Adolescent gynaecology: anaesthetic and peri-operative care implications.

Adolescents represent a quarter of the world's population, yet their specific healthcare needs have often not been acknowledged. Whilst many operations in this population will be performed in specialist tertiary centres and children's hospitals, it is likely that care will be sought in a variety of healthcare settings, and so it is important to have an understanding of the particular approach to this age group. Paediatric and adolescent gynaecology emerged as a speciality in 2000 with the inauguration of the British Society for Paediatric and Adolescent Gynaecology, a specialist society of the Royal College of Obstetricians and Gynaecologists. This is a multidisciplinary group, comprising paediatricians, paediatric surgeons, psychologists and nurses, although the majority of the members are gynaecologists. In this review, we will describe the peri-operative implications of adolescent gynaecological surgery and the considerations that need to be applied to this specific age group, such as consent, the operative setting and key personnel. We will also discuss specialist situations which are likely to fall to an adolescent gynaecology setting, such as management of those with Mullerian abnormalities, which often present with pelvic pain in adolescence. We discuss those with a history of ritual female genital cutting (female genital mutilation), trans men and those with significant learning difficulties. In all circumstances, teamwork, reflection and pragmatism are key.

Double-lumen tracheal tubes and bougies: a bench study to investigate factors that influence the risk of shearing.

Tracheal intubation with a double-lumen tube can be more challenging than with a single-lumen tube. A bougie can be used to facilitate intubation. Case reports have described fragment shearing from bougies when they are removed from the tube after intubation. These fragments have the potential to cause harm. It has even been suggested that bougies and double-lumen tubes should not be used together. We conducted a benchtop trial to investigate factors that influence the risk of shearing. We investigated three brands of double-lumen tube (each in three sizes and both lateralities) and four brands of bougie. We simulated one intubation and 29 further insertions/removals of bougie with every bougie-double-lumen tube combination. We inspected the inside of the tube for evidence of shearing after first, tenth and thirtieth removals. We found that brand of bougie, brand of double-lumen tube and size of double-lumen tube (but not its laterality) all influenced the degree of shearing. Certain bougie-double-lumen tube combinations produced a particularly high degree of shearing, so these should be avoided.

Monocyte activation and cytokine production in Malawian children presenting with P. falciparum malaria.

Malaria in malaria-naïve adults is associated with an inflammatory response characterized by expression of specific activation markers on innate immune cells. Here, we investigate activation and adhesion marker expression, and cytokine production in monocytes from children presenting with cerebral malaria (CM, n = 36), severe malarial anaemia (SMA, n = 42) or uncomplicated malaria (UM, n = 66), and healthy aparasitemic children (n = 52) in Blantyre, Malawi. In all malaria groups, but particularly in the two severe malaria groups, monocyte expression of CD11b, CD11c, CD18, HLA-DR and CD86, and percentages of TNF-α- and IL-6-producing monocytes were lower than in healthy controls, while expression of CD11a, TLR2 and TLR4 was lower in children with severe malaria compared with controls. These levels mostly normalized during convalescence, but percentages of cytokine-producing monocytes remained suppressed in children with SMA. In all malaria groups, especially the SMA group, a greater proportion of monocytes were loaded with haemozoin than among controls. In a P. falciparum hyperendemic area, monocytes in children with acute symptomatic malaria have reduced expression of adhesion molecules and activation markers and reduced inflammatory cytokine production. This immune suppression could be due to accumulation of haemozoin and/or previous exposure to P. falciparum.

Pharmacokinetics of Antituberculosis Drugs in HIV-Positive and HIV-Negative Adults in Malawi.

Limited data address the impact of HIV coinfection on the pharmacokinetics (PK) of antituberculosis drugs in sub-Saharan Africa. A total of 47 Malawian adults underwent rich pharmacokinetic sampling at 0, 0.5, 1, 2, 3, 4, 6, 8, and 24 h postdose. Of the subjects, 51% were male, their mean age was 34 years, and 65% were HIV-positive with a mean CD4 count of 268 cells/µl. Antituberculosis drugs were administered as fixed-dose combinations (150 mg rifampin, 75 mg isoniazid, 400 mg pyrazinamide, and 275 mg ethambutol) according to recommended weight bands. Plasma drug concentrations were determined by high-performance liquid chromatography (rifampin and pyrazinamide) or liquid chromatography-mass spectrometry (isoniazid and ethambutol). Data were analyzed by noncompartmental methods and analysis of variance of log-transformed summary parameters. The pharmacokinetic parameters were as follows (median [interquartile range]): for rifampin, maximum concentration of drug in plasma (Cmax) of 4.129 µg/ml (2.474 to 5.596 µg/ml), area under the curve from 0 to 24 h (AUC0-∞) of 21.32 µg/ml · h (13.57 to 28.60 µg/ml · h), and half-life of 2.45 h (1.86 to 3.08 h); for isoniazid, Cmax of 3.97 µg/ml (2.979 to 4.544 µg/ml), AUC0-24 of 22.5 (14.75 to 34.59 µg/ml · h), and half-life of 3.93 h (3.18 to 4.73 h); for pyrazinamide, Cmax of 34.21 µg/ml (30.00 to 41.60 µg/ml), AUC0-24 of 386.6 µg/ml · h (320.0 to 463.7 µg/ml · h), and half-life of 6.821 h (5.71 to 8.042 h); and for ethambutol, Cmax of 2.278 µg/ml (1.694 to 3.098 µg/ml), AUC0-24 of 20.41 µg/ml · h (16.18 to 26.27 µg/ml · h), and half-life of 7.507 (6.517 to 8.696 h). The isoniazid PK data analysis suggested that around two-thirds of the participants were slow acetylators. Dose, weight, and weight-adjusted dose were not significant predictors of PK exposure, probably due to weight-banded dosing. In this first pharmacokinetic study of antituberculosis drugs in Malawian adults, measures of pharmacokinetic exposure were comparable with those of other studies for all first-line drugs except for rifampin, for which the Cmax and AUC0-24 values were notably lower. Contrary to some earlier observations, HIV status did not significantly affect the AUC of any of the drugs. Increasing the dose of rifampin might be beneficial in African adults, irrespective of HIV status. Current co-trimoxazole prophylaxis was associated with an increase in the half-life of isoniazid of 41% (P = 0.022). Possible competitive interactions between isoniazid and sulfamethoxazole mediated by the N-acetyltransferase pathway should therefore be explored further.

Laboratory evidence of disseminated intravascular coagulation is associated with a fatal outcome in children with cerebral malaria despite an absence of clinically evident thrombosis or bleeding.

BACKGROUND: A procoagulant state is implicated in cerebral malaria (CM) pathogenesis, but whether disseminated intravascular coagulation (DIC) is present or associated with a fatal outcome is unclear. OBJECTIVES: To determine the frequency of overt DIC, according to ISTH criteria, in children with fatal and non-fatal CM. METHODS/PATIENTS: Malawian children were recruited into a prospective cohort study in the following diagnostic groups: retinopathy-positive CM (n = 140), retinopathy-negative CM (n = 36), non-malarial coma (n = 14), uncomplicated malaria (UM), (n = 91), mild non-malarial febrile illness (n = 85), and healthy controls (n = 36). Assays in the ISTH DIC criteria were performed, and three fibrin-related markers, i.e. protein C, antithrombin, and soluble thrombomodulin, were measured. RESULTS AND CONCLUSIONS: Data enabling assignment of the presence or absence of 'overt DIC' were available for 98 of 140 children with retinopathy-positive CM. Overt DIC was present in 19 (19%), and was associated with a fatal outcome (odds ratio [OR] 3.068; 95% confidence interval [CI] 1.085-8.609; P = 0.035]. The levels of the three fibrin-related markers and soluble thrombomodulin were higher in CM patients than in UM patients (all P < 0.001). The mean fibrin degradation product level was higher in fatal CM patients (71.3 µg mL(-1) [95% CI 49.0-93.6]) than in non-fatal CM patients (48.0 µg mL(-1) [95% CI 37.7-58.2]; P = 0.032), but, in multivariate logistic regression, thrombomodulin was the only coagulation-related marker that was independently associated with a fatal outcome (OR 1.084 for each ng mL(-1) increase [95% CI 1.017-1.156]; P = 0.014). Despite these laboratory derangements, no child in the study had clinically evident bleeding or thrombosis. An overt DIC score and high thrombomodulin levels are associated with a fatal outcome in CM, but infrequently indicate a consumptive coagulopathy.

Acute brain MRI findings in 120 Malawian children with cerebral malaria: new insights into an ancient disease.

BACKGROUND AND PURPOSE: There have been few neuroimaging studies of pediatric CM, a common often fatal tropical condition. We undertook a prospective study of pediatric CM to better characterize the MRI features of this syndrome, comparing findings in children meeting a stringent definition of CM with those in a control group who were infected with malaria but who were likely to have a nonmalarial cause of coma. MATERIALS AND METHODS: Consecutive children admitted with traditionally defined CM (parasitemia, coma, and no other coma etiology evident) were eligible for this study. The presence or absence of malaria retinopathy was determined. MRI findings in children with ret+ CM (patients) were compared with those with ret- CM (controls). Two radiologists blinded to retinopathy status jointly developed a scoring procedure for image interpretation and provided independent reviews. MRI findings were compared between patients with and without retinopathy, to assess the specificity of changes for patients with very strictly defined CM. RESULTS: Of 152 children with clinically defined CM, 120 were ret+, and 32 were ret-. Abnormalities much more common in the patients with ret+ CM were markedly increased brain volume; abnormal T2 signal intensity; and DWI abnormalities in the cortical, deep gray, and white matter structures. Focal abnormalities rarely respected arterial vascular distributions. Most of the findings in the more clinically heterogeneous ret- group were normal, and none of the abnormalities noted were more prevalent in controls. CONCLUSIONS: Distinctive MRI findings present in patients meeting a stringent definition of CM may offer insights into disease pathogenesis and treatment.

Population pharmacokinetics of sulfadoxine and pyrimethamine in Malawian children with malaria.

In addition to parasite resistance, inadequate levels of exposure to antimalarial drugs may contribute to treatment failure. We developed population pharmacokinetic (PK) models to describe the distribution of sulfadoxine (SDX) and pyrimethamine (PYM) in children with uncomplicated malaria in Malawi. The concentration levels of antimalarial drugs in whole blood were determined using high-performance liquid chromatography. We found no evidence of underdosing in children as compared with adults; the children had drug exposure levels similar to those described in adults. Treatment failure was more likely in children with lower PYM concentrations on day 14 (P = 0.024), and there was a trend for lower SDX concentrations on day 14 (P = 0.061). SDX and PYM concentrations at levels predictive of treatment failure have been identified at day 14. Less than one-third of the children displayed drug concentration levels above these thresholds after receiving the recommended SDX-pyrimethamine (SP) dose. Our findings suggest that PK factors contributed to the observed high rate of treatment failure, and we therefore recommend a higher SP dose for children under the age of 5 years.

The effects of hypoxia on the ERG in paediatric cerebral malaria.

BACKGROUND/AIMS: Cerebral malaria (CM) is a disease of high mortality worldwide. It can be associated with malarial retinopathy (MR) resulting from impaired perfusion within the retinal microvasculature. Areas of capillary non-perfusion (CNP) appear white (retinal whitening) on ophthalmoloscopy. In this study, electrophysiological investigations were performed to investigate the physiological consequences of these hypoxic and ischaemic changes. METHODS: Children admitted with CM were assessed for inclusion in the study. Those with MR underwent further detailed fundus assessment to quantify retinal whitening and were then designated a severity score. Electrophysiological recordings were performed using a miniganzfeldt stimulator with calibration to the International Society for Clinical Electrophysiology of Visual (ISCEV) standards. ERG data were then analysed with respect to presence of MR and also graded disease severity. RESULTS: Thirty-one children were recruited with a diagnosis of CM, 20 had MR (group 1), and 11 had absent MR (group 2). Statistical analyses of these two groups showed a significant relationship between reduced single flash cone b wave amplitude (CBWA) and increased severity of retinal whitening/CNP (P<0.05). Cone and maximal response b : a wave ratios remained >1 in all subjects. CONCLUSION: Retinal whitening/CNP in MR is associated with significant changes in ERG cone b wave function. The relatively high b : a ratio is compatible with the high frequency of MR resolution without sequelae.

The outcome of non-typhoidal salmonella meningitis in Malawian children, 1997-2006.

INTRODUCTION: The clinical course and outcome of non-typhoidal salmonella (NTS) meningitis in Malawian children over a 10-year period (1997-2006) is described. METHODS: Demographic, clinical and laboratory data were collected for all children over 2 months of age admitted with salmonella meningitis to Queen Elizabeth Central Hospital from 1997 to 2006. In the 1st year, salmonellae were susceptible to chloramphenicol, and children received 2 weeks of chloramphenicol treatment. When NTS resistance to chloramphenicol started to appear in 1998, treatment was changed to ceftriaxone. From 2002, the duration of antibiotic therapy was extended to 4-weeks which included 2 weeks of intravenous ceftriaxone and a further 2 weeks of oral ciprofloxacin. RESULTS: The in-hospital case fatality rate (CFR) was 52.3% (48.2% until 2002 and 53.9% after prolonged antibiotic therapy was introduced). Of the survivors, one in 12 (8.3%) became completely well (sequelae-free) in the period 1997-2001 while 18 of 31 survivors (58.1%) made a complete recovery during 2002-2006 (p<0.01). After the 4-week course of antimicrobial therapy was introduced, the number of relapses or recurrences fell from nine in 15 (60%) survivors treated with chloramphenicol or ceftriaxone to three in 35 (8.7%) survivors who received 4 weeks of antibiotics (p<0.0001). CONCLUSION: In Malawi, salmonella meningitis has a CFR of approximately 50%, which has remained constant over many years. Residual morbidity, however, has decreased over 10 years, despite rising numbers of multi-drug-resistant cases of NTS. This improvement might be owing to better treatment and management and/or reduced pathogenicity of the multi-drug-resistant bacteria.

Simple measures are as effective as invasive techniques in the diagnosis of pulmonary tuberculosis in Malawi.

SETTING: Detection of smear-positive pulmonary tuberculosis (PTB) cases is vital for tuberculosis (TB) control. Methods to augment sputum collection are available, but their additional benefit is uncertain in resource-limited settings. OBJECTIVE: To compare the diagnostic yields using five methods to obtain sputum from adults diagnosed with smear-negative PTB in Malawi. DESIGN: Self-expectorated sputum was collected under supervision for microscopy and mycobacterial culture in the study laboratory. Confirmed smear-negative patients provided physiotherapy-assisted sputum and induced sputum, followed the next morning by gastric washing and bronchoalveolar lavage (BAL) samples. RESULTS: A total of 150 patients diagnosed with smear-negative PTB by the hospital service were screened; 39 (26%) were smear-positive from supervised self-expectorated sputum examined in the study laboratory. The remaining 111 confirmed smear-negative patients were enrolled in the study; 89% were human immunodeficiency virus positive. Seven additional smear-positive cases were diagnosed using the augmented sputum collection techniques. No differences were observed in the numbers of cases detected using the different methods. Of the 46 smear-positive cases, 44 (95.6%) could be detected from self-expectorated and physiotherapy-assisted samples. CONCLUSIONS: For countries such as Malawi, the best use of limited resources to detect smear-positive PTB cases would be to improve the quality of self-expectorated sputum collection and microscopy. The additional diagnostic yield using BAL after induced sputum is limited.

Variation in the ICAM1 gene is not associated with severe malaria phenotypes.

Evidence from autopsy and in vitro binding studies suggests that adhesion of erythrocytes infected with Plasmodium falciparum to the human host intercellular adhesion molecule (ICAM)-1 receptor is important in the pathogenesis of severe malaria. Previous association studies between polymorphisms in the ICAM1 gene and susceptibility to severe malarial phenotypes have been inconclusive and often contradictory. We performed genetic association studies with 15 single nucleotide polymorphisms (SNPs) around the ICAM1 locus. All SNPs were screened in a family study of 1071 trios from The Gambia, Malawi and Kenya. Two key non-synonymous SNPs with previously reported associations, rs5491 (K56M or 'ICAM-1(Kilifi)') and rs5498 (K469E), were tested in an additional 708 Gambian trios and a case-control study of 4058 individuals. None of the polymorphisms were associated with severe malaria phenotypes. Pooled results across our studies for ICAM-1(Kilifi) were, in severe malaria, odds ratio (OR) 1.02, 95% confidence interval (CI) 0.96-1.09, P=0.54, and cerebral malaria OR 1.07, CI 0.97-1.17, P=0.17. We assess the available epidemiological, population genetic and functional evidence that links ICAM-1(Kilifi) to severe malaria susceptibility.

Malawians permit research bronchoscopy due to perceived need for healthcare.

OBJECTIVES: Bronchoalveolar lavage obtained at bronchoscopy is useful for research on pulmonary defence mechanisms. Bronchoscopy involves some discomfort and risk to subjects. We audited the process of consent, experienced adverse effects and reasons for participation among research bronchoscopy volunteers. DESIGN: 100 consecutive volunteer research subjects attending for bronchoscopy, repeat bronchoscopy or routine recruitment clinic were interviewed. Information was gathered about volunteer motivation, perception of the consent process and adverse effects of bronchoscopy. Suggestions for improvement were requested. Responses were themed by a second investigator prior to data analysis. RESULTS: 81 bronchoscopy-experienced subjects (total of 263 procedures) and 19 new volunteers were interviewed. 19 subjects (21%) reported adverse symptoms during or after bronchoscopy, but no symptoms were of sufficient severity that they would not repeat the procedure. The frequency of symptoms was not related to gender, the quality of the lavage or the HIV status of the subject. 76 subjects (94%) reported that the information given pre-procedure was useful and adequate but 43 (56%) had further questions mostly relating to their own results. The reasons given for research participation were access to health assessment (75 subjects), access to treatment when ill (61 subjects), desire to participate in research (15 subjects) and remuneration (6 subjects). 7 subjects complained that the remuneration was inadequate. CONCLUSIONS: The main incentive to participation in research bronchoscopy was access to healthcare. Informed consent and procedure technique were adequate but subjects would value more feedback about individual and project results.

Plasmodium falciparum-infected erythrocytes induce tissue factor expression in endothelial cells and support the assembly of multimolecular coagulation complexes.

BACKGROUND: Plasmodium falciparum malaria infects 300-500 million people every year, causing 1-2 million deaths annually. Evidence of a coagulation disorder, activation of endothelial cells (EC) and increase in inflammatory cytokines are often present in malaria. OBJECTIVES: We have asked whether interaction of parasitized red blood cells (pRBC) with EC induces tissue factor (TF) expression in vitro and in vivo. The role of phosphatidylserine-containing pRBC to support the assembly of blood coagulation complexes was also investigated. RESULTS: We demonstrate that mature forms of pRBC induce functional expression of TF by EC in vitro with productive assembly of the extrinsic Xnase complex and initiation of the coagulation cascade. Late-stage pRBC also support the prothrombinase and intrinsic Xnase complex formation in vitro, and may function as activated platelets in the amplification phase of the blood coagulation. Notably, post-mortem brain sections obtained from P. falciparum-infected children who died from cerebral malaria and other causes display a consistent staining for TF in the EC. CONCLUSIONS: These findings place TF expression by endothelium and the amplification of the coagulation cascade by pRBC and/or activated platelets as potentially critical steps in the pathogenesis of malaria. Furthermore, it may allow investigators to test other therapeutic alternatives targeting TF or modulators of EC function in the treatment of malaria and/or its complications.

Practical HPLC methods for the quantitative determination of common antimalarials in Africa.

This article describes high-performance liquid chromatographic assays for the quantification of sulfadoxine (SDX), pyrimethamine (PYM), chloroquine (CQ), amodiaquine (AQ) and desethylamodiaquine (AQM) from whole blood. All four assays were set up and validated in Malawi using a common high-performance liquid chromatography platform and column and involved the use of simple mobile phase and extraction reagents. Calibration curves were linear (r(2)>0.95) in the ranges 5-100microg/ml, 50-1000, 150-1500, 100-1000 and 100-1000ng/ml for SDX, PYM, CQ, AQ and AQM, respectively. Intra-assay and inter-assay coefficients of variation were <15% at 3 points spanning the concentration range and <20% at the lower limit of quantification. The assays were specific with no interference from the other antimalarials described in this report. All four assays use liquid-liquid extraction, reversed-phase chromatography and UV detection and require between 50 and 200microl of blood. Because the assays share common instruments and reagents, they are cost-efficient and could be used to optimise antimalarial drug therapies in other resource poor settings.

When is "malaria" malaria? The different burdens of malaria infection, malaria disease, and malaria-like illnesses.

In this review we discuss the different meanings of the term 'malaria' and urge writers and readers to distinguish accurately between them. The distinction is important in clinical practice, clinical trials, epidemiology, and the evaluation of control programs. Both over- and underdiagnosis of malaria as the cause of a disease episode are inevitable; overdiagnosis is common in high-transmission areas and underdiagnosis is common in areas with little or no transmission. Parasite density thresholds, attributable fractions, and clinical algorithms have played important but only partial roles in strengthening diagnosis. Methods by which malaria infection could be confidently identified as the cause, rather than an irrelevant accompaniment, of an illness, are important targets for research. One such 'signature' is a distinctive retinopathy that occurs in severe malaria and not in clinically similar diseases. Other indicators of a malarial etiology of clinical disease are needed to strengthen clinical and scientific approaches to the control of malaria.