Hypertension and diabetes in Africa: design and implementation of a large population-based study of burden and risk factors in rural and urban Malawi.

BACKGROUND: The emerging burden of cardiovascular disease and diabetes in sub-Saharan Africa threatens the gains made in health by the major international effort to combat infectious diseases. There are few data on distribution of risk factors and outcomes in the region to inform an effective public health response. A comprehensive research programme is being developed aimed at accurately documenting the burden and drivers of NCDs in urban and rural Malawi; to design and test intervention strategies. The programme includes population surveys of all people aged 18 years and above, linking individuals with newly diagnosed hypertension and diabetes to healthcare and supporting clinical services. The successes, challenges and lessons learnt from the programme to date are discussed. RESULTS: Over 20,000 adults have been recruited in rural Karonga and urban Lilongwe. The urban population is significantly younger and wealthier than the rural population. Employed urban individuals, particularly males, give particular recruitment challenges; male participation rates were 80.3 % in the rural population and 43.6 % in urban, whilst female rates were 93.6 and 75.6 %, respectively. The study is generating high quality data on hypertension, diabetes, lipid abnormalities and risk factors. CONCLUSIONS: It is feasible to develop large scale studies that can reliably inform the public health approach to diabetes, cardiovascular disease and other NCDs in Sub-Saharan Africa. It is essential for studies to capture both rural and urban populations to address disparities in risk factors, including age structure. Innovative approaches are needed to address the specific challenge of recruiting employed urban males.

Using patient-held records to evaluate contraceptive use in Malawi.

OBJECTIVE: To investigate a method of using patient-held records to collect contraception data in Malawi, that could be used to explore contraceptive discontinuation and method switching. METHODS: In 2012, all 7393 women aged 15 to 49 years living in the area covered by the Karonga demographic surveillance site were offered a family planning card, which was attached to the woman's health passport - a patient-held medical record. Health-care providers were trained to use the cards to record details of contraception given to women. During the study, providers underwent refresher training sessions and received motivational text messages to improve data completeness. After one year, the family planning cards were collected for analysis. FINDINGS: Of the 7393 eligible women, 6861 (92.8%) received a family planning card and 4678 (63.3%) returned it after one year. Details of 87.3% (2725/3122) of contacts between health-care providers and the women had been recorded by health-care providers on either family planning cards or health passports. Lower-level health-care providers were more diligent at recording data on the family planning cards than higher-level providers. CONCLUSION: The use of family planning cards was an effective way of recording details of contraception provided by family planning providers. The involvement of health-care providers was key to the success of this approach. Data collected in this way should prove helpful in producing accurate estimates of method switching and the continuity of contraceptive use by women.

Comparison of Short-Term Postoperative Analgesia by Epidural, Femoral Nerve Block, or Combination Femoral and Sciatic Nerve Block in Dogs Undergoing Tibial Plateau Leveling Osteotomy.

OBJECTIVE: To compare early postoperative analgesia in dogs undergoing unilateral tibial plateau leveling osteotomy (TPLO) that received bupivacaine via preoperative femoral nerve block (FNB), combination femoral-sciatic nerve block (F+SNB), or lumbosacral epidural (EPI). STUDY DESIGN: Randomized, blinded, prospective clinical trial. ANIMALS: Forty-five client-owned dogs undergoing unilateral TPLO. METHODS: Dogs undergoing unilateral TPLO were enrolled and randomly allocated to 1 of 3 treatments: FNB, F+SNB, or EPI. Assessments were completed by an observer blinded to treatment at 0, 1, 2, 4, 6, and 8 hours after extubation using the Glasgow Composite Pain Score-Short Form (GCPS-SF). Dogs with a total score ≥ 6 or ≥ 3 in any category were given a rescue analgesic. Outcome measures analyzed for differences across treatments were the GCPS-SF at each time point, time to first rescue analgesic, and total number of rescue analgesic doses per dog. RESULTS: The GCPS-SF score at extubation was significantly higher for FNB (median 3) compared to F+SNB (median 2). A significantly higher proportion of dogs receiving FNB (4/14) than F+SNB (0/17) required rescue analgesic at extubation. There was no significant difference in the proportion of dogs requiring rescue at extubation between FNB and EPI (2/14) or between F+SNB and EPI. There was no significant difference in the median time to first rescue between FNB (0 hours) and F+SNB (2 hours) or between F+SNB and EPI (1.5 hours). CONCLUSION: In dogs undergoing unilateral TPLO, bupivacaine administered via FNB, alone or in combination with sciatic nerve block, can provide short-term postoperative analgesia not different to that with administration via lumbosacral epidural.

Monitoring the impact of decentralised chronic care services on patient travel time in rural Africa--methods and results in Northern Malawi.

BACKGROUND: Decentralised health services form a key part of chronic care strategies in resource-limited settings by reducing the distance between patient and clinic and thereby the time and costs involved in travelling. However, few tools exist to evaluate the impact of decentralisation on patient travel time or what proportion of patients attend their nearest clinic. Here we develop methods to monitor changes in travel time, using data from the antiretroviral therapy (ART) roll-out in a rural district in North Malawi. METHODS: Clinic position was combined with GPS information on the home village of patients accessing ART services in Karonga District (North Malawi) between July 2005 and July 2009. Potential travel time was estimated as the travel time for an individual attending their nearest clinic, and estimated actual travel time as the time to the clinic attended. This allowed us to calculate changes in potential and actual travel time as new clinics opened and track the proportion and origin of patients not accessing their nearest clinic. RESULTS: The model showed how the opening of further ART clinics in Karonga District reduced median potential travel time from 83 to 43 minutes, and median actual travel time fell from 83 to 47 minutes. The proportion of patients not attending their nearest clinic increased from 6% when two clinics were open, to 12% with four open. DISCUSSION: Integrating GPS information with patient data shows the impact of decentralisation on travel time and clinic choice to inform policy and research questions. In our case study, travel time decreased, accompanied by an increased uptake of services. However, the model also identified an increasing proportion of ART patients did not attend their nearest clinic.

BCG vaccination induces different cytokine profiles following infant BCG vaccination in the UK and Malawi.

BACKGROUND: BCG vaccination of infants is thought to provide good protection in all settings. This study investigated whether Malawian infants made weaker responses across a cytokine panel after BCG vaccination, compared with UK infants. METHODS: Diluted whole-blood samples were cultured with Mycobacterium tuberculosis purified protein derivative for 6 days from BCG-vaccinated infants 3 months (n = 40 Malawi, 28 UK) and 12 months (n = 34 Malawi, 26 UK) after vaccination, and also from UK unvaccinated infants (n = 9 at 3 months, n = 10 at 12 months). Forty-two cytokines were measured in supernatants using a multiplex bead array assay. Principal component analysis was used to summarize the overall patterns in cytokine responses. RESULTS: We found differences in median responses in 27 of the 42 cytokines: 7 higher in the UK and 20 higher in Malawi. The cytokines with higher responses in the UK were all T helper 1 related. The cytokines with higher responses in Malawi included innate proinflammatory cytokines, regulatory cytokines, interleukin 17, T helper 2 cytokines, chemokines, and growth factors. Principal component analysis separated the BCG-vaccinated infants from Malawi from the UK vaccinated infants and from the unvaccinated infants. CONCLUSIONS: Malawian infants make cytokine responses following BCG vaccination, but the cytokine profile is different from that in the UK. The different biosignatures following BCG vaccination in the 2 settings may indicate variability in the protective efficacy of infant BCG vaccination.

Comparison of left fourth and fifth intercostal space thoracotomy for open-chest cardiopulmonary resuscitation in dogs.

OBJECTIVE: To determine whether ease of access to thoracic structures for performing open-chest cardiopulmonary resuscitation (OC-CPR) differed between fourth and fifth intercostal space (ICS) left lateral thoracotomies in dogs, and to determine if "shingling" improved access for OC-CPR manipulations. DESIGN: Prospective single-blinded study. SETTING: Laboratory. ANIMALS: Twelve mixed breed canine cadavers weighing approximately 20 kg. INTERVENTIONS: Left lateral thoracotomies were performed at the 4th ICS (n = 6) or 5th ICS (n = 6). Shingling at the 4th or 5th ICS, as applicable, was performed after initial data collection and outcomes were reassessed. MEASUREMENTS AND MAIN RESULTS: Three evaluators blinded to the surgical approach scored the following parameters on a 0 to 10 scale (0 = easiest, 10 = most difficult): ease of access of the phrenicopericardial ligament, ease of pericardial incision, ease of appropriate hand position, ease of aortic access, ease of Rumel tourniquet application, and ease of proper placement of defibrillation paddles. Objective measurements (time to completion or number of attempts) were made for all but ease of pericardial incision and ease of appropriate hand position. Outcomes were reassessed after shingling. The 5th ICS was superior for ease of aortic access (P = 0.042), time to visualization of aorta (P = 0.009), and ease of application of a Rumel tourniquet (P = 0.019). When comparing scores pre- and post-shingling, shingling improved time to visualization of the aorta (P < 0.001), time to placement of Rumel tourniquet (P < 0.001), ease of paddle placement (P = 0.017), and time to paddle placement (P < 0.001). CONCLUSIONS: Either 4th or 5th ICS thoracotomy may provide adequate access to intrathoracic structures pertinent to performing OC-CPR in dogs weighing approximately 20 kg, but 5th ICS was preferred for most manipulations, and shingling improved access for most of the measured parameters.

The effect of bupivacaine and morphine in a coculture model of diarthrodial joints.

PURPOSE: To perform a controlled laboratory study to evaluate the effect of bupivacaine and morphine on chondrocytes and synovium in a coculture model of diarthrodial joints. METHODS: A proven coculture model that allows for the assessment of cartilage and synovium exists. The model allows for simulation of the diarthrodial joint in both health and disease by using culture media with or without the addition of interleukin-1. Effects of the presence of bupivacaine and morphine were evaluated by measuring media concentration of glycosamino glycans (GAG), nitric oxide (NO), and prostaglandin E(2) (PGE(2)), and tissue concentration of GAG, water, and collagen. Cell viability was determined through the use of confocal microscopy on days 1 and 2. RESULTS: Cell viability 2 days after exposure to 0.5% bupivacaine was significantly less in the presence of bupivacaine than in the other groups, nearing a 100% decrease in viability. There was little effect of bupivacaine on cartilage water content or the tissue concentration of GAG and collagen. Morphine and bupivacaine both inhibited the expected rise in NO and PGE(2) when interleukin-1 was added to the media. CONCLUSIONS: Continuous 0.5% bupivacaine exposure has a clear detrimental effect on chondrocytes in this in vitro study. Both bupivacaine and morphine appear to have anti-inflammatory effects. Continuous morphine exposure does not cause gross chondrotoxicity in vitro and presents itself as a potential alternative intra-articular analgesic. CLINICAL RELEVANCE: Intra-articular bupivacaine infusion is an effective analgesic strategy and is frequently used in both office and outpatient surgical settings. This study provides evidence that the continued usage of postoperative bupivacaine continuous infusion pumps may have a detrimental effect on chondrocytes. Morphine has been shown to be an effective intra-articular analgesic, and its anti-inflammatory role seen in this study makes it a potential alternative to bupivacaine.

Comparison of the amounts of air leakage into the thoracic cavity associated with four thoracostomy tube placement techniques in canine cadavers.

OBJECTIVE: To compare the amount of air leakage into the thoracic cavity associated with each of 4 thoracostomy tube placement techniques in canine cadavers. SAMPLE POPULATION: 28 canine cadavers. PROCEDURES: Thoracostomy tube placement techniques (7 cadavers/technique) included subcutaneous tunneling with a silicone tube by use of Carmalt forceps or with a polyvinyl chloride tube by use of a trocar (SC-CARM and SC-TRO, respectively) and tunneling under the latissimus dorsi muscle with similar tube-instrument techniques (LD-CARM and LD-TRO, respectively). Differences in intrapleural pressures (IPPs) measured before and after tube placement and before and after tube removal were calculated; duration of air leakage around the tubes was assessed by use of a 3-chamber thoracic drainage system. RESULTS: Tunneling method and depth had no interaction effect on the difference in IPP measured before and after tube placement; the IPP difference for both forceps technique groups was significantly greater than findings for both trocar technique groups. Tunneling method and depth had an interaction effect on the difference in IPP measured before and after tube removal; compared with SC-TRO and LD-CARM group differences, the SC-CARM group difference was significantly greater, but the LD-TRO group difference was similar. More intermittent air leakage was associated with the 2 forceps techniques than with the 2 trocar techniques. CONCLUSIONS AND CLINICAL RELEVANCE: Trocar-implemented thoracostomy tube placement in canine cadavers resulted in less air leakage than the forceps method. Air leakage upon tube removal was less pronounced for the LD-CARM technique than the SC-CARM technique. The LD-TRO technique is recommended to prevent iatrogenic pneumothorax in dogs.

Comparison of IFN-gamma responses to mycobacterial antigens as markers of response to BCG vaccination.

An increase in interferon-gamma (IFN-gamma) production to Mycobacterium tuberculosis purified protein derivative (Mtb PPD), as measured in the cultured diluted whole blood assay, is one indicator of a protective immune response to BCG vaccine. We have explored the potential for this assay to be improved by measuring IFN-gamma responses to more defined antigens of M. tuberculosis (short-term and mid-term culture filtrates, ESAT-6, 38 kDa), Mycobacterium bovis (MPB70), M. bovis BCG (Antigen 85) and Mycobacterium leprae (35 kDa), in UK teenagers before and 1 year after BCG vaccination (or no vaccination as controls). There was a significant increase in response to the culture filtrates post-vaccination, but this was no greater than that to Mtb PPD. Many teenagers responded to the purified antigens, in particular to Antigen 85, prior to vaccination, and BCG vaccination could only augment this pre-existing response to a limited extent; prior exposure to environmental mycobacteria can thus induce cross-reactive responses to antigens which complicate interpretation of in vitro assays of vaccine response. In contrast, ESAT-6 was recognised by only one teenager prior to vaccination, and, as expected, responses were not boosted by BCG. We therefore conclude that Mtb PPD is the antigen preparation of choice for assessing the immunogenicity of BCG vaccination.

Persistence of the immune response induced by BCG vaccination.

BACKGROUND: Although BCG vaccination is recommended in most countries of the world, little is known of the persistence of BCG-induced immune responses. As novel TB vaccines may be given to boost the immunity induced by neonatal BCG vaccination, evidence concerning the persistence of the BCG vaccine-induced response would help inform decisions about when such boosting would be most effective. METHODS: A randomised control study of UK adolescents was carried out to investigate persistence of BCG immune responses. Adolescents were tested for interferon-gamma (IFN-gamma) response to Mycobacterium tuberculosis purified protein derivative (M.tb PPD) in a whole blood assay before, 3 months, 12 months (n = 148) and 3 years (n = 19) after receiving teenage BCG vaccination or 14 years after receiving infant BCG vaccination (n = 16). RESULTS: A gradual reduction in magnitude of response was evident from 3 months to 1 year and from 1 year to 3 years following teenage vaccination, but responses 3 years after vaccination were still on average 6 times higher than before vaccination among vaccinees. Some individuals (11/86; 13%) failed to make a detectable antigen-specific response three months after vaccination, or lost the response after 1 (11/86; 13%) or 3 (3/19; 16%) years. IFN-gamma response to Ag85 was measured in a subgroup of adolescents and appeared to be better maintained with no decline from 3 to 12 months. A smaller group of adolescents were tested 14 years after receiving infant BCG vaccination and 13/16 (81%) made a detectable IFN-gamma response to M.tb PPD 14 years after infant vaccination as compared to 6/16 (38%) matched unvaccinated controls (p = 0.012); teenagers vaccinated in infancy were 19 times more likely to make an IFN-gamma response of > 500 pg/ml than unvaccinated teenagers. CONCLUSION: BCG vaccination in infancy and adolescence induces immunological memory to mycobacterial antigens that is still present and measurable for at least 14 years in the majority of vaccinees, although the magnitude of the peripheral blood response wanes from 3 months to 12 months and from 12 months to 3 years post vaccination. The data presented here suggest that because of such waning in the response there may be scope for boosting anti-tuberculous immunity in BCG vaccinated children anytime from 3 months post-vaccination. This supports the prime boost strategies being employed for some new TB vaccines currently under development.

Glycated haemoglobin A1c (HbA1c) for detection of diabetes mellitus and impaired fasting glucose in Malawi: a diagnostic accuracy study.

OBJECTIVES: To examine the accuracy of glycated haemoglobin A1c (HbA1c) in detecting type 2 diabetes and impaired fasting glucose among adults living in Malawi. DESIGN: A diagnostic validation study of HbA1c. Fasting plasma glucose (FPG) ≥7.0 mmol/L was the reference standard for type 2 diabetes, and FPG between 6.1 and 6.9 mmol/L as impaired fasting glucose. PARTICIPANTS: 3645 adults (of whom 63% were women) recruited from two demographic surveillance study sites in urban and rural Malawi. This analysis excluded those who had a previous diagnosis of diabetes or had history of taking diabetes medication. RESULTS: HbA1c demonstrated excellent validity to detect FPG-defined diabetes, with an area under the receiver operating characteristic (AUROC) curve of 0.92 (95% CI 0.90 to 0.94). At HbA1c ≥6.5% (140 mg/dL), sensitivity was 78.7% and specificity was 94.0%. Subgroup AUROCs ranged from 0.86 for participants with anaemia to 0.94 for participants in urban Malawi. There were clinical and metabolic differences between participants with true diabetes versus false positives when HbA1c was ≥6.5% (140 mg/dL). CONCLUSIONS: The findings from this study provide justification to use HbA1c to detect type 2 diabetes. As HbA1c testing is substantially less burdensome to patients than either FPG testing or oral glucose tolerance testing, it represents a useful option for expanding access to diabetes care in sub-Saharan Africa.

Prevalence of obesity, hypertension, and diabetes, and cascade of care in sub-Saharan Africa: a cross-sectional, population-based study in rural and urban Malawi.

BACKGROUND: Sub-Saharan Africa is in rapid demographic transition, and non-communicable diseases are increasingly important causes of morbidity and mortality. We investigated the burden of diabetes, overweight and obesity, hypertension, and multimorbidity, their treatment, and their associations with lifestyle and other factors in Malawi, a very poor country with a predominantly rural-but rapidly growing urban-population, to identify high-risk populations and inform appropriate interventions. METHODS: In this cross-sectional, population-based study, we enrolled all adults (≥18 years) residing in two defined geographical areas within Karonga District and Lilongwe city. All adults self-defining as usually resident in the study areas were eligible, and recruited at household level. Participants were interviewed, had anthropometry and blood pressure measured, and had fasting blood samples collected. The study outcomes were prevalence estimates and risk ratios for diabetes (defined as fasting blood glucose of at least 7·0 mmol/L or self-report of a previous diagnosis of diabetes), hypertension (systolic blood pressure of at least 140 mm Hg, diastolic blood pressure of at least 90 mm Hg, or self-report of current antihypertensive medication), overweight (BMI of 25·0-29·9 kg/m2) and obesity (BMI of 30·0 kg/m2 or more), and multimorbidity (two or more of the above conditions) by location-specific (urban vs rural), age-specific, and sex-specific groups, calculated using negative binomial regression. We used χ2 likelihood ratio tests to assess heterogeneity by age, location, and sex. FINDINGS: Between May 16, 2013, and Feb 8, 2016, we enrolled 15 013 (62%) of 24 367 eligible urban adults in Lilongwe and 13 878 (88%) of 15 806 eligible rural adults in Karonga District. Overweight and obesity, hypertension, and diabetes were highly prevalent, more so in urban residents, the less poor, and better educated than in rural, the poorest, and least educated participants. 18% of urban men (961 of 5211 participants) and 44% (4115 of 9282) of urban women, and 9% (521 of 5834) of rural men and 27% (2038 of 7497) of rural women were overweight or obese; 16% (859 of 5212), 14% (1349 of 9793), 13% (787 of 5847), and 14% (1101 of 8025) had hypertension; and 3% (133 of 3928), 3% (225 of 7867), 2% (84 of 5004), and 2% (124 of 7116) had diabetes, respectively. Of 566 participants with diabetes, 233 (41%) were undiagnosed, and of 4096 participants with hypertension, 2388 (58%) were undiagnosed. Fewer than half the participants on medication for diabetes or hypertension had well controlled diabetes (84 [41%] of 207 participants) or blood pressure (440 [37%] of 1183 participants). Multimorbidity was highest in urban women (n=519, 7%). INTERPRETATION: Overweight and obesity, hypertension, and diabetes are highly prevalent in urban and rural Malawi, yet many patients are undiagnosed and management is limited. Local-evidence-informed multisectoral, innovative, and targeted interventions are needed urgently to manage the already high burden. FUNDING: Wellcome Trust.

Implementing electronic data capture at a well-established health and demographic surveillance site in rural northern Malawi.

This article aims to assess multiple issues of resources, staffing, local opinion, data quality, cost, and security while transitioning to electronic data collection (EDC) at a long-running community research site in northern Malawi. Levels of missing and error fields, delay from data collection to availability, and average number of interviews per day were compared between EDC and paper in a complex, repeated annual household survey. Three focus groups with field and data staff with experience using both methods, and in-depth interviews with participants were carried out. Cost for each method were estimated and compared. Missing data was more common on paper questionnaires than on EDC, and a similar number were carried out per day. Fieldworkers generally preferred EDC, but data staff feared for their employment. Most respondents had no strong preference for a method. The cost of the paper system was estimated to be higher than using EDC. The existing infrastructure and technical expertise could be adapted to using EDC, but changes have an impact on data processing jobs as fewer, and better qualified staff are required. EDC is cost-effective, and, for a long-running site, may offer further savings, as devices can be used in multiple studies and perform several other functions. EDC is accepted by fieldworkers and respondents, has good levels of quality and timeliness, and security can be maintained. EDC is well-suited for use in a well-established research site using and developing existing infrastructure and expertise.

Prevalence and risk factors associated with outcome of surgical removal of pedunculated lipomas in horses: 102 cases (1987-2002).

OBJECTIVE: To determine the prevalence of pedunculated lipomas and identify risk factors affecting postoperative complications and survival in horses at a veterinary teaching hospital undergoing surgery for colic caused by pedunculated lipomas. DESIGN: Retrospective study. ANIMALS: 102 horses with a diagnosis of pedunculated lipoma. PROCEDURE: Age, breed, weight, and sex of horses with pedunculated lipomas were compared with the total equine hospital population and the population of horses admitted for abdominal surgery during the same period. Follow-up information was obtained by reevaluation or contact with owners via telephone or written request. RESULTS: Prevalence of pedunculated lipomas as a reason for abdominal surgery in horses, compared with the population of horses with and without lipomas admitted for abdominal surgery, was 10%. Castrated male Saddlebred and Arabian horses > 14 years old were identified as being at risk for developing pedunculated lipomas. Postoperative complications were detected in 72% of horses with pedunculated lipomas. Variables associated with low survival rates included surgery before 1992, heart rate > 80 beats/min, abnormal color of abdominal fluid, pale mucous membranes, surgery requiring intestinal resection, and inability to attain a mean arterial pressure > or = 100 mm Hg. Horses undergoing surgery from 1992 to 1996, weighing < 409 kg (900 lb), or requiring jejunojejunal anastomosis had a high survival rate. CONCLUSIONS AND CLINICAL RELEVANCE: Although many of the variables reflected the health of the horse at the time of surgery, results may help veterinarians recognize risk factors associated with development of pedunculated lipomas and better predict the outcome of horses undergoing surgery for colic caused by pedunculated lipomas.

Maternal HIV status associated with under-five mortality in rural Northern Malawi: a prospective cohort study.

BACKGROUND: Under-five mortality is decreasing but with little change in neonatal mortality rates. We examined the effect of maternal HIV status on under-five mortality and cause of death since widespread availability of antiretroviral therapy in rural Malawi. METHODS: Children born in 2006-2011 in the Karonga demographic surveillance area were included. Maternal HIV status was available from HIV serosurveys. Age-specific mortality rate ratios for children born to HIV-positive and HIV-negative mothers were obtained by fitting a Poisson model accounting for child clustering by mother and adjusting for potential confounders. Cause of death was ascertained by verbal autopsy. FINDINGS: There were 352 deaths among 6913 under-five singleton children followed for 20,754 person-years (py), giving a mortality rate of 17.0/1000 py overall, 218/1000 py (16.5/1000 live births) in neonates, 20/1000 py (17.4/1000 live births) in postneonatal infants, and 8/1000 py in 1-4 years old. Comparing those born to HIV-positive and HIV-negative mothers, the rate ratio adjusted for child age, sex, maternal age, parity, and drinking water source was 1.5 (95% confidence interval [CI]: 0.6 to 3.7) in neonates, 11.5 (95% CI: 7.2 to 18.5) in postneonatal infants, and 4.6 (95% CI: 2.7 to 7.9) in 1-4 years old. Birth injury/asphyxia, neonatal sepsis, and prematurity contributed >70% of neonatal deaths, whereas acute infections, malaria, diarrhea, and pneumonia accounted for most deaths in older children. CONCLUSIONS: Maternal HIV status had little effect on neonatal mortality but was associated with much higher mortality in the postneonatal period and among older children. Greater attention to HIV care in pregnant women and mothers should help improve child survival, but broader interventions are needed to reduce neonatal mortality.

Identification of immunological biomarkers which may differentiate latent tuberculosis from exposure to environmental nontuberculous mycobacteria in children.

A positive gamma interferon (IFN-γ) response to Mycobacterium tuberculosis early secretory antigenic target-6 (ESAT-6)/culture filtrate protein-10 (CFP-10) has been taken to indicate latent tuberculosis (TB) infection, but it may also be due to exposure to environmental nontuberculous mycobacteria in which ESAT-6 homologues are present. We assessed the immune responses to M. tuberculosis ESAT-6 and cross-reactive responses to ESAT-6 homologues of Mycobacterium avium and Mycobacterium kansasii. Archived culture supernatant samples from children at 3 years post-BCG vaccination were tested for cytokine/chemokine responses to M. tuberculosis antigens. Furthermore, the IFN-γ responses to M. tuberculosis antigens were followed up for 40 children at 8 years post-BCG vaccination, and 15 TB patients were recruited as a control group for the M. tuberculosis ESAT-6 response in Malawi. IFN-γ enzyme-linked immunosorbent assays (ELISAs) on supernatants from diluted whole-blood assays, IFN-γ enzyme-linked immunosorbent spot (ELISpot) assays, QuantiFERON TB Gold-In Tube tests, and multiplex bead assays were performed. More than 45% of the responders to M. tuberculosis ESAT-6 showed IFN-γ responses to M. avium and M. kansasii ESAT-6. In response to M. tuberculosis ESAT-6/CFP-10, interleukin 5 (IL-5), IL-9, IL-13, and IL-17 differentiated the stronger IFN-γ responders to M. tuberculosis ESAT-6 from those who preferentially responded to M. kansasii and M. avium ESAT-6. A cytokine/chemokine signature of IL-5, IL-9, IL-13, and IL-17 was identified as a putative immunological biosignature to differentiate latent TB infection from exposure to M. avium and M. kansasii in Malawian children, indicating that this signature might be particularly informative in areas where both TB and exposure to environmental nontuberculous mycobacteria are endemic.

Profile: the Karonga Health and Demographic Surveillance System.

The Karonga Health and Demographic Surveillance System (Karonga HDSS) in northern Malawi currently has a population of more than 35 000 individuals under continuous demographic surveillance since completion of a baseline census (2002-2004). The surveillance system collects data on vital events and migration for individuals and for households. It also provides data on cause-specific mortality obtained by verbal autopsy for all age groups, and estimates rates of disease for specific presentations via linkage to clinical facility data. The Karonga HDSS provides a structure for surveys of socio-economic status, HIV sero-prevalence and incidence, sexual behaviour, fertility intentions and a sampling frame for other studies, as well as evaluating the impact of interventions, such as antiretroviral therapy and vaccination programmes. Uniquely, it relies on a network of village informants to report vital events and household moves, and furthermore is linked to an archive of biological samples and data from population surveys and other studies dating back three decades.

BCG vaccination: a role for vitamin D?

BACKGROUND: BCG vaccination is administered in infancy in most countries with the aim of providing protection against tuberculosis. There is increasing interest in the role of vitamin D in immunity to tuberculosis. This study objective was to determine if there was an association between circulating 25(OH)D concentrations and BCG vaccination status and cytokine responses following BCG vaccination in infants. METHODS: Blood samples were collected from UK infants who were vaccinated with BCG at 3 (n = 47) and 12 (n = 37) months post BCG vaccination. These two time-points are denoted as time-point 1 and time-point 2. Two blood samples were also collected from age-matched unvaccinated infants (n = 32 and 28 respectively), as a control group. Plasma vitamin D concentrations (25(OH)D) were measured by radio-immunoassay. The cytokine IFNγ was measured in supernatants from diluted whole blood stimulated with M.tuberculosis (M.tb) PPD for 6 days. RESULTS: 58% of infants had some level of hypovitaminosis (25(OH)D <30 ng/ml) at time-point 1, and this increased to 97% 9 months later. BCG vaccinated infants were almost 6 times (CI: 1.8-18.6) more likely to have sufficient vitamin D concentrations than unvaccinated infants at time-point 1, and the association remained strong after controlling for season of blood collection, ethnic group and sex. Among vaccinees, there was also a strong inverse association between IFNγ response to M.tb PPD and vitamin D concentration, with infants with higher vitamin D concentrations having lower IFNγ responses. CONCLUSIONS: Vitamin D may play an immuno-regulatory role following BCG vaccination. The increased vitamin D concentrations in BCG vaccinated infants could have important implications: vitamin D may play a role in immunity induced by BCG vaccination and may contribute to non-specific effects observed following BCG vaccination.

Targeted combined aerosol chemotherapy in dogs and radiologic toxicity grading.

BACKGROUND: We investigated whether combination chemotherapy, targeted with the AeroProbe® Intracorporeal Nebulizing Catheter (INC), could be safely administered, and developed a radiologic grading scheme to monitor subclinical effects on the lungs. METHODS: In anesthetized and mechanically ventilated healthy dogs (n = 3), we introduced the INC via a flexible bronchoscope into the right caudal lung lobe and administered escalating dosages of gemcitabine (1, 2, 3, or 6 mg/kg) followed by cisplatin (10 mg/m(2)). Treatments were performed every 2 weeks for 4 treatments and dogs were monitored weekly with physical examination, biochemical tests, and thoracic radiographs. Dogs were sacrificed 2 weeks after the final treatment and tissues examined histologically. A radiologic grading scheme was developed to monitor subclinical pulmonary toxicity. RESULTS: No significant side effects occurred in any dog. All dogs developed focal pneumonitis radiographically, and chronic, severe pneumonia with fibrosis histologically limited to the treated portion of the lung. Radiologic scores increased over time following increasing doses of chemotherapy. CONCLUSIONS: Targeted aerosol delivery of gemcitabine and cisplatin by INC was clinically well tolerated. This minimally invasive method is promising for lung cancer treatment, especially given the lack of clinical toxicity. The proposed radiologic grading scheme provides a method to monitor subclinical local drug toxicity.

Comparison of ultrasonic Doppler flow monitor, oscillometric, and direct arterial blood pressure measurements in ill dogs.

OBJECTIVE: To compare blood pressure measurements obtained via ultrasonic Doppler flow monitor (DOP) and 2 oscillometric noninvasive blood pressure monitors (CAR and PAS) to invasive blood pressure (IBP) in hospitalized, conscious dogs with a range of blood pressures. DESIGN: Prospective clinical study. SETTING: University teaching hospital. ANIMALS: Eleven client-owned dogs aged between 4 months and 11.5 years (median 6 y), and weighing between 5.8 and 37.5 kg (median 30.2 kg). INTERVENTIONS: Blood pressure measurement. MEASUREMENTS AND MAIN RESULTS: Three consecutive measurements of systolic, diastolic, and mean arterial pressure (MAP) were recorded for each of the 3 indirect devices (only systolic for DOP), along with concurrent IBP measurements. The data were categorized into 3 groups: hypotensive (direct MAP<80 mm Hg), normotensive (80 mm Hgor=100 mm Hg), and hypertensive (direct MAP>100 mm Hg). Each indirect method was compared with the corresponding direct arterial pressure using the Bland-Altman method. Within the hypotensive group, each indirect method overestimated the corresponding IBP. Within the normotensive group all indirect systolic measurements and the PAS diastolic measurements underestimated the corresponding IBP. The remaining indirect measurements overestimated the corresponding IBP. Within the hypertensive group, DOP and CAR systolic measurements underestimated the corresponding IBP, and the remaining indirect measurements overestimated the corresponding IBP. In hypertensive dogs oscillometric systolic measurements were more accurate than MAP. In hypotensive dogs MAP measurements were more accurate than systolic measurements. All indirect measurements were most accurate in hypertensive dogs. CONCLUSIONS: The noninvasive blood pressure monitors in our study did not meet the validation standards set in human medicine. However, CAR diastolic and MAP measurements within the normotensive group, CAR MAP measurements within the hypertensive group, and PAS diastolic measurements in all groups were close to these standards. All indirect measurements showed greater bias during hypotension. Precision was poorer for all indirect systolic measurements than for MAP.