A step towards harmonising human biomonitoring study setup on European level: Materials provided and lessons learnt in HBM4EU.

Internal exposure of the human body to potentially harmful chemical substances can be assessed by Human Biomonitoring (HBM). HBM can be used to generate conclusive data that may provide an overview of exposure levels in entire or specific population groups. This knowledge can promote the understanding of potential risks of the substances of interest or help monitoring the success of regulatory measures taken on the political level. Study planning and design are key elements of any epidemiologic study to generate reliable data. In the field of HBM, this has been done using differing approaches on various levels of population coverage so far. Comparison and combined usage of the resulting data would contribute to understanding exposure and its factors on a larger scale, however, the differences between studies make this a challenging and somewhat limited endeavour. This article presents templates for documents that are required to set up an HBM study, thus facilitating the generation of harmonised HBM data as a step towards standardisation of HBM in Europe. They are designed to be modular and adaptable to the specific needs of a single study while emphasising minimum requirements to ensure comparability. It further elaborates on the challenges encountered during the process of creating these documents during the runtime of the European Joint Programme HBM4EU in a multi-national expert team and draws up lessons learnt in the context of knowledge management.

HBM4EU from the Coordinator's perspective: lessons learnt from managing a large-scale EU project.

We discuss some important management issues of the Human Biomonitoring Initiative (HBM4EU) from the perspective of the Coordinator that may be valuable for the design and management of similar projects. As a large-scale international collaborative project, HBM4EU comprised 118 institutions from 30 countries and the European Environment Agency and had a budget of about €74 million. It has set up an innovative cooperative network of national and EU authorities and scientific institutions at the science-policy interface. A project of this scale raises major management challenges and requires transparent, efficient, and well-organized administrative and scientific steering structures. We present four major points: First, prior to the beginning of the project, the Consortium Agreement needs to be well elaborated to prevent conflicts during the project lifetime. Second, a strong role for national and EU policy-making authorities in the administrative governance structure enhances the interest of recipients of project results. Third, large-scale international collaborative projects need an elaborate and well-financed scientific governance structure. Fourth, a differentiation of funding rates among project activities threatens to create conflicts. HBM4EU provides a prototype for EU funded large-scale projects targeting future policies for realizing the Green Deal and Zero Pollution Ambition in the field of chemicals, health, and environment.

The questionnaire design process in the European Human Biomonitoring Initiative (HBM4EU).

BACKGROUND: Designing questionnaires is a key point of epidemiological studies assessing human exposure to chemicals. The lack of validated questionnaires can lead to the use of previously developed and sub-optimally adapted questionnaires, which may result in information biases that affect the study's validity. On this ground, a multidisciplinary group of researchers developed a series of tools to support data collection within the HBM4EU initiative. The objective of this paper is to share the process of developing HBM4EU questionnaires, as well as to provide researchers with harmonized procedures that could help them to design future questionnaires to assess environmental exposures. METHODS: In the frame of the work package on survey design and fieldwork of the HBM4EU, researchers carried out procedures necessary for the development of quality questionnaires and related data collection tools. These procedures consisted of a systematic search to identify questionnaires used in previous human biomonitoring (HBM) studies, as well as the development of a checklist and evaluation sheet to assess the questionnaires identified. The results of these evaluations were taken into consideration for the development of the final questionnaires. RESULTS: The main points covered by each of the sections included in HBM4EU questionnaires are described and discussed in detail. Additional tools developed for data collection in the HBM4EU (e.g. non-responder questionnaire, satisfaction questionnaire, matrix-specific questionnaire) are also addressed. Special attention is paid to the limitations faced and hurdles overcome during the process of questionnaire development. CONCLUSIONS: Designing questionnaires for use in HBM studies requires substantial effort by a multidisciplinary team to guarantee that the quality of the information collected meets the study's objectives. The process of questionnaire development described herein will contribute to improve the harmonization of HBM studies within the social and environmental context of the EU countries.

A Phased Approach for preparation and organization of human biomonitoring studies.

BACKGROUND: Human biomonitoring (HBM) studies like other epidemiological studies are costly and time-consuming. They require the administration of questionnaires and collection of biological samples, putting substantial burden on the participants which may result in low participation rates. The growing importance of HBM studies in epidemiology, exposure assessment and risk assessment underline the importance of optimizing study planning, designing and implementation thus minimizing the above-mentioned difficulties. METHODS: Based on frameworks from survey design and fieldwork preparation of the European Joint Program HBM4EU, the German Environment Surveys and the COPHES/DEMOCOPHES twin projects combined with elements of project management strategies, a Phased Approach has been developed, introducing a step-by-step guideline for the development of epidemiological studies. RESULTS: The Phased Approach splits the process of developing a study into six phases: Phase 0 (Scoping and Planning): All aspects that are necessary to conduct a study are compiled and put on the agenda for decision-making. Phase 1 (Preparation and Testing): Instruments (e.g. questionnaires), materials (e.g. guidelines, information), and ethics and data management issues, needing thorough preparation and testing before a study can start. Phase 2 (Initiation): Organization and acquisition of necessary equipment and engaging and training personnel. Phase 3 (Implementation): All procedures that require temporal proximity to the start date of fieldwork, such as obtaining contact information of invitees. Phase 4 (Fieldwork and Analysis): Involvement of participants and chemical analysis of the collected samples. Phase 5 (Results and Evaluation): Final procedures leading to closure of the project, such as providing and communicating results. CONCLUSIONS: The separation of the planning and conduct of human biomonitoring studies into different phases creates the basis for a structured procedure and facilitates a step-by-step approach reducing costs, warranting high participation rates and increasing quality of conduct. Emphasis is put on a comprehensive scoping phase ensuring high quality of the study design, which is indispensable for reliable results.

Definitive radiation therapy for infiltrative thyroid carcinoma in dogs.

The medical records of eight dogs with histopathologically confirmed infiltrative thyroid carcinoma treated with external beam radiation were reviewed and a retrospective analysis of survival and local tumor control were performed. The dogs received a definitive radiotherapy protocol of 46.8-48 Gray. All dogs had a reduction in tumor size to a clinically undetectable level on follow up examinations. Kaplan-Meier analysis indicated a median survival time of 24.5 months. Pulmonary metastasis was detected in three dogs and one of these dogs had concurrent bone metastasis. One dog had bone metastasis alone. Two dogs were alive at the censor. This study suggests that fractionated, definitive radiation therapy using multiple, moderate doses of radiation is an effective treatment for local control of invasive thyroid carcinoma in dogs.

Risk factors for prophylaxis failure in patients receiving aerosol pentamidine for Pneumocystis carinii pneumonia prophylaxis.

OBJECTIVE: The purposes of this study were (1) to determine the incidence of prophylaxis failure in HIV-infected patients receiving aerosol pentamidine (AP) for Pneumocystis carinii pneumonia (PCP) prophylaxis, and (2) to identify risk factors for PCP prophylaxis failure. SETTING AND DESIGN: In Ontario, Canada, AP has been made available for outpatient PCP prophylaxis through a centralized government program, the Ontario Drug Distribution and Monitoring Program. Data from this administrative observational database were extracted for 2,227 patients who received AP between May 1989 and December 1998. OUTCOME MEASUREMENTS: The incidence of breakthrough PCP (BPCP) was calculated from the database. A Cox regression model with time-varying covariates was created to examine factors associated with BPCP. The follow-up time was divided into three eras: 1989 to 1991, 1992 to 1994, and 1995 to 1998. These eras were meant to reflect major changes in antiretroviral medication regimens. RESULTS: The overall risk of BPCP was 16.2% over a mean follow-up of 1.67 years. The overall BPCP rate was 9.7/100 patient-years, with rates of 8.8/100, 13.1/100, and 6.3/100 patient-years in each of the three treatment eras. In the multivariate analysis, significant risk factors for prophylaxis failure were low CD4 count, previous diagnosis of PCP, history of AIDS-defining conditions other than PCP, and antiretroviral treatment era defined above. CONCLUSION: The overall rate of PCP prophylaxis failure has decreased significantly after 1995, coincident with the era of highly active antiretroviral therapies. Initiation of PCP prophylaxis remains necessary in patients with risk factors.

Autotransfusion decreases blood usage following cardiac surgery -- a prospective randomized trial.

INTRODUCTION: 10% of blood issued by the National Blood Service (220,000) is utilised in cardiac procedures. Transfusion reactions, infection risk and cost should stimulate us to decrease this transfusion rate. We tested the efficacy of autotransfusion of washed postoperative mediastinal fluid in a prospective randomized trial. PATIENTS AND METHODS: 166 patients undergoing coronary artery bypass grafting (CABG), valve or CABG + valve procedures were randomized into three groups. The indication for transfusion was a postoperative haemoglobin (Hb) < 10 g/l or a packed cell volume (PCV) < 30. When applicable, group A patients received washed post-operative drainage fluid. Group B all received blood processed from the cardiopulmonary bypass (CPB) circuit following separation from CPB and if appropriate washed post-operative drainage fluid. Group C were controls. Groups were compared using analysis of variance. RESULTS: There was no significant difference in age, sex, type of operation, CPB time and preoperative Hb and PCV between the groups. Blood requirements were as shown. [table - see text] Twelve patients in group A and 10 in group B did not require a homologous transfusion following processing of the mediastinal drainage fluid. CONCLUSION: Autotransfusion of washed postoperative mediastinal fluid can decrease the amount of homologous blood transfused following cardiac surgery. There was no demonstrable benefit in processing blood from the CPB circuit as well as mediastinal drainage fluid.

Autotransfusion of washed shed mediastinal fluid decreases the requirement for autologous blood transfusion following cardiac surgery: a prospective randomized trial.

OBJECTIVES: The National Blood Service issues 2.2 million units of blood per year, 10% of these (220000) are utilized in cardiac procedures. Transfusion reactions, infection risk and cost should stimulate us to decrease this transfusion rate. We test the efficacy of autotransfusion following surgery in a prospective randomized trial. METHODS: One hundred and twelve patients undergoing CABG, valve or CABG + valve procedures were randomized into two groups. Group A received washed postoperative drainage fluid and group C were controls. The indication for transfusion was a postoperative haemoglobin (Hb) < 10 g/l or a PCV < 30. There was no significant difference in preoperative and operative variables between the groups. RESULTS: Twenty-eight patients in group A and 46 in group C required homologous transfusion (P = 0.0008). Group A patients required 298+/-49 ml of banked blood per patient, group C 508+/-49 ml (P = 0.003). There was no difference in total blood required (volume autotransfused + volume banked blood transfused) between the groups (group A 404+/-50 ml, group C 508+/-50 ml) or in mean total mediastinal fluid drainage (group A 652+/-51 ml, group C 686+/-50ml). The mean Hb concentration was significantly higher in group A on day 1 (11.2 g/dl+/-51 vs. 10.6 g/dl+/-13 (P = 0.002)). No morbidity was associated with autotransfusion. CONCLUSION: Autotransfusion can decrease the amount of homologous blood transfused following cardiac surgery. This represents a benefit to the patient and a decrease in cost to the health service.

Paranasal sinus cyst as a cause of stridor in a standardbred colt.

Sinus cysts are epithelium-lined, fluid-filled cavities that can occur in the paranasal sinuses of horses. Extensive damage to the permanent tooth buds was a significant feature in this case. The sequellae of these abnormalities, although not apparent at the time of presentation, remain an important consideration for prognosis.

Effects of long-term aerosol pentamidine for Pneumocystis carinii prophylaxis on pulmonary function.

OBJECTIVE: The purpose of the study was to evaluate the long-term effects of aerosolized pentamidine (AP) on the pulmonary function of HIV-positive individuals receiving AP for Pneumocystis carinii pneumonia (PCP) prophylaxis. DESIGN: A retrospective analysis of serial pulmonary function tests (PFTs) performed on a cohort of HIV-positive patients who had received AP for >2 years. METHODS: Of the 1,787 HIV-positive patients receiving AP prophylaxis in our database, 380 patients had been receiving AP for at least 24 months. Of these 380 patients, the PFTs at baseline and at 24 months after starting AP therapy were documented in 179. We compared the baseline PFTs of these 179 patients with results obtained 24 months later to evaluate if there was any change in pulmonary function parameters. RESULTS: Baseline and 24-month PFT parameters (total lung capacity [TLC], FVC, residual volume [RV], FEV1, FEV1/FVC, maximum midexpiratory flow rate at 50% of vital capacity [MEF50], diffusion of carbon monoxide [DLCO]) were all within the normal ranges. However, AP therapy over 24 months was associated with a modest decline in lung volume parameters (TLC, FVC, RV), a slight reduction in flow rates (FEV1, FEV1/FVC, and MEF50), but no change in DLCO. The mean treatment duration was 23.8 months (range, 21 to 27 months). CONCLUSIONS: Long-term AP therapy is associated with a mild combined restrictive and obstructive pulmonary defect. Since 24-month PFT parameters remained within the normal ranges, this level of decline is of unclear clinical significance. Overall, AP has good pulmonary tolerance when used up to 24 months for PCP prophylaxis in patients with normal baseline pulmonary function.

Effects of respiratory gas composition on transthoracic impedance.

The transthoracic current generated during defibrillation comprises a cardiac and extracardiac component. Changes in impedance of transthoracic pathways will alter the transmyocardial current and may thus affect the outcome from defibrillation. The lungs comprise a large component of extracardiac tissue but the effects of different respiratory gases on transthoracic impedance has not been documented. We therefore measured transthoracic impedance (TTI) using different respiratory gas mixtures. TTI across self-adhesive defibrillation pads placed in the antero-apical position was measured at end-expiration using a 30 kHz low amplitude AC current. Ten healthy subjects aged 22-34 years (eight male) were studied whilst breathing alternate mixtures of air, 100% oxygen. 70% helium in 30% oxygen, and 70% nitrous oxide in 30% oxygen administered in a random sequence. There was no significant difference in TTI between any of the four respiratory gases. Therefore transthoracic current during defibrillation is unlikely to be affected by different respiratory gases. This is the first study to document that these respiratory gases do not change the impedance of transthoracic pathways.

Acute pulmonary effects of three nebulizers for administering aerosol pentamidine: comparison of Parineb to Fisoneb and Respirgard II.

We conducted a prospective, unblinded, nonrandomized, multiple crossover study to assess the acute pulmonary effects of a new jet nebulizer-Parineb, comparing it to Respirgard II (jet nebulizer) and Fisoneb (ultrasonic nebulizer) for administering aerosol pentamidine (AP). Twenty-three HIV patients received AP at 60 mg dissolved in 3 ml sterile water with Parineb and Fisoneb and 300 mg dissolved in 5 ml sterile water with Respirgard II on three successive clinic visits. Twelve patients known to develop bronchospasm with AP received 200 micrograms of salbutamol as premedication for all three nebulizers. Eleven subjects received AP without bronchodilator premedication. All subjects had a reduction in flow rates with AP. No significant difference was noted in the reduction of flow rates between the three nebulizers in those patients without prior history of bronchospasm with AP. However, there was a significantly greater reduction in flow rates with Parineb in patients with known AP-induced bronchospasm despite premedication with bronchodilator. This decrease in flow rates with Parineb was not felt by patients based on the subjective rating of cough using a visual analog score when compared to the other two nebulizers. Parineb should be used cautiously in individuals with known AP-induced bronchospasm.

An effectiveness community-based clinical trial of Respirgard II and Fisoneb nebulizers for Pneumocystis carinii prophylaxis with aerosol pentamidine in HIV-infected individuals. Toronto Aerosol Pentamidine Study (TAPS) Group.

STUDY OBJECTIVE: To compare the effectiveness of a standard jet nebulizer, Respirgard II, and a standard ultrasonic nebulizer, Fisoneb, for the administration of aerosolized pentamidine (AP) as primary and secondary prophylaxis against Pneumocystis carinii pneumonia (PCP) in HIV-infected individuals. DESIGN: A retrospective, nonrandomized, parallel group comparative study. SETTING: Patients were enrolled in a community-based AP program (APP) between May 1989 and April 1992 in Ontario, Canada. They received AP in either (1) a centralized treatment facility ("clinic") or (2) their attending physician's office or regionalized centers ("nonclinic"). Clinic administration of pentamidine was via Fisomeb; nonclinic via Respirgard II. PATIENTS: The study group comprised of 1,762 HIV-infected individuals requiring AP for either primary (CD4 < 200/mm3) or secondary PCP prophylaxis. Of these, 1,151 used Fisoneb (clinic) and 611 used Respirgard II (nonclinic). RESULTS: In the primary prophylaxis group, 41 of the 892 patients using Fisoneb (4.6%; mean follow-up, 18 months) compared with 16 of 435 patients using Respirgard II (3.7%; mean follow-up, 14.6 months) developed PCP (p = 0.44). A total of 28 of 259 (10.8%; mean follow-up, 15.3 months) patients using Fisoneb for secondary prophylaxis compared with 11 of 176 (6.3%; mean follow-up, 14.4 months) patients using Respirgard II for secondary prophylaxis developed PCP (p = 0.1). CONCLUSIONS: Despite the difference in dosage (120 mg/mo vs 300 mg/mo), type of nebulizer (ultrasonic vs jet), and frequency of administration (twice vs once monthly), the results of this study indicate that both regimens of AP provide comparable protection against PCP. This study further supports the effectiveness of AP as a solid second-line prophylaxis for HIV-infected individuals who are intolerant to trimethoprim/sulfamethoxazole or dapsone.

Lack of desensitization to aerosol pentamidine with long-term use.

OBJECTIVE: To assess whether long-term exposure to aerosol pentamidine (AP) results in desensitization. STUDY DESIGN: Phase I-A retrospective, two group comparative study. Phase II-A prospective intervention study. METHODS: Patients were selected from a 5-year database of 1200 individuals infected with the human immunodeficiency virus (HIV) who received AP as prophylaxis for Pneumocystis carinii pneumonia (PCP). In phase I, serial pre- and post-AP spirometry data of 33 subjects with significant bronchospasm on initial exposure to AP, who thus received aerosol salbutamol (AS) as regular pre-AP premedication for over 18 months, were compared to 33 matched controls who did not use AS. In phase II, 13 of the original group of 33 patients who required regular AS consented to a follow-up AP treatment without AS premedication to examine the effects of discontinuing AS premedication. RESULTS: Phase I: on their initial AP treatment without AS premedication, the drop in mean FVC, FEV1, and FEV1/FVC values post-AP therapy was significantly lower for the AS group compared to the control group. The mean FEV1/FVC value for the AS group was 84% pre-AP and dropped to 75% post-AP therapy. For the control group the corresponding FEV1/FVC values were 83% (pre-AP) and 79% (post-AP). After using AS as premedication for AP for 18 months, the AS group did not show any reduction in flow rates as the mean FEV1/FVC values were 77% (pre-AP) and 80% (post-AP). The values in the control group were 80 and 78%, respectively. In phase II, when the 13 subjects who needed regular AS premedication were exposed to AP without premedication with AS, the flow rates are reduced in the same magnitude as observed at initial exposure to AP. CONCLUSIONS: The results of this study show that the prevention of bronchospasm with AS premedication while receiving long-term AP administration is due to the bronchodilator effect of AS, as desensitization is not achieved after over 18 months of exposure. These findings support long-term regular premedication with AS in patients with documented AP-induced bronchospasm.

Community acquired, nursing home acquired and hospital acquired pneumonia: A five-year review of the clinical, bacteriological and radiological characteristics.

PURPOSE: To assess the contemporary clinical, bacteriological and radiographic features of hospitalized patients with community acquired (ca), nursing home acquired (na) and hospital acquired pneumonia (ha) and to examine patient outcome. PATIENTS AND METHODS: All hospital records of patients with pneumonia over a five-year period from April 1987 to March 1992 were reviewed retrospectively. Patients included in the study were all those with a diagnosis of pneumonia as identified by computer records of diagnostic codes at discharge; patients with a specific diagnosis of Pneumocystis carinii pneumonia were excluded. Of 74,435 discharges over the five-year period, 1782 patients met the inclusion criteria. RESULTS: Charts of 1622 of the total 1782 cases were reviewed. Mean age was 64.4 years with 59.4% men and 40.6% women. Sixty-three per cent were ca, 28.5% were ha and 8.5% were na. A total of 1542 patients (95%) had at least one concomitant medical condition. Chest roentgenogram was abnormal in 97%. Common organisms isolated overall were Haemophilus influenzae (from 204 patients), Staphylococcus aureas (from 152 patients), Streptococcus pneumoniae (from 143 patients ), Escherichia coli (from 113 patients) and Pseudomonas aeruginosa (from 111 patients). H influenzae and S pneumoniae were most common in ca pneumonia, whereas S aureus and Gram-negative organisms were more common in the ha group and Gram-negative agents in the na group. One hundred and four patients developed complications. Fifteen per cent required intensive care unit admission. The average length of hospitalization in the ca and na groups was 17 days and in the ha group, 43 days. At time of discharge 1261 patients (78%) were cured or improved, and 361 patients (22%) died during the admission. CONCLUSIONS: These results suggest that hospitalization for pneumonia in the 1990s is primarily for elderly patients with significant co-morbidity. Although microbiology appears unchanged compared with earlier reports, the contemporary population is significantly sicker than previous cohorts. This may account for the persistently high morbidity and mortality despite better or newer antibiotics.

A prospective comparison of Porta-sonic and Fisoneb ultrasonic nebulizers for administering aerosol pentamidine.

OBJECTIVE: To report patient acceptability and overall therapeutic effectiveness of two different ultrasonic nebulizers, Fisoneb and Porta-sonic, for the administration of aerosol pentamidine for Pneumocysitis carinii prophylaxis in human immunodeficiency virus (hiv)-infected individuals. DESIGN: Prospective assessment of a random subgroup of 174 individuals from an inception cohort of 1093 patients attending a central aerosol pentamidine treatment centre in Toronto, Ontario. METHODS: One hundred and seventy-four patients who had been receiving aerosolized pentamidine for more than 10 weeks using Fisoneb at 60 mg every two weeks were switched to Porta-sonic. Subjective evaluation included three standard 10 cm visual analogue scales rating cough/wheeze, aftertaste and overall preference. The individuals were also asked to compare the duration of time spent on the aerosol treatments. Objective evaluation included spirometry performed immediately before and 15 mins after pentamidine administration. Prospective surveillance of the entire cohort was preformed to record and document episodes of breakthrough P carinii pneumonia. RESULTS: Porta-sonic was the overall preferred nebulizer in 82% of patients. Less time was spent on aerosol treatment using the Porta-sonic nebulizer compared with the Fisoneb in 66% of patients. The Porta-sonic nebulizer system produced less aftertaste compared with Fisoneb. Both nebulizers produced significant but modest reduction in flow rates. During the study period there was no statistically significant difference in the rates of breakthrough P carinii pneumonia between the two groups. A total of 91 episodes occurred, at a rate of 0.5 episodes per patient-month on Porta-sonic compared with 0.7 episodes per patient-month on Fisoneb (P=0.2536). DISCUSSION: Aerosol pentamidine remains the proven second-line prophylaxis against P carinii pneumonia in hiv/aids for those intolerant to trimethoprim-sulphamethoxazole. Cough, bronchospasm and poor taste are side effects that may limit patient tolerance and acceptability. The results of this study show that the Porta-sonic nebulizer system significantly reduces some of these side effects and increases patient preference. CONCLUSION: This study suggests that Porta-sonic, the newer nebulizer system, with more ideal in vitro characteristics may become a favoured device in clinical practice.

Differential diagnosis of lesser metatarsalgia.

Pain in the lesser metatarsophalangeal area of the foot remains a diagnostic challenge. This pathology often is attributed to neuromas. These painful lesions, although predisposed to this area, are not nearly as common as they are thought to be. The "systems approach" to diagnosis can be extremely helpful in establishing an accurate cause and subsequent proper diagnosis of lesser metatarsophalangeal joint pain.