate of intimate partner violence. Male risk factors were similar. Some 4.7% of female students and 11.7% of male students reported they had perpetrated forced sex. Experience of forced sex was strongly associated with perpetration and other risk factors for perpetration were similar to those for victimisation.
Forced or coerced sex remained common among female and male youth in 2007. Experience of sexual abuse in childhood is recognised to increase the risk of HIV infection. The association the authors found between forced sex and school-level factors suggests preventive interventions in schools could help to tackle the HIV epidemic in southern Africa.
Article summary
Article focus
Cross-sectional studies 2003 and 2007.
History of coerced sex and its perpetration.
Individual, school and community risk factors.
Key messages
No evidence of decline 2003–2007.
Community factors include views of transactional sex.
School factors show clustering.
Strengths and limitations of this study
Cross-sectional study limits causal inferences.
School base excludes out of school youth.
PMCID: PMC3293138  PMID: 22389362

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