Impact of a novel pre-hospital stroke notification programme on acute stroke care key performance indicators in Hong Kong: a multicentre prospective cohort study with historical controls.

INTRODUCTION: Early identification and initiation of reperfusion therapy is essential for suspected acute ischaemic stroke. A pre-hospital stroke notification (PSN) protocol using FASE (facial drooping, arm weakness, speech difficulties, and eye palsy) was implemented to improve key performance indicators (KPIs) in acute stroke care delivery. We assessed KPIs and clinical outcomes before and after PSN implementation in Hong Kong. METHODS: This prospective cohort study with historical controls was conducted in the Accident and Emergency Departments of four public hospitals in Hong Kong. Patients were screened using the PSN protocol between August 2021 and February 2022. Suspected stroke patients between August 2020 and February 2021 were included as historical controls. Door-to-needle (DTN) and door-to-computed tomography (DTC) times before and after PSN implementation were compared. Clinical outcomes including National Institutes of Health Stroke Scale score at 24 hours and modified Rankin Scale score at 3 months after intravenous recombinant tissue-type plasminogen activator (IV-rtPA) were also assessed. RESULTS: Among the 715 patients (266 PSN and 449 non-PSN) included, 50.8% of PSN patients and 37.7% of non-PSN patients had a DTC time within 25 minutes (P<0.001). For the 58 PSN and 134 non-PSN patients given IV-rtPA, median DTN times were 67 and 75.5 minutes, respectively (P=0.007). The percentage of patients with a DTN time within 60 minutes was higher in the PSN group than in the non-PSN group (37.9% vs 21.6%; P=0.019). No statistically significant differences in clinical outcomes were observed. CONCLUSION: Although the PSN protocol shortened DTC and DTN times, clinical outcomes did not significantly differ.

Cardiovascular disease-related mortality and factors associated with cardiovascular events in the TREAT Asia HIV Observational Database (TAHOD).

OBJECTIVES: With aging of the HIV-positive population, cardiovascular disease (CVD) increasingly contributes to morbidity and mortality. We investigated CVD-related and other causes of death (CODs) and factors associated with CVD in a multi-country Asian HIV-positive cohort. METHODS: Patient data from 2003-2017 were obtained from the Therapeutics, Research, Education and AIDS Training in Asia (TREAT Asia) HIV Observational Database (TAHOD). We included patients on antiretroviral therapy (ART) with > 1 day of follow-up. Cumulative incidences were plotted for CVD-related, AIDS-related, non-AIDS-related, and unknown CODs, and any CVD (i.e. fatal and nonfatal). Competing risk regression was used to assess risk factors of any CVD. RESULTS: Of 8069 patients with a median follow-up of 7.3 years [interquartile range (IQR) 4.4-10.7 years], 378 patients died [incidence rate (IR) 6.2 per 1000 person-years (PY)], and this total included 22 CVD-related deaths (IR 0.36 per 1000 PY). Factors significantly associated with any CVD event (IR 2.2 per 1000 PY) were older age [sub-hazard ratio (sHR) 2.21; 95% confidence interval (CI) 1.36-3.58 for age 41-50 years; sHR 5.52; 95% CI 3.43-8.91 for ≥ 51 years, compared with < 40 years], high blood pressure (sHR 1.62; 95% CI 1.04-2.52), high total cholesterol (sHR 1.89; 95% CI 1.27-2.82), high triglycerides (sHR 1.55; 95% CI 1.02-2.37) and high body mass index (BMI) (sHR 1.66; 95% CI 1.12-2.46). CVD crude IRs were lower in the later ART initiation period and in lower middle- and upper middle-income countries. CONCLUSIONS: The development of fatal and nonfatal CVD events in our cohort was associated with older age, and treatable risk factors such as high blood pressure, triglycerides, total cholesterol and BMI. Lower CVD event rates in middle-income countries may indicate under-diagnosis of CVD in Asian-Pacific resource-limited settings.

Estimating chronic hepatitis C prognosis using transient elastography-based liver stiffness: A systematic review and meta-analysis.

Chronic hepatitis C (CHC) is a leading cause of hepatic fibrosis and cirrhosis. The level of fibrosis is traditionally established by histology, and prognosis is estimated using fibrosis progression rates (FPRs; annual probability of progressing across histological stages). However, newer noninvasive alternatives are quickly replacing biopsy. One alternative, transient elastography (TE), quantifies fibrosis by measuring liver stiffness (LSM). Given these developments, the purpose of this study was (i) to estimate prognosis in treatment-naïve CHC patients using TE-based liver stiffness progression rates (LSPR) as an alternative to FPRs and (ii) to compare consistency between LSPRs and FPRs. A systematic literature search was performed using multiple databases (January 1990 to February 2016). LSPRs were calculated using either a direct method (given the difference in serial LSMs and time elapsed) or an indirect method given a single LSM and the estimated duration of infection and pooled using random-effects meta-analyses. For validation purposes, FPRs were also estimated. Heterogeneity was explored by random-effects meta-regression. Twenty-seven studies reporting on 39 groups of patients (N = 5874) were identified with 35 groups allowing for indirect and 8 for direct estimation of LSPR. The majority (~58%) of patients were HIV/HCV-coinfected. The estimated time-to-cirrhosis based on TE vs biopsy was 39 and 38 years, respectively. In univariate meta-regressions, male sex and HIV were positively and age at assessment, negatively associated with LSPRs. Noninvasive prognosis of HCV is consistent with FPRs in predicting time-to-cirrhosis, but more longitudinal studies of liver stiffness are needed to obtain refined estimates.

Smoking and projected cardiovascular risk in an HIV-positive Asian regional cohort.

OBJECTIVES: The aim of the study was to assess the prevalence and characteristics associated with current smoking in an Asian HIV-positive cohort, to calculate the predictive risks of cardiovascular disease (CVD), coronary heart disease (CHD) and myocardial infarction (MI), and to identify the impact that simulated interventions may have. METHODS: Logistic regression analysis was used to distinguish associated current smoking characteristics. Five-year predictive risks of CVD, CHD and MI and the impact of simulated interventions were calculated utilizing the Data Collection on Adverse Effects of Anti-HIV Drugs Study (D:A:D) algorithm. RESULTS: Smoking status data were collected from 4274 participants and 1496 of these had sufficient data for simulated intervention calculations. Current smoking prevalence in these two groups was similar (23.2% vs. 19.9%, respectively). Characteristics associated with current smoking included age > 50 years compared with 30-39 years [odds ratio (OR) 0.65; 95% confidence interval (CI) 0.51-0.83], HIV exposure through injecting drug use compared with heterosexual exposure (OR 3.03; 95% CI 2.25-4.07), and receiving antiretroviral therapy (ART) at study sites in Singapore, South Korea, Malaysia, Japan and Vietnam in comparison to Thailand (all OR > 2). Women were less likely to smoke than men (OR 0.11; 95% CI 0.08-0.14). In simulated interventions, smoking cessation demonstrated the greatest impact in reducing CVD and CHD risk and closely approximated the impact of switching from abacavir to an alternate antiretroviral in the reduction of 5-year MI risk. CONCLUSIONS: Multiple interventions could reduce CVD, CHD and MI risk in Asian HIV-positive patients, with smoking cessation potentially being the most influential.

Biomarker-predicted sugars intake compared with self-reported measures in US Hispanics/Latinos: results from the HCHS/SOL SOLNAS study.

OBJECTIVE: Measurement error in self-reported total sugars intake may obscure associations between sugars consumption and health outcomes, and the sum of 24 h urinary sucrose and fructose may serve as a predictive biomarker of total sugars intake. DESIGN: The Study of Latinos: Nutrition & Physical Activity Assessment Study (SOLNAS) was an ancillary study to the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) cohort. Doubly labelled water and 24 h urinary sucrose and fructose were used as biomarkers of energy and sugars intake, respectively. Participants' diets were assessed by up to three 24 h recalls (88 % had two or more recalls). Procedures were repeated approximately 6 months after the initial visit among a subset of ninety-six participants. SETTING: Four centres (Bronx, NY; Chicago, IL; Miami, FL; San Diego, CA) across the USA. SUBJECTS: Men and women (n 477) aged 18-74 years. RESULTS: The geometric mean of total sugars was 167·5 (95 % CI 154·4, 181·7) g/d for the biomarker-predicted and 90·6 (95 % CI 87·6, 93·6) g/d for the self-reported total sugars intake. Self-reported total sugars intake was not correlated with biomarker-predicted sugars intake (r=-0·06, P=0·20, n 450). Among the reliability sample (n 90), the reproducibility coefficient was 0·59 for biomarker-predicted and 0·20 for self-reported total sugars intake. CONCLUSIONS: Possible explanations for the lack of association between biomarker-predicted and self-reported sugars intake include measurement error in self-reported diet, high intra-individual variability in sugars intake, and/or urinary sucrose and fructose may not be a suitable proxy for total sugars intake in this study population.

Radiation recall dermatitis: A review of the literature.

PURPOSE/OBJECTIVES: Radiation recall dermatitis (RRD) is a skin reaction limited to an area of prior radiation triggered by the subsequent introduction of systemic therapy. To characterize RRD, we conducted a literature search, summarized RRD features, and compared the most common drug classes implicated in this phenomenon. MATERIALS/METHODS: PubMed, Embase, Scopus, Web of Science, and Cochrane DBSR databases were queried through July 1, 2019 using key words: radiation recall, RRD, and radiodermatitis (limited to humans and English language). Studies included case reports in which patients treated with radiotherapy were initiated on a new line of systemic therapy and subsequently developed a skin reaction in the irradiated area. RRD cases were organized by whether RRD occurred after a single drug or multiple drug administration. RESULTS: One-hundred fifteen studies representing 129 RRD cases (96 single-drug RRD, 33 multi-drug) were included. Sixty-three drugs were associated with RRD. Docetaxel (22) and gemcitabine (18) were the two drugs most commonly associated with RRD. Breast cancer (69 cases) was the most commonly associated tumor type. For single-drug RRD, the median radiotherapy dose was 45.0 Gy (range, 30.0-63.2 Gy). The median time from radiotherapy to drug exposure, time from drug exposure to RRD and time to significant improvement was 8 weeks (range, 2-132 weeks), 5 days (range, 2-56 days), and 14 days (range, 7-49 days), respectively. Variables significantly associated with grade ≥2 toxicity were docetaxel (P = 0.04) and non-antifolate antimetabolite (P = 0.05). The only variable significantly associated with grade ≥3 toxicity was capecitabine (P = 0.04). CONCLUSIONS: RRD is a complex toxicity that can occur after a wide range of radiotherapy doses and many different systemic agents. Most commonly, it presents in patients diagnosed with breast cancer and after administration of a taxane or antimetabolite medication. RRD treatment generally consists of corticosteroids with consideration of antibiotics if superinfection is suspected. Drug re-challenge may be considered after RRD if the initial reaction was of mild intensity.

Patient-reported outcomes version of the common terminology criteria for adverse events and quality-of-life linear analogue self-assessment in breast cancer patients receiving radiation therapy: single-institution prospective registry.

PURPOSE/OBJECTIVES: We sought to investigate the impact of patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE) on overall quality-of-life (QOL) employing linear analogue self-assessment (LASA) in breast cancer (BC) patients undergoing radiation therapy (RT). MATERIALS/METHODS: All patients treated with RT for BC with curative intent from 2015 to 2019 at our institution were included. Breast specific PRO-CTCAE and overall QOL LASA questionnaires were administered at baseline, end-of-treatment, 3, 6, 12 months, and then annually. Minimal clinically important difference in overall QOL was a 10-point change in LASA. Hypofractionation was any treatment > 2 Gy per fraction. Mixed models for repeated measures were used to determine the association of PRO-CTCAE and overall QOL LASA. RESULTS: Three hundred thirty-one (331) patients with a median follow-up of 3.1 years (range 0.4-4.9) were included. Average overall QOL LASA scores were 78.5 at baseline, 79.8 at end-of-treatment, 79.8 at 3 months, 77.1 at 6 months, 79.4 at 12 months, and 79.7 at 24 months. On univariate analysis, patients reporting a grade ≥ 3 PRO-CTCAE had, on average, a 10.4-point reduction in overall LASA QOL (p < 0.0001). On multivariate analysis, not being treated with hypofractionation and higher BMI were predictive for worse overall LASA QOL with a 10-point reduction in LASA for patients reporting a grade ≥ 3 PRO-CTCAE (p < 0.0001). CONCLUSIONS: Patients reporting a grade ≥ 3 PRO-CTCAE experienced statistically significant and clinically meaningful deterioration in overall QOL LASA. Hypofractionation improved QOL while higher BMI predicted for worse QOL. PRO-CTCAE should be integrated into future clinical trials.

Phase sensitive SPR sensor for wide dynamic range detection.

Phase detection has been utilized to enhance the sensitivity of surface plasmon resonance (SPR) sensors for a long time. However, an inherent drawback for phase sensitive SPR sensors are their limited dynamic range, which has greatly hindered wide applications of such sensors. In this Letter, a design combining phase detection and angular interrogation has been proposed to provide an SPR sensor with both high sensitivity and wide dynamic range. As a result, a resolution of 2.2×10-7 RIU with a dynamic range of over 0.06 RIU has been achieved simultaneously. An added advantage of this design is the flexibility for sensitivity and dynamic range adjustment.

Identification of C3 beta chain as the human serum eosinophil cytotoxicity inhibitor.

An eosinophil cytotoxicity inhibitor (ECI) was purified from serum of a human subject with severe allergic dermatitis. Molecular weight of the isolated polypeptide (75,000) and its NH2-terminal amino acid sequence identified it as the beta chain of the C3 complement component (apparently free, but perhaps attached to very small fragments of the alpha chain). Free beta chain, prepared from normal plasma by reduction of C3, inhibited both eosinophil cytotoxicity and neutrophil adherence functions, with half-maximal activity at approximately 250 ng/ml. Apparently free C3 beta chain was detected in certain human biological fluids associated with inflammation; the presence of C3 beta chain correlated with ECI activity. This evidence demonstrates a potential role for free C3 beta chain as a suppressor of eosinophil and neutrophil functions in inflammation.

Analysis of multiple restriction fragment length polymorphisms of the gene for the human complement receptor type I. Duplication of genomic sequences occurs in association with a high molecular mass receptor allotype.

Human CR1 exhibits an unusual form of polymorphism in which allotypic variants differ in the molecular weight of their respective polypeptide chains. To address mechanisms involved in the generation of the CR1 allotypes, DNA from individuals having the F allotype (250,000 Mr), the S allotype (290,000 Mr), and the F' allotype (210,000 Mr) was digested by restriction enzymes, and Southern blots were hybridized with CR1 cDNA and genomic probes. With the use of Bam HI and Sac I, an additional restriction fragment was observed in 20 of 21 individuals having the S allotype with no associated loss of other restriction fragments. Southern blot analysis with a noncoding genomic probe derived from the S allotype-specific Bam HI fragment showed hybridization to this fragment and to two other fragments that were also present in FF individuals. Thus, an intervening sequence may be repeated twice in the F allele and three times in the S allele. A restriction fragment length polymorphism (RFLP) unique to two individuals expressing the F' allotype was seen with Eco RV, but the absence of persons homozygous for this rare allotype prevented further comparisons with the F and S allotypes. Analysis of the CR1 transcripts associated with the three CR1 allotypes indicated that these differed by 1.3-1.5 kb and had the same rank order as the corresponding allotypes. Taken together, these findings suggest that the S allele was generated from the F allele by the acquisition of additional sequences, the coding portion of which may correspond to a long homologous repeat of approximately 1.4 kb that has been identified in CR1 cDNA. We saw two other RFLPs with Hind III and Pvu II that were in linkage dysequilibrium with the Bam HI-Sac I RFLPs associated with the S allotype, and a third polymorphism was seen with Eco RI that was not in linkage dysequilibrium with the other polymorphisms. Thus, 10 commonly occurring CR1 alleles can be defined, making this locus a useful marker for the long arm of chromosome 1 to which the CR1 gene maps.

Identification of a restriction fragment length polymorphism by a CR1 cDNA that correlates with the number of CR1 on erythrocytes.

A genetic basis for the regulation of the number of CR1 on E of different normal individuals was investigated by probing Southern blots of their genomic DNA with a 0.75-kb fragment of CR1 cDNA. Using Hind III, we observed a RFLP involving fragments of 7.4 kb and 6.9 kb that correlated with the number of CR1 on E. 32 individuals having only the 7.4-kb restriction fragment had a mean of 661 +/- 33 (SEM) CR1/E, 11 donors having both restriction fragments had a mean of 455 +/- 52 CR1/E, and 7 individuals having only the 6.9-kb fragment had a mean of 156 +/- 13 CR1/E, all means being significantly different (p less than 0.005). Cosegregation in a normal family of the Hind III restriction fragments with the S, F, and F' structural allotypes of CR1 confirmed that the regulatory element identified by these fragments is linked to the CR1 gene. Moreover, an analysis of the relative expression on E of these structural allotypes in association with either the 7.4-kb Hind III fragment or the 6.9-kb fragment showed that this regulatory element is cis-acting. In contrast, quantitation of CR1 of B lymphocytes and neutrophils revealed no differences in total CR1 expression between individuals homozygous for the 7.4-kb and 6.9-kb Hind III fragments. Thus, we have identified a genomic polymorphism that is linked to the CR1 gene and is associated with a cis-acting regulatory element for the expression of CR1 on E.

Human C3b/C4b receptor (CR1). Demonstration of long homologous repeating domains that are composed of the short consensus repeats characteristics of C3/C4 binding proteins.

10 overlapping CR1 cDNA clones that span 5.5 kb were isolated from a tonsillar library and sequenced in whole or in part. A single long open reading frame beginning at the 5' end of the clones and extending 4.7 kb downstream to a stop codon was identified. This sequence represents approximately 80% of the estimated 6 kb of coding sequence for the F allotype of CR1. Three tandem, direct, long homologous repeats (LHRs) of 450 amino acids were identified. Analysis of the sequences of tryptic peptides provided evidence for a fourth LHR in the F allotype of CR1. Amino acid identity between the LHRs ranged from 70% between the first and third repeats to 99% between the NH2-terminal 250 amino acids of the first and second repeats. Each LHR comprises seven short consensus repeats (SCRs) of 60-70 amino acids that resemble the SCRs of other C3/C4 binding proteins, such as complement receptor type 2, factors B and H, C4 binding protein, and C2. Two additional SCRs join the LHRs to a single membrane-spanning domain of 25 amino acids; thus, the F allotype of CR1 probably contains at least 30 SCRs, 23 of which have been sequenced. Each SCR is predicted to form a triple loop structure in which the four conserved half-cystines form disulfide linkages. The linear alignment of 30 SCRs as a semi-rigid structure would extend 1,140A from the plasma membrane and might facilitate the interaction of CR1 with C3b and C4b located within the interstices of immune complexes and microbial cell walls. The COOH-terminal cytoplasmic domain of 43 residues contains a six-amino-acid sequence that is homologous to the sequence in the epidermal growth factor receptor that is phosphorylated by protein kinase C.

Structure of the human CR1 gene. Molecular basis of the structural and quantitative polymorphisms and identification of a new CR1-like allele.

Structural and quantitative polymorphisms have been described in human CR1. In the former, the S allotype is larger than the F allotype by 40-50 kD, the size of a long homologous repeat (LHR). In the latter, homozygotes for a 7.4-kb Hind III fragment express fourfold more CR1 per erythrocyte than do homozygotes for the allelic 6.9-kb restriction fragment. The basis for these genomic polymorphisms has been determined by restriction mapping the entire S allele and part of the F allele. The S allele is 158 kb and contains 5 LHRs of 20-30 kb, designated -A, -B/A, -B, -C, and -D, respectively, 5' to 3'. Extensive homology was found among the LHRs in their restriction maps, exon organization, and the coding and noncoding sequences. The presence of LHR-B/A in the S allele but not in the F allele accounts for the longer transcripts and polypeptide associated with the former allotype. At least 42 exons are present in the S allele, with distinct exons for the leader sequence, the transmembrane and cytoplasmic regions and most of the SCRs comprising the extracellular portion of CR1. Consistent with the mapping of the ligand binding site to the first two SCRs in each LHR, the second SCRs in LHR-A, -B/A, -B, and -C are encoded by two exons, reflecting a specialized function for this unit. The allelic 7.4/6.9-kb Hind III fragments extend from the 3' region of LHR-C to LHR-D. The 6.9-kb restriction fragment is the result of a new Hind III site generated by a single base change in the intron between the exons encoding the second SCR of LHR-D. A second cluster of genomic clones has been identified by hybridization to CR1 probes. Although they contain regions of hybridization to the cDNA and genomic probes derived from CR1, these cannot be overlapped with the structural gene owing to their distinct restriction maps. Three genomic polymorphisms previously identified by CR1 cDNA probes map to this region. These additional clones may represent part of a duplicated allele located nearby within the CR1 locus.

Factors associated with isolated anti-hepatitis B core antibody in HIV-positive patients: impact of compromised immunity.

In regions that are hyperendemic for chronic hepatitis B virus (HBV) infection, prevalence of and risk factors associated with isolated anti-hepatitis B core antibody (anti-HBc) in HIV-positive patients are less well described. HIV-positive patients who were tested for hepatitis B surface antigen (HBsAg), anti-hepatitis B surface antibody (anti-HBs) and anti-HBc at designated hospitals for HIV care in Taiwan were included for analysis. HBV DNA was detected by real-time polymerase chain reaction in patients with and without isolated anti-HBc. Of 2351 HIV-positive patients, 450 (19.1%) were HBsAg positive, 411 (17.5%) were anti-HBc positive alone and 963 (41.0%) for both anti-HBs and anti-HBc. Compared with patients who were positive for both anti-HBs and anti-HBc, patients with isolated anti-HBc were older, less likely to have anti-hepatitis C virus antibody (anti-HCV), had lower CD4 lymphocyte counts and higher plasma HIV RNA loads. Older age (adjusted odds ratio, 1.029; 95% confidence interval, 1.015-1.043) and CD4 <100 cells/microL (adjusted odds ratio, 1.524; 95% confidence interval, 1.025-2.265) were independently associated with isolated anti-HBc by logistic regression, while presence of anti-HCV and injecting drug use were not. HBV DNA was detectable in 8.3% of 277 patients with isolated anti-HBc and 14.3% of 56 patients with both anti-HBs and anti-HBc (P = 0.160). In a country hyperendemic for HBV infection, HIV-positive patients at older age and with CD4 <100 cells/microL were more likely to have isolated anti-HBc, suggesting that compromised immunity plays a role in the presence of this marker.

Cost-effectiveness analysis of selective first-line use of biologics for unresectable RAS wild-type left-sided metastatic colorectal cancer.

Background: Evidence from a retrospective analysis of multiple large phase iii trials suggested that primary tumour location (ptl) in RAS wild-type metastatic colorectal cancer (wtRAS mcrc) might have predictive value with respect to response to drug therapies. Recent studies also show a potential preferential benefit for epidermal growth factor inhibitors (egfris) for left-sided tumours. In the present study, we aimed to determine the incremental cost-effectiveness ratio (icer) for the first-line use of an egfri for patients with left-sided wtRAS mcrc. Methods: We developed a state-transition model to determine the cost effectiveness of alternative treatment strategies in patients with left-sided mcrc:■ Standard of care■ Use of an egfri in first-line therapyThe cohort for the study consisted of patients diagnosed with unresectable wtRAS mcrc with an indication for chemotherapy and previously documented ptl. Model parameters were obtained from the published literature and calibration. The perspective was that of a provincial ministry of health in Canada. We used a 5-year time horizon and an annual discount rate of 1.5%. Results: Selecting patients for first-line egfri treatment based on left-sided location of their colorectal primary tumour was more effective than the standard of care, resulting in an increase in quality-adjusted life-years (qalys) of 0.226 (or 0.644 life-years gained). However, the strategy was also more expensive, costing an average of $60,639 more per patient treated. The resulting icer was $268,094 per qaly. A 35% price reduction in the cost of egfri would be needed to make this strategy cost-effective at a willingness-to-pay threshold (wtp) of $100,000 per qaly. Conclusions: Selective use of an egfri based on ptl was more cost-effective than unselected use of those agents; however, based on traditional wtp thresholds, it was still not cost-effective. While awaiting the elucidation of more precise predictive biomarkers that might improve cost-effectiveness, the price of egfris could be reduced to meet the wtp threshold.

Socio-economic status and risk of tuberculosis: a case-control study of HIV-infected patients in Asia.

SETTING: Tuberculosis (TB) is the most common human immunodeficiency virus (HIV) related opportunistic infection and cause of acquired immune-deficiency syndrome related death. TB often affects those from a low socio-economic background. OBJECTIVE: To assess the socio-economic determinants of TB in HIV-infected patients in Asia. DESIGN: This was a matched case-control study. HIV-positive, TB-positive cases were matched to HIV-positive, TB-negative controls according to age, sex and CD4 cell count. A socio-economic questionnaire comprising 23 questions, including education level, employment, housing and substance use, was distributed. Socio-economic risk factors for TB were analysed using conditional logistic regression analysis. RESULTS: A total of 340 patients (170 matched pairs) were recruited, with 262 (77.1%) matched for all three criteria. Pulmonary TB was the predominant type (n = 115, 67.6%). The main risk factor for TB was not having a university level education (OR 4.45, 95%CI 1.50-13.17, P = 0.007). Burning wood or coal regularly inside the house and living in the same place of origin were weakly associated with TB diagnosis. CONCLUSIONS: These data suggest that lower socio-economic status is associated with an increased risk of TB in Asia. Integrating clinical and socio-economic factors into HIV treatment may help in the prevention of opportunistic infections and disease progression.

Genetic regulation of a structural polymorphism of human C3b receptor.

Two forms of the human C3b receptor (C3bR), which have relative molecular weights (Mr) of 250,000 and 260,000 and are designated F and S, respectively, have been identified in specific immunoprecipitates from erythrocytes and leukocytes by polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate. Both forms of the receptor were visualized on gels by autoradiography of 125I-labeled antigen and by silver nitrate staining. Individual donors expressed one of three possible patterns of C3bR, either the F or S form alone or both, and these patterns represented stable phenotypic characteristics of their erythrocytes and polymorphonuclear and mononuclear leukocytes. Removal of N-linked oligosaccharides by endoglycosidase-F treatment decreased the Mr of both forms but did not abolish the difference in their electrophoretic mobilities. That both forms of the receptor were functional was indicated by the capacity of all antigenic C3bR sites on erythrocytes from individuals having any of the three phenotypes to bind dimeric C3b with affinities ranging from 3 to 5 X 10(7) M-1. Analyses of the occurrence of the F and S forms of C3bR in 76 individuals from 15 families revealed that this polymorphism was regulated by two alleles transmitted in an autosomal codominant manner. Of 111 normal unrelated individuals, 64.9% were homozygous for the F form (FF), 1.8% were homozygous for the S form (SS), and 33.3% were heterozygotes (FS). This distribution did not differ from that calculated by the Hardy-Weinberg equilibrium based on two codominant alleles that regulate the expression of the F and S forms and that have frequencies of 81.5 and 18.5%, respectively. The locus regulating structural polymorphism of C3bR is designated C3BRM (M for mobility or Mr), and is distinct from the recently described locus regulating the quantitative expression of C3bR on erythrocytes.

Autoantibody to the C3b/C4b receptor and absence of this receptor from erythrocytes of a patient with systemic lupus erythematosus.

A 29-yr-old woman with systemic lupus erythematosus (SLE) was found to have no detectable C3b/C4b receptors (CR1) on her erythrocytes (E) when they were assayed by the binding of rabbit polyclonal and murine monoclonal (Yz-1) anti-CR1. Analysis by two-color fluorescent flow cytometry of CR1 expression on the patient's B lymphocytes that had been stained indirectly with monoclonal anti-B1 and rabbit F(ab')2 anti-CR1 also revealed a marked deficiency of CR1. Total cellular CR1 of neutrophils, assessed by a sandwich radioimmunoassay, was about half that of neutrophils from normal individuals. Because her E had expressed 173 sites/cell 2 yr before, the CR1 deficiency was considered to be acquired and a possible mechanism was sought. Autoantibody to CR1 was measured by a radioimmunoassay in which serum or its fractions were incubated in microtiter wells that had been coated with purified CR1, and binding of immunoglobulin to the wells was quantitated with 125I-labeled goat IgG antihuman F(ab')2. The CR1-specific binding of immunoglobulin from the patient's serum was 19.1 ng/well of the detecting antibody when her E had eight CR1 sites per cell; that of 28 healthy donors was 1.3 +/- 0.5 ng/well (mean +/- SEM), and that of 34 additional patients with SLE was 0.5 +/- 0.3 ng/well. The activity was present also in purified IgG and its F(ab')2 fragment, indicating that the binding of serum immunoglobulin to CR1 was not mediated by C3 fragments. The specificity of the patient's IgG for CR1 was confirmed when pretreatment of the CR1-coated wells with affinity-purified rabbit F(ab')2 anti-CR1 was shown to inhibit by 68% the binding of the IgG. The autoantibody also interacted with CR1 in cell membranes, as assessed by its capacity to inhibit the binding of indirectly fluoresceinated Yz-1 to neutrophils, and, when combined with goat IgG antihuman F(ab')2, to diminish the binding of dimeric C3b to normal E. During the period of the marked deficiency of CR1 the patient experienced an exacerbation of disease activity which was treated with prednisone. Clinical improvement was accompanied by a decrease in the serum concentration of anti-CR1 to levels present 2 yr earlier, and an increase of CR1 to 170 sites/E. The temporal association between high titers of an autoantibody to CR1, absence of CR1 from E, and heightened activity of SLE suggest that the former may have had a role in the other manifestations of the patient's disease.

Lysine and protein metabolism in young women. Subdivision based on the novel use of multiple stable isotopic labels.

A multitracer stable isotope study of lysine kinetics was carried out in fasted adult female volunteers to determine whether a multicompartmental model that partitions protein synthesis and breakdown into at least two types of tissue components can be constructed from plasma and breath data. Five female subjects, maintained on formula diets, received L-[13C1]lysine (27 mumol/kg) as an i.v. bolus and L-[15N2]lysine (27 mumol/kg) as an oral bolus 4 h postprandially. Plasma and breath samples were collected for 6 h. On an alternate day, subjects received NaH13CO3 (10 mumol/kg) as an i.v. bolus and breath samples were collected for 6 h. Plasma tracer lysine levels were determined by gas chromatography-mass spectrometry isotope ratiometry, and breath 13CO2 levels were measured by mass spectrometric gas isotope ratiometry. The tracer data could be fitted to a mammillary multicompartmental model that consisted of a lysine central compartment and slow- and fast-exchanging peripheral compartments containing 37, 38, and 324 mumol/kg, respectively. The rates of lysine oxidation, incorporation into protein, and release by protein breakdown were 21, 35, and 56 mmol/kg/h, respectively, in the fast-exchanging compartment, whereas the rates of protein synthesis and breakdown in the slow compartment were both 53 mmol/kg/min. These values corresponded to a whole-body lysine flux of 106 mmol/kg/h. The kinetic parameters were in excellent agreement with reported values obtained by constant-infusion methods. The measurements indicated that it will be possible to detect changes in amino acid pool sizes and protein synthesis and breakdown associated with the mobilization of protein stores from plasma and breath measurements in multitracer stable isotope experiments.