Social determinants of health and long-term conditions in people of Black African and Black Caribbean ethnicity living with HIV in London: A qualitative study.

BACKGROUND: People living with human immunodeficiency virus (HIV) are disproportionately impacted by socioeconomic deprivation and are at increased risk of developing other long-term conditions (LTCs). These illnesses require transformative action to tackle the adverse effects on their health. Data on lived experiences of LTCs among people living with HIV of Black African and Black Caribbean ethnicities are sparse, and how people with LTCs are impacted by social determinants of health (SDoH). METHODS: Through a phenomenological study design this qualitative study, conducted in 2022, comprised four focus group discussions (FGDs) with 20 people of Black ethnicities living with HIV were purposively invited from a community organisation (CO) in London, including four semistructured interviews with CO staff. Following transcription, qualitative data were analysed thematically and measures to validate the findings were implemented. RESULTS: The findings are presented in terms of the following four levels of SDoH: (1) individual determinants (such as the impact of SDoH on lifestyle modification and self-management); (2) interpersonal determinants (such as positive experiences of accessing healthcare for LTCs); (3) clinical determinants (such as care pathway barriers) and (4) systemic determinants (such as systemic barriers related to race/ethnicity). CONCLUSIONS: It is necessary to provide ongoing and interactive education to community members who live with HIV, focusing on risks and management of LTCs. Additionally, individuals would benefit from support to navigate increasingly complex and fragmented health services. Health Service staff require cultural competence when caring for patients of Black African and Black Caribbean ethnicities with complex health and psychosocial needs. PATIENT OR PUBLIC CONTRIBUTION: The research team collaborated with an HIV CO in South London from the very start of the project to agree the study design and learn about the realities of their daily lived experiences. Community collaborators helped to develop the semistructured interview and FGD topic guides, and were directly involved in the data gathering, analysis and validation.

Host factors predisposing to kidney disease in people with HIV.

PURPOSE OF REVIEW: To highlight advances in understanding of host factors, in particular host genetics, in the development of chronic kidney disease (CKD) in people with HIV. RECENT FINDINGS: In Black populations, the G1 and G2 variants of the apolipoprotein L1 (APOL1) gene predispose to HIV-associated nephropathy (HIVAN). The risk of HIVAN is mostly confined to individuals with two APOL1 variants (kidney-risk genotypes). APOL1 kidney-risk genotypes are present in approximately 80% of patients with HIVAN and account for nearly half the burden of end-stage CKD in people of African ancestry with HIV. Progress has been made in elucidating the mechanisms of kidney injury in APOL1 nephropathy, and several targeted molecular therapies are being investigated in clinical trials. Genome- and epigenome-wide association studies are identifying additional genes and pathways that may be involved in the pathogenesis of CKD in people with HIV. SUMMARY: Genetic variants of APOL1 are strongly associated with severe CKD and contribute to the high rates of CKD in Black populations with HIV. Most individuals with APOL1 kidney-risk genotypes, however, do not develop kidney disease and further studies are required to understand the role of additional genetic and environmental factors that may affect CKD risk in this population.

Creatinine and cystatin C-based estimated glomerular filtration rate estimates of kidney function in Black people with HIV on antiretroviral therapy.

BACKGROUND: To reduce health inequalities, the creatinine-based chronic kidney disease epidemiology collaboration 2021 formula for estimated glomerular filtration rate (eGFR) is replacing the 2009 formula, which required adjustment specifically for Black individuals. We compared the 2021 and 2009 creatinine-based formulae with cystatin C-based eGFR in Black people on antiretroviral therapy (ART) with HIV RNA <200 c/ml. METHODS: Cross-sectional analysis of paired serum creatinine and cystatin C measurements. Bias, imprecision, accuracy, and performance for identifying individuals with eGFR cystatin C <60 (units: ml/min per 1.73 m 2 ) were determined. The effects of ART with no, mild-moderate, or marked effect on tubular creatinine secretion on the performance of the 2021 formula was assessed. RESULTS: We included 362 individuals (mean age 51 years, 56% female, mean eGFR-cystatin C 88.3). Overall, the 2021 (vs. the 2009 race-adjusted) formula was less biased and had improved imprecision and accuracy compared with eGFR-cystatin C but underestimated eGFR-cystatin C in those with eGFR ≥90 and overestimated eGFR-cystatin C in those with eGFR <60. The 2021 (vs. the 2009) formula had high specificity (95% vs. 97%) and negative predictive value (97% vs. 96%), but low sensitivity (56% vs. 52%) and positive predictive value (44% vs. 54%) for identifying individuals with eGFR-cystatin C <60 ( P  > 0.25). Performance at the eGFR <60 cut-off was minimally affected by ART exposure group. CONCLUSION: The CKD-EPI 2021 creatinine-based formula was better aligned with eGFR-cystatin C than the 2009 formula. eGFR-cystatin C may provide clinically useful information in Black people with eGFR <60 irrespective of ART regimen.

Integration of High-Throughput Imaging and Multiparametric Metabolic Profiling Reveals a Mitochondrial Mechanism of Tenofovir Toxicity.

Nephrotoxicity is a major cause of kidney disease and failure in drug development, but understanding of cellular mechanisms is limited, highlighting the need for better experimental models and methodological approaches. Most nephrotoxins damage the proximal tubule (PT), causing functional impairment of solute reabsorption and systemic metabolic complications. The antiviral drug tenofovir disoproxil fumarate (TDF) is an archetypal nephrotoxin, inducing mitochondrial abnormalities and urinary solute wasting, for reasons that were previously unclear. Here, we developed an automated, high-throughput imaging pipeline to screen the effects of TDF on solute transport and mitochondrial morphology in human-derived RPTEC/TERT1 cells, and leveraged this to generate realistic models of functional toxicity. By applying multiparametric metabolic profiling-including oxygen consumption measurements, metabolomics, and transcriptomics-we elucidated a highly robust molecular fingerprint of TDF exposure. Crucially, we identified that the active metabolite inhibits complex V (ATP synthase), and that TDF treatment causes rapid, dose-dependent loss of complex V activity and expression. Moreover, we found evidence of complex V suppression in kidney biopsies from humans with TDF toxicity. Thus, we demonstrate an effective and convenient experimental approach to screen for disease relevant functional defects in kidney cells in vitro, and reveal a new paradigm for understanding the pathogenesis of a substantial cause of nephrotoxicity.

Genetic Variants of APOL1 Are Major Determinants of Kidney Failure in People of African Ancestry With HIV.

Introduction: Variants of the APOL1 gene are associated with chronic kidney disease (CKD) in people of African ancestry, although evidence for their impact in people with HIV are sparse. Methods: We conducted a cross-sectional study investigating the association between APOL1 renal risk alleles and kidney disease in people of African ancestry with HIV in the UK. The primary outcome was end-stage kidney disease (ESKD; estimated glomerular filtration rate [eGFR] of <15 ml/min per 1.73 m2, chronic dialysis, or having received a kidney transplant). The secondary outcomes included renal impairment (eGFR <60 ml/min per 1.73 m2), albuminuria (albumin-to-creatinine ratio [ACR] >30 mg/mmol), and biopsy-proven HIV-associated nephropathy (HIVAN). Multivariable logistic regression was used to estimate the associations between APOL1 high-risk genotypes (G1/G1, G1/G2, G2/G2) and kidney disease outcomes. Results: A total of 2864 participants (mean age 48.1 [SD 10.3], 57.3% female) were genotyped, of whom, 354 (12.4%) had APOL1 high-risk genotypes, and 99 (3.5%) had ESKD. After adjusting for demographic, HIV, and renal risk factors, individuals with APOL1 high-risk genotypes were at increased odds of ESKD (odds ratio [OR] 10.58, 95% CI 6.22-17.99), renal impairment (OR 5.50, 95% CI 3.81-7.95), albuminuria (OR 3.34, 95% CI 2.00-5.56), and HIVAN (OR 30.16, 95% CI 12.48-72.88). An estimated 49% of ESKD was attributable to APOL1 high-risk genotypes. Conclusion: APOL1 high-risk genotypes were strongly associated with kidney disease in people of African ancestry with HIV and accounted for approximately half of ESKD cases in this cohort.

Sickle Cell Trait and Kidney Disease in People of African Ancestry With HIV.

Introduction: Sickle cell trait (SCT) has been associated with chronic kidney disease (CKD) in African Americans, although evidence for its impact in Africans and people with HIV is currently lacking. We conducted a cross-sectional study investigating the association between SCT and kidney disease in people of African ancestry with HIV in the UK. Methods: The primary outcome was estimated glomerular filtration rate (eGFR) <60 ml/min per 1.73 m2. Secondary outcomes were eGFR <90 ml/min per 1.73 m2, end-stage kidney disease (ESKD; eGFR <15 ml/min per 1.73 m2, chronic dialysis, or having received a kidney transplant), proteinuria (protein-to-creatinine ratio >50 mg/mmol), and albuminuria (albumin-to-creatinine ratio >3 mg/mmol). Multivariable logistic regression was used to estimate the associations between SCT and kidney disease outcomes. Results: A total of 2895 participants (mean age 48.1 [SD 10.3], 57.2% female) were included, of whom 335 (11.6%) had SCT and 352 (12.2%) had eGFR <60 ml/min per 1.73 m2. After adjusting for demographic, HIV, and kidney risk factors including APOL1 high-risk genotype status, individuals with SCT were more likely to have eGFR <60 ml/min per 1.73 m2 (odds ratio 1.62 [95% CI 1.14-2.32]), eGFR <90 ml/min per 1.73 m2 (1.50 [1.14-1.97]), and albuminuria (1.50 [1.09-2.05]). Stratified by APOL1 status, significant associations between SCT and GFR <60 ml/min per 1.73 m2, eGFR <90 ml/min per 1.73 m2, proteinuria, and albuminuria were observed for those with APOL1 low-risk genotypes. Conclusion: Our results extend previously reported associations between SCT and kidney disease to people with HIV. In people of African ancestry with HIV, these associations were largely restricted to those with APOL1 low-risk genotypes.

The epidemiology of kidney disease in people of African ancestry with HIV in the UK.

BACKGROUND: Chronic kidney disease (CKD) is a leading cause of morbidity and mortality globally. The risk of CKD is increased in people of African ancestry and with Human Immunodeficiency Virus (HIV) infection. METHODS: We conducted a cross-sectional study investigating the relationship between region of ancestry (East, Central, South or West Africa) and kidney disease in people of sub-Saharan African ancestry with HIV in the UK between May 2018 and February 2020. The primary outcome was renal impairment (estimated glomerular filtration rate [eGFR] of <60 mL/min/1.73 m2). Secondary outcomes were stage 5 CKD (eGFR <15 ml/min/1.73 m2, on dialysis for over 3 months or who had received a kidney transplant), proteinuria (urine protein/creatinine ratio >50 mg/mmol), and biopsy-confirmed HIV-associated nephropathy (HIVAN), focal segmental glomerulosclerosis (FSGS) or arterionephrosclerosis. Multivariable robust Poisson regression estimated the effect of region of African ancestry on kidney disease outcomes. FINDINGS: Of the 2468 participants (mean age 48.1 [SD 9.8] years, 62% female), 193 had renal impairment, 87 stage 5 CKD, 126 proteinuria, and 43 HIVAN/FSGS or arterionephrosclerosis. After adjusting for demographic characteristics, HIV and several CKD risk factors and with East African ancestry as referent, West African ancestry was associated with renal impairment (prevalence ratio [PR] 2.06 [95% CI 1.40-3.04]) and stage 5 CKD (PR 2.23 [1.23-4.04]), but not with proteinuria (PR 1.27 [0.78-2.05]). West African ancestry (as compared to East/South African ancestry) was also strongly associated with a diagnosis of HIVAN/FSGS or arterionephrosclerosis on kidney biopsy (PR 6.44 [2.42-17.14]). INTERPRETATION: Our results indicate that people of West African ancestry with HIV are at increased risk of kidney disease. Although we cannot rule out the possibility of residual confounding, geographical region of origin appears to be a strong independent risk factor for CKD as the association did not appear to be explained by several demographic, HIV or renal risk factors.

Prevalence of HIV/hepatitis B and HIV/hepatitis C coinfection among people of East, South, Central and West African ancestry in the United Kingdom.

Regional variability in the prevalence of hepatitis B (HBV) and C (HCV) is reported in sub-Saharan Africa, although data for people with HIV are sparse. We determined the prevalence of HBV/HCV in 2473 people of African ancestry with HIV in the UK. Overall, 6.2% were co-infected with HBV and 1.3% with HCV. Central [adjusted odds ratio (aOR) 2.40 (95% confidence interval (CI) 1.23--4.67) and West [2.10 (1.29-3.41)] African ancestry was associated with HBV and Central [6.98 (2.00-24.43)] African ancestry with HCV.

The use of sirolimus in patients with recurrent cytomegalovirus infection after kidney transplantation: A retrospective case series analysis.

Cytomegalovirus (CMV) is one of opportunistic infections post solid organ transplant and remains a cause of morbidity and mortality. Mammalian target of rapamycin inhibitors has a theoretical antiviral advantage compared to conventional immunosuppression. The primary outcome was to assess the viremic response and kidney function in a cohort of kidney transplant recipients (KTRs) with difficult to manage CMV infection when converted to sirolimus. We retrospectively analyzed the outcome of substituting sirolimus for mycophenolate mofetil (MMF) or tacrolimus in 18 KTR with difficult to manage, resistant/recurrent CMV viremia unresponsive or intolerant of standard anti-CMV treatment, or immunosuppression reduction. Safety and feasibility of sirolimus conversion were assessed through studying CMV viral loads, creatinine levels, immunosuppression, antiviral therapy, kidney function, and acute rejection episodes before and after starting sirolimus as well as the sirolimus side effects. Data were collected from the hospital filing system. The Wilcoxon matched-pairs signed-rank test and Friedman test were used for statistical analysis. The area under the curve for Log10 CMV viral load (log10 copies/ml) was significantly higher before than after the sirolimus switch (P = 0.0156). The median number of days on antiviral treatment was reduced after conversion to sirolimus [48 days (0-95); vs. 68 days (21-146)]. Acute rejection occurred more commonly before than after starting sirolimus [n =5 (27.7%) vs. n = 2 (11.1%)]. Median serum creatinine before conversion to sirolimus was 175.5 µmol/L (79-243), and showed no deterioration three months and one year after conversion [148 (69-271) and 162.5 (69-287) µmol/L, respectively, P = 0.002]. The use of sirolimus, often alongside tacrolimus and after discontinuation of MMF, is a useful strategy in treating recurrent CMV viremia without provoking rejection.

Kidney disease in Africans with HIV and tuberculosis.

OBJECTIVE: To describe the spectrum of kidney disease in African patients with HIV and tuberculosis (TB). METHODS: We used data from three cohorts: consecutive patients with HIV/TB in South London (UK, 2004-2016; n = 95), consecutive patients with HIV/TB who underwent kidney biopsy in Cape Town (South Africa, 2014-2017; n = 70), and consecutive patients found to have HIV/TB on autopsy in Abidjan (Cote d'Ivoire, 1991; n = 100). Acute kidney injury (AKI) was ascertained using the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. In the Cape Town cohort, predictors of recovery of kidney function at 6 months were assessed using Cox regression. RESULTS: In the London cohort, the incidence of moderate/severe AKI at 12 months was 15.1 (95% CI 8.6-26.5) per 100 person-years, and the prevalence of chronic and end-stage kidney disease (ESKD) 13.7 and 5.7%, respectively. HIV-associated nephropathy (HIVAN) was diagnosed in 6% of patients in London, and in 6% of autopsy cases in Abidjan. Evidence of renal TB was present in 60% of autopsies in Abidjan and 61% of kidney biopsies in Cape Town. HIVAN and acute tubular necrosis (ATN) were also common biopsy findings in Cape Town. In Cape Town, 40 patients were dialyzed, of whom 28 (70%) were able to successfully discontinue renal replacement therapy. Antiretroviral therapy status, CD4 cell count, estimated glomerular filtration rate (eGFR) at biopsy and renal histology, other than ATN, were not predictive of eGFR recovery. CONCLUSION: Kidney disease was common in Africans with HIV/TB. Monitoring of kidney function, and provision of acute dialysis to those with severe kidney failure, is warranted.

Differences in Prevalence of Muscle Weakness (Sarcopenia) in Haemodialysis Patients Determined by Hand Grip Strength Due to Variation in Guideline Definitions of Sarcopenia.

BACKGROUND: Muscle weakness is associated with increased mortality, and hemodialysis (HD) patients are at an increased risk for muscle loss. There is no agreed definition for muscle weakness, so we determined whether using different cut-off criteria recommended by guideline groups altered the prevalence in HD patients. METHODS: We measured hand grip strength (HGS) in HD outpatients, comparing HGS with clinical guideline cut-offs (European Working Group on Sarcopenia in Older People [EWGSOP] and North American Foundation for the National Institutes of Health Sarcopenia Project [FNIH]) used to define muscle wasting (sarcopenia) with age-matched and gender-matched normative data. RESULTS: We studied 459 patients, 61.4% male, 47.3% diabetic. The prevalence of muscle weakness was significantly different when measuring HGS; 84.5% using the EWGSOP cut-off and 73.2% with FNIH criteria, and 75.2% using North American normative data and 56.6% U.K. normative data (P < .01). On logistic regression, muscle weakness was associated with age (odds ratio [OR] 1.05, P < .001), weight (OR 0.96, P < .001), serum albumin (OR 0.89, P = .007), and being nondiabetic (OR 0.31, P = .001). Of patients with no comorbidity, 66.7% were weak when compared with 93.8% with the highest comorbidity scores (P < .001). CONCLUSION: There is currently no agreed universal definition for sarcopenia, but the EWGSOP and FNIH advocate HGS cut-offs as part of their definition. The prevalence of muscle weakness varies according to cut-off and whether age-matched and gender-matched normative data are used. In addition, patient characteristics in terms of age and comorbidity determine the prevalence of muscle weakness.

Differences in Prevalence of Muscle Wasting in Patients Receiving Peritoneal Dialysis per Dual-Energy X-Ray Absorptiometry Due to Variation in Guideline Definitions of Sarcopenia.

BACKGROUND: Muscle wasting is associated with increased risk for mortality. There is no agreed universal definition for muscle wasting (sarcopenia), and we wished to determine whether using different criteria altered the prevalence in patients treated by peritoneal dialysis. METHODS: We measured lean body and appendicular lean mass indices in 325 outpatients by dual-energy x-ray absorptiometry, comparing muscle mass with that used to define muscle wasting (sarcopenia) by various clinical guideline publications. RESULTS: Lean body and appendicular lean mass indices did not differ by sex: female, 17.7 ± 4.6 kg/m2; male, 17.4 ± 4.3; female, 6.9 (5.6-8.5) kg/m2; male, 6.7 (5.3-8.3), respectively. Depending on the criteria, the prevalence of muscle wasting varied from 2.2%-31.3% for women and 25.1%-75.6% for men. Male patients were older (58.3 ± 16 vs 53.4 ± 15.7 years). Criteria based on cutoffs derived from young healthy patients gave the higher prevalence rates. The prevalence of muscle wasting was not associated with dialysis adequacy, estimated protein intake, duration of dialysis treatment, comorbidity, diabetes, or ethnicity. The prevalence of sarcopenic obesity was low (<5% females, 7% males). CONCLUSION: We found that the prevalence varied markedly depending on the cutoff criteria used to define muscle wasting. Very few patients had sarcopenic obesity. The higher prevalence for males requires further study but was not associated with dialysis treatment. Our study highlights the need for agreed criteria to define pathologic muscle wasting from that which is age associated to allow for interventional screening programs.

Comparison of estimates of resting energy expenditure equations in haemodialysis patients.

PURPOSE: Waste products of metabolism accumulate in patients with chronic kidney disease, and require clearance by haemodialysis (HD). We wished to determine whether there was an association between resting energy expenditure (REE) and total energy expenditure (TEE) in HD patients and body composition. SUBJECTS/METHODS: We determined REE by recently validated equations (CKD equation) and compared REE with that estimated by standard equations for REE, and TEE calculated from patient reported physical activity, in HD patients with corresponding body composition measured by dual energy X-ray absorptiometry (DEXA) scanning. RESULTS: We studied 107 patients, 69 male (64.5%), mean age 62.7 ± 15.1 years. The CKD equation REE was 72.5 ± 13.3 watts (W) and TEE 83.2 ± 9.7 W. There was a strong association between REE with body surface area (BSA) (r2 = 0.80), total soft lean and fat lean tissue mass (r2 = 0.69), body mass index (BMI) (r2 = 0.34), all p<0.001. REE estimated using the modified Harris Benedict, Mifflin St. Jeor, Katch McArdle, Bernstein and Robertson equations underestimated REE compared to the CKD equation. TEE was more strongly associated with BSA (r2 = 0.51), appendicular muscle mass (r2 = 0.42), than BMI (r2 = 0.15) all p<0.001.TEE was greater for those employed (104.9 ± 10.7 vs. 83.1 ± 12.3 W, p<0.001), and with no co-morbidity (88.7 ± 14.8 vs. 82.7 ± 12.3 W, p<0.05). CONCLUSIONS: Standard equations underestimate REE in HD patients compared to the CKD equation. TEE was greater in those with more skeletal muscle mass, in those who were employed and in those with the least co-morbidity. More metabolically active patients may well require greater dialytic clearances.

The cost of ipilimumab toxicity: a single-centre analysis.

There are no published data on the costs associated with investigating and managing toxicity from ipilimumab treatment in patients with metastatic melanoma. Patients treated with ipilimumab at The Royal Marsden Hospital between 1 September 2010 and 1 April 2013 were identified. Data on demographics, investigations and survival outcomes were collected. Patients with grade 3 or higher immune-related adverse events were identified, and costs of investigating and managing toxicities in them were calculated on the basis of standard National Health Service tariffs. Out of the 110 patients, 29 experienced grade 3/4 immune-related adverse events. The total cost of investigating and managing these patients was £140,680, or a median cost of £2860 per patient. Patients experiencing grade 3/4 toxicities had 1-, 2- and 3-year survival rates of 79, 59 and 46%, compared with 24, 17 and 15% in the group that did not experience significant toxicity (P<0.0005). The most common treatment-related toxicity identified was colitis. Two patients died from complications associated with ipilimumab colitis. The cost of ipilimumab toxicity is marginal in comparison with the total treatment cost. Patients treated with ipilimumab who develop significant toxicity have a higher than expected 1-, 2- and 3-year survival.

Mutation analysis of patients with neurodegenerative disorders using NeuroX array.

Genetic analyses of patients with neurodegenerative disorders have identified multiple genes that need to be investigated for the presence of damaging variants. However, mutation analysis by Sanger sequencing is costly and time consuming. We tested the utility of a recently designed semi-custom genome-wide array (NeuroX; Illumina, Inc) tailored to study neurodegenerative diseases (e.g., mutation screening). We investigated 192 patients with 4 different neurodegenerative disorders for the presence of rare damaging variations in 77 genes implicated in these diseases. Several causative mutations were identified and confirmed by Sanger sequencing, including PSEN1 p.M233T responsible for Alzheimer's disease in a large Italian family, as well as SOD1 p.A4V and p.I113T in patients with amyotrophic lateral sclerosis. In total, we identified 78 potentially damaging rare variants (frequency <1%), including ABCA7 p.L400V in a family with Alzheimer's disease and LRRK2 p.R1514Q in 6 of 98 patients with Parkinson's disease (6.1%). In conclusion, NeuroX appears to be helpful for rapid and accurate mutation screening, although further development may be still required to improve some current caveats.

Itchy lesions in pigmented skin.

A 37-year-old woman with type VI skin presented with 1-year history of pruritic lesions affecting her arms, chest and legs. The lesions were approximately 5 mm in diameter, annular and with a raised border. A skin biopsy was performed which showed a diagnosis of disseminated superficial actinic porokeratosis. Porokeratosis is an unusual presentation in pigmented skin and there are very limited reports of this occurrence in the literature.

Does the use of a bougie reduce the force of laryngoscopy in a difficult airway with manual in-line stabilisation?: a randomised crossover simulation study.

CONTEXT: Manual in-line stabilisation is usually used during tracheal intubation of trauma patients to minimise movement of the cervical spine and prevent any further neurological injury. Use of a bougie in combination with laryngoscopy may reduce the forces exerted on the cervical spine. OBJECTIVE: To evaluate the difference in force applied to the head and neck during tracheal intubation with a Macintosh laryngoscope with or without simultaneous use of a bougie. DESIGN: Randomised, crossover simulation study. SETTING: Simulation laboratory, Anaesthetic Department, Queen's Hospital, Romford between March and April 2012. PARTICIPANTS: Twenty anaesthetists, all with a minimum of 1 year of anaesthetic experience. INTERVENTIONS: Participants used either a Macintosh laryngoscope alone, or in combination with a bougie in a Laerdal SimMan manikin with a simulated difficult airway and manual in-line stabilisation. MAIN OUTCOME MEASURES: The force exerted during laryngoscopy. Success rate and time taken to tracheal intubation were also measured. RESULTS: Significantly less force was exerted utilising a Macintosh laryngoscope in combination with a bougie compared with the laryngoscope alone (24.9 versus 44.5 N; P < 0.001). The trachea was successfully intubated on all occasions within 120 s. The use of a bougie was associated with a nonsignificant reduction in the time to tracheal intubation. CONCLUSION: To minimise the force of laryngoscopy and movement of a potentially unstable cervical spine injury, consideration should be given to the early use of a bougie.

GPIb VNTR C/C genotype may predict embolic events in infective endocarditis.

BACKGROUND AND AIM OF THE STUDY: Infective endocarditis (IE) is frequently complicated by septic embolism, a need for valve replacement, and death. The development of these complications is associated with the presence, size and mobility of cardiac vegetations, which may form as a result of bacterium-platelet interactions mediated by the platelet glycoprotein GPIb receptor. Variable number tandem repeat (VNTR) and single nucleotide polymorphisms of the gene encoding the GPIb receptor have been described, but their correlation with platelet function, development of vegetations and complications of IE is unknown. METHODS: The GPIb Kozak T/C, VNTR and human platelet antigen-2a/2b (HPA-2a/2b) genotype of healthy volunteers (n = 156) and patients with IE (n = 35) was determined, and the influence of these polymorphisms on Staphylococcus aureus-induced platelet aggregation in vitro, platelet activation in vivo and clinical outcome in IE was then investigated. RESULTS: The GPIb VNTR C/C genotype was associated with an increased risk of embolism (p = 0.039), with no influence on platelet activation or aggregation, vegetation characteristics or mortality (p > 0.05 for all). The GPIb Kozak T/C and HPA-2a/2b polymorphisms did not influence the development of complications in patients with IE (all p > 0.05). CONCLUSION: The results of these exploratory studies suggest that the GPIb VNTR C/C genotype may predict the development of septic emboli in patients with IE. This hypothesis should be analyzed in larger studies and, if confirmed, would represent an important clinical finding, as it implies that early surgery in patients with the GPIb VNTR C/C genotype could reduce morbidity and mortality in IE.