Challenges in Pharmacokinetic Modelling of [18F]fluoro-PEG-folate PET/CT Imaging in Epithelial Ovarian Cancer Patients.

PURPOSE: To describe the pharmacokinetic properties of the [18F]fluoro-polyethylene glycol(PEG)-folate radiotracer in PET/CT imaging of patients with advanced stage epithelial ovarian cancer (EOC). PROCEDURES: In five patients with advanced EOC (FIGO stage IIIB/IIIC, Fédération Internationale de Gynécologie et d'Obstétrique), a 90-min dynamic PET acquisition of the pelvis was performed directly after i.v. administration of 185 MBq [18F]fluoro-PEG6-folate. Arterial blood samples collected at nineteen timepoints were used to determine the plasma input function. A static volume of interest (VOI) for included tumor lesions was drawn manually on the PET images. Modelling was performed using PMOD software. Three different models (a 1-tissue compartment model (1T2k) and two 2-tissue compartment models, irreversible (2T3k) and reversible (2T4k)) were compared in goodness of fit with the time activity curves by means of the Akaike information criterion. RESULTS: The pharmacokinetic analysis in the pelvic area has proven to be much more challenging than expected. Only four out of 22 tumor lesions in five patients were considered suitable to perform modelling on. The remaining tumor lesions were inapt due to either low tracer uptake, small size, proximity to other [18F]fluoro-PEG6-folate -avid structures and/or displacement by abdominal organ motion in the dynamic scan. Data from the four analyzed tumor lesions suggest that the irreversible 2T3k may best describe the pharmacokinetics. All 22 lesions were immunohistochemically stained positive for the folate receptor alpha (FRα) after resection. CONCLUSION: Performing pharmacokinetic analysis in the abdominal pelvic region is very challenging. This brief article describes the challenges and pitfalls in pharmacokinetic analysis of a tracer with high physiological accumulation in the intestines, in case of lesions of limited size in the abdominal pelvic area.

Perspectives of ICU Patients on Deferred Consent in the Context of Post-ICU Quality of Life: A Substudy of a Randomized Clinical Trial.

OBJECTIVES: Deferred consent enables research to be conducted in the ICU when patients are unable to provide consent themselves, and there is insufficient time to obtain consent from surrogates before commencing (trial) treatment. The aim of this study was to evaluate how former ICU patients reflect on their participation in a study with deferred consent and examine whether their opinions are influenced by the quality of life (QoL) following hospital discharge. DESIGN: Survey study by questionnaire. SETTING: Eight ICUs in The Netherlands. PATIENTS: Former ICU patients who participated in the ICONIC trial, a multicenter randomized clinical trial that evaluated oxygenation targets in mechanically ventilated ICU patients. INTERVENTIONS: Participants enrolled in the ICONIC trial in one of the eight participating centers in The Netherlands received a questionnaire 6 months after randomization. The questionnaire included 12 close-ended questions on their opinion about the deferred consent procedure. QoL was measured using the EQ-5D-5L questionnaire. By calculating the EQ-5D index, patients were divided into four QoL quartiles, where Q1 reflects the lowest and Q4 is the highest. MEASUREMENTS AND MAIN RESULTS: Of 362 participants who were contacted, 197 responded (54%). More than half of the respondents (59%) were unaware of their participation in the ICONIC study. In total 61% were content with the deferred consent procedure, 1% were not content, 25% neutral, 9% did not know, and 9% answered "other." Those with a higher QoL were more likely to be content ( p = 0.02). In all QoL groups, the legal representative was the most often preferred individual to provide consent. CONCLUSIONS: Former ICU patients who participated in the ICONIC study often did not remember their participation but were predominantly positive regarding the use of deferred consent. Those with a higher QoL were most likely to be content.

Conservative versus Liberal Oxygenation Targets in Intensive Care Unit Patients (ICONIC): A Randomized Clinical Trial.

Rationale: Supplemental oxygen is widely administered to ICU patients, but appropriate oxygenation targets remain unclear. Objectives: This study aimed to determine whether a low-oxygenation strategy would lower 28-day mortality compared with a high-oxygenation strategy. Methods: This randomized multicenter trial included mechanically ventilated ICU patients with an expected ventilation duration of at least 24 hours. Patients were randomized 1:1 to a low-oxygenation (PaO2, 55-80 mm Hg; or oxygen saturation as measured by pulse oximetry, 91-94%) or high-oxygenation (PaO2, 110-150 mm Hg; or oxygen saturation as measured by pulse oximetry, 96-100%) target until ICU discharge or 28 days after randomization, whichever came first. The primary outcome was 28-day mortality. The study was stopped prematurely because of the COVID-19 pandemic when 664 of the planned 1,512 patients were included. Measurements and Main Results: Between November 2018 and November 2021, a total of 664 patients were included in the trial: 335 in the low-oxygenation group and 329 in the high-oxygenation group. The median achieved PaO2 was 75 mm Hg (interquartile range, 70-84) and 115 mm Hg (interquartile range, 100-129) in the low- and high-oxygenation groups, respectively. At Day 28, 129 (38.5%) and 114 (34.7%) patients had died in the low- and high-oxygenation groups, respectively (risk ratio, 1.11; 95% confidence interval, 0.9-1.4; P = 0.30). At least one serious adverse event was reported in 12 (3.6%) and 17 (5.2%) patients in the low- and high-oxygenation groups, respectively. Conclusions: Among mechanically ventilated ICU patients with an expected mechanical ventilation duration of at least 24 hours, using a low-oxygenation strategy did not result in a reduction of 28-day mortality compared with a high-oxygenation strategy. Clinical trial registered with the National Trial Register and the International Clinical Trials Registry Platform (NTR7376).

Higher versus lower oxygenation strategies in the general intensive care unit population: A systematic review, meta-analysis and meta-regression of randomized controlled trials.

PURPOSE: Oxygen therapy is vital in adult intensive care unit (ICU) patients, but it is indistinct whether higher or lower oxygen targets are favorable. Our aim was to update the findings of randomized controlled trials (RTCs) comparing higher and lower oxygen strategies. MATERIALS AND METHODS: MEDLINE, EMBASE, and Web of Science were searched. RCTs comparing higher (liberal, hyperoxia) and lower (conservative, normoxia) oxygen in adult mechanically ventilated ICU patients were included. The main outcome was 90-day mortality; other outcomes include serious adverse events (SAE), support free days and length of stay (LOS). RESULTS: No significant difference was observed for 90-day mortality. A lower incidence was found for SAEs, favoring lower oxygenation (OR, 0.86; 95%CI, 0.77-0.96; I 2 13%). No differences were observed in either support free days at day 28 or ICU and hospital LOS. CONCLUSIONS: No difference was found for 90-day mortality, support free days and ICU and hospital LOS. However, a lower incidence of SAEs was found for lower oxygenation. These findings may have clinical implications for practice guidelines, yet it remains of paramount importance to continue conducting clinical trials, comparing groups with a clinically relevant contrast and focusing on the impact of important side effects.

Association Between an Increase in Serum Sodium and In-Hospital Mortality in Critically Ill Patients.

OBJECTIVES: In critically ill patients, dysnatremia is common, and in these patients, in-hospital mortality is higher. It remains unknown whether changes of serum sodium after ICU admission affect mortality, especially whether normalization of mild hyponatremia improves survival. DESIGN: Retrospective cohort study. SETTING: Ten Dutch ICUs between January 2011 and April 2017. PATIENTS: Adult patients were included if at least one serum sodium measurement within 24 hours of ICU admission and at least one serum sodium measurement 24-48 hours after ICU admission were available. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A logistic regression model adjusted for age, sex, and Acute Physiology and Chronic Health Evaluation-IV-predicted mortality was used to assess the difference between mean of sodium measurements 24-48 hours after ICU admission and first serum sodium measurement at ICU admission (Δ48 hr-[Na]) and in-hospital mortality. In total, 36,660 patients were included for analysis. An increase in serum sodium was independently associated with a higher risk of in-hospital mortality in patients admitted with normonatremia (Δ48 hr-[Na] 5-10 mmol/L odds ratio: 1.61 [1.44-1.79], Δ48 hr-[Na] > 10 mmol/L odds ratio: 4.10 [3.20-5.24]) and hypernatremia (Δ48 hr-[Na] 5-10 mmol/L odds ratio: 1.47 [1.02-2.14], Δ48 hr-[Na] > 10 mmol/L odds ratio: 8.46 [3.31-21.64]). In patients admitted with mild hyponatremia and Δ48 hr-[Na] greater than 5 mmol/L, no significant difference in hospital mortality was found (odds ratio, 1.11 [0.99-1.25]). CONCLUSIONS: An increase in serum sodium in the first 48 hours of ICU admission was associated with higher in-hospital mortality in patients admitted with normonatremia and in patients admitted with hypernatremia.

Hyperoxia provokes a time- and dose-dependent inflammatory response in mechanically ventilated mice, irrespective of tidal volumes.

BACKGROUND: Mechanical ventilation and hyperoxia have the potential to independently promote lung injury and inflammation. Our purpose was to study both time- and dose-dependent effects of supplemental oxygen in an experimental model of mechanically ventilated mice. METHODS: Healthy male C57Bl/6J mice, aged 9-10 weeks, were intraperitoneally anesthetized and randomly assigned to the mechanically ventilated group or the control group. In total, 100 mice were tracheotomized and mechanically ventilated for either 8 or 12 h after allocation to different settings for the applied fractions of inspired oxygen (FiO2, 30, 50, or 90%) and tidal volumes (7.5 or 15 ml/kg). After euthanisation arterial blood, bronchoalveolar lavage fluid (BALf) and tissues were collected for analyses. RESULTS: Mechanical ventilation significantly increased the lung injury score (P < 0.05), mean protein content (P < 0.001), and the mean number of cells (P < 0.01), including neutrophils in BALf (P < 0.001). In mice ventilated for 12 h, a significant increase in TNF-α, IFN-γ, IL-1ß, IL-10, and MCP-1 (P < 0.01) was observed with 90% FiO2, whereas IL-6 showed a decreasing trend (P for trend = 0.03) across FiO2 groups. KC, MIP-2, and sRAGE were similar between FiO2 groups. HMGB-1 was significantly higher in BALf of mechanically ventilated mice compared to controls and showed a gradual increase in expression with increasing FiO2. Cytokine and chemokine levels in BALf did not markedly differ between FiO2 groups after 8 h of ventilation. Differences between the tidal volume groups were small and did not appear to significantly interact with the oxygen levels. CONCLUSIONS: We demonstrated a severe vascular leakage and a pro-inflammatory pulmonary response in mechanically ventilated mice, which was enhanced by severe hyperoxia and longer duration of mechanical ventilation. Prolonged ventilation with high oxygen concentrations induced a time-dependent immune response characterized by elevated levels of neutrophils, cytokines, and chemokines in the pulmonary compartment.

Hemodynamic effects of short-term hyperoxia after coronary artery bypass grafting.

BACKGROUND: Although oxygen is generally administered in a liberal manner in the perioperative setting, the effects of oxygen administration on dynamic cardiovascular parameters, filling status and cerebral perfusion have not been fully unraveled. Our aim was to study the acute hemodynamic and microcirculatory changes before, during and after arterial hyperoxia in mechanically ventilated patients after coronary artery bypass grafting (CABG) surgery. METHODS: This was a single-center physiological study in a tertiary care ICU in the Netherlands. Twenty-two patients scheduled for ICU admission after elective CABG were enrolled in the study between September 2014 and September 2015. In the ICU, patients were exposed to a fraction of inspired oxygen (FiO2) of 90% allowing a 15-min wash-in period. Various hemodynamic parameters were measured using direct pressure signals and continuous arterial waveform analysis at three sequential time points: before, during and after hyperoxia. RESULTS: During a 15-min exposure to a fraction of inspired oxygen (FiO2) of 90%, the partial pressure of arterial oxygen (PaO2) and arterial oxygen saturation (SaO2) were significantly higher. The systemic resistance increased (P < 0.0001), without altering the heart rate. Stroke volume variation and pulse pressure variation decreased slightly. The cardiac output did not significantly decrease (P = 0.08). Mean systemic filling pressure and arterial critical closing pressure increased (P < 0.01whereas the percentage of perfused microcirculatory vessels decreased (P < 0.01). Other microcirculatory parameters and cerebral blood flow velocity showed only slight changes. CONCLUSIONS: We found that short-term hyperoxia affects hemodynamics in ICU patients after CABG. This was translated in several changes in central circulatory variables, but had only slight effects on cardiac output, cerebral blood flow and the microcirculation. Clinical trial registration Netherlands Trial Register: NTR5064.

Metrics of Arterial Hyperoxia and Associated Outcomes in Critical Care.

OBJECTIVE: Emerging evidence has shown the potential risks of arterial hyperoxia, but the lack of a clinical definition and methodologic limitations hamper the interpretation and clinical relevance of previous studies. Our purpose was to evaluate previously used and newly constructed metrics of arterial hyperoxia and systematically assess their association with clinical outcomes in different subgroups in the ICU. DESIGN: Observational cohort study. SETTING: Three large tertiary care ICUs in the Netherlands. PATIENTS: A total of 14,441 eligible ICU patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: In total, 295,079 arterial blood gas analyses, including the PaO2, between July 2011 and July 2014 were extracted from the patient data management system database. Data from all admissions with more than one PaO2 measurement were supplemented with anonymous demographic and admission and discharge data from the Dutch National Intensive Care Evaluation registry. Mild hyperoxia was defined as PaO2 between 120 and 200 mm Hg; severe hyperoxia as PaO2 greater than 200 mm Hg. Characteristics of existing and newly constructed metrics for arterial hyperoxia were examined, and the associations with hospital mortality (primary outcome), ICU mortality, and ventilator-free days and alive at day 28 were retrospectively analyzed using regression models in different subgroups of patients. Severe hyperoxia was associated with higher mortality rates and fewer ventilator-free days in comparison to both mild hyperoxia and normoxia for all metrics except for the worst PaO2. Adjusted effect estimates for conditional mortality were larger for severe hyperoxia than for mild hyperoxia. This association was found both within and beyond the first 24 hours of admission and was consistent for large subgroups. The largest point estimates were found for the exposure identified by the average PaO2, closely followed by the median PaO2, and these estimates differed substantially between subsets. Time spent in hyperoxia showed a linear and positive relationship with hospital mortality. CONCLUSIONS: Our results suggest that we should limit the PaO2 levels of critically ill patients within a safe range, as we do with other physiologic variables. Analytical metrics of arterial hyperoxia should be judiciously considered when interpreting and comparing study results and future studies are needed to validate our findings in a randomized fashion design.

Age-Dependent Changes in the Pulmonary Renin-Angiotensin System Are Associated With Severity of Lung Injury in a Model of Acute Lung Injury in Rats.

OBJECTIVES: A growing body of evidence suggests that age affects the main pathophysiologic mechanisms of the acute respiratory distress syndrome. This may imply the need for developing age-tailored therapies for acute respiratory distress syndrome. However, underlying molecular mechanisms governing age-related susceptibility first need to be unraveled. In a rat model of acute lung injury, we investigated whether age affects the balance between the two key enzymes of the pulmonary renin-angiotensin system, angiotensin-converting enzyme, and angiotensin-converting enzyme 2. We hypothesized that aging shifts the balance toward the lung injury-promoting angiotensin-converting enzyme, which may form an explanation for the differences in severity of lung injury between different age groups. DESIGN: Prospective, randomized controlled animal study. SETTING: University medical research laboratory. SUBJECTS: Infant (15 ± 2 d), juvenile (37 ± 2 d), adult (4 ± 0.2 mo), and elderly (19.5 ± 0.5 mo) male RCCHan Wistar rats. INTERVENTIONS: Lung injury was induced by intratracheal administration of lipopolysaccharide (5 mg/kg) and 4 hours of mechanical ventilation (15 mL/kg). MEASUREMENTS AND MAIN RESULTS: In lipopolysaccharide-exposed and mechanical ventilated rats, angiotensin-converting enzyme activity in bronchoalveolar lavage fluid increased 3.2-fold in elderly when compared with infants. No changes in bronchoalveolar lavage fluid angiotensin-converting enzyme 2 activity were found. In addition, membrane-bound angiotensin-converting enzyme activity decreased. Together with the presence of angiotensin-converting enzyme-sheddase ADAM9 (a disintegrin and metalloproteinase domain-containing protein 9) and an age-dependent increase in tumor necrosis factor-α, an activator of ADAM9, these results indicate increased shedding of angiotensin-converting enzyme in the alveolar compartment, thereby shifting the balance toward the injurious pathway. This imbalance was associated with an increased inflammatory mediator response and more lung injury (wet-to-dry ratio and histology) in elderly rats. CONCLUSIONS: Increasing age is associated with an imbalance of the pulmonary renin-angiotensin system, which correlates with aggravated inflammation and more lung injury. These changes might form the ground for new therapeutic strategies in terms of dosing and effectiveness of renin-angiotensin system-modulating agents for treatment of acute respiratory distress syndrome.

Effectiveness and Clinical Outcomes of a Two-Step Implementation of Conservative Oxygenation Targets in Critically Ill Patients: A Before and After Trial.

OBJECTIVES: Conservative oxygen therapy is aimed at the prevention of harm by iatrogenic hyperoxia while preserving adequate tissue oxygenation. Our aim was to study the effectiveness and clinical outcomes of a two-step implementation of conservative oxygenation targets in the ICU. DESIGN: This was a before and after stepwise implementation study of conservative oxygenation targets, between July 2011 and July 2014. The primary endpoint was the proportion of PaO2 values within the target range. Secondary outcomes included ventilator-free days at day 28, length of stay, and mortality. SETTING: Three closed-format ICUs in the Netherlands. PATIENTS: We analyzed data on 15,045 eligible admissions. INTERVENTIONS: The first implementation phase consisted of providing training and feedback on new guidelines instructing for explicit targets for arterial oxygen tension (PaO2, 55-86 mm Hg) and oxyhemoglobin saturation (SpO2, 92-95%). In the second phase, bedside clinicians were additionally assisted in guideline adherence by a computerized decision-support system. MEASUREMENTS AND MAIN RESULTS: The proportion of PaO2 in the target range increased from 47% at baseline to 63% in phase 1 and to 68% in phase 2 (p < 0.0001). Episodes of hyperoxia decreased (p < 0.0001), whereas hypoxic episodes remained unchanged (p = 0.06) during the study. Mechanical ventilation time was significantly lower (p < 0.01) during both study phases. After adjustment for potential confounders, ventilator-free days in phase 1 and phase 2 were higher than baseline: adjusted mean difference, 0.55 (95% CI, 0.25-0.84) and 0.48 (95% CI, 0.11-0.86), respectively. Adjusted ICU mortality and ICU-free days did not significantly differ between study phases. Hospital mortality decreased in reference to baseline: adjusted odds ratio, 0.84 (95% CI, 0.74-0.96) for phase 1 and 0.82 (95% CI, 0.69-0.96) for phase 2. CONCLUSIONS: Stepwise implementation of conservative oxygenation targets was feasible, effective, and seemed safe in critically ill patients. The implementation was associated with several changes in clinical outcomes, but the causal impact of conservative oxygenation is still to be determined.

Associations of arterial carbon dioxide and arterial oxygen concentrations with hospital mortality after resuscitation from cardiac arrest.

INTRODUCTION: Arterial concentrations of carbon dioxide (PaCO2) and oxygen (PaO2) during admission to the intensive care unit (ICU) may substantially affect organ perfusion and outcome after cardiac arrest. Our aim was to investigate the independent and synergistic effects of both parameters on hospital mortality. METHODS: This was a cohort study using data from mechanically ventilated cardiac arrest patients in the Dutch National Intensive Care Evaluation (NICE) registry between 2007 and 2012. PaCO2 and PaO2 levels from arterial blood gas analyses corresponding to the worst oxygenation in the first 24 h of ICU stay were retrieved for analyses. Logistic regression analyses were performed to assess the relationship between hospital mortality and both categorized groups and a spline-based transformation of the continuous values of PaCO2 and PaO2. RESULTS: In total, 5,258 cardiac arrest patients admitted to 82 ICUs in the Netherlands were included. In the first 24 h of ICU admission, hypocapnia was encountered in 22 %, and hypercapnia in 35 % of included cases. Hypoxia and hyperoxia were observed in 8 % and 3 % of the patients, respectively. Both PaCO2 and PaO2 had an independent U-shaped relationship with hospital mortality and after adjustment for confounders, hypocapnia and hypoxia were significant predictors of hospital mortality: OR 1.37 (95 % CI 1.17-1.61) and OR 1.34 (95 % CI 1.08-1.66). A synergistic effect of concurrent derangements of PaCO2 and PaO2 was not observed (P = 0.75). CONCLUSIONS: The effects of aberrant arterial carbon dioxide and arterial oxygen concentrations were independently but not synergistically associated with hospital mortality after cardiac arrest.

Bench-to-bedside review: the effects of hyperoxia during critical illness.

Oxygen administration is uniformly used in emergency and intensive care medicine and has life-saving potential in critical conditions. However, excessive oxygenation also has deleterious properties in various pathophysiological processes and consequently both clinical and translational studies investigating hyperoxia during critical illness have gained increasing interest. Reactive oxygen species are notorious by-products of hyperoxia and play a pivotal role in cell signaling pathways. The effects are diverse, but when the homeostatic balance is disturbed, reactive oxygen species typically conserve a vicious cycle of tissue injury, characterized by cell damage, cell death, and inflammation. The most prominent symptoms in the abundantly exposed lungs include tracheobronchitis, pulmonary edema, and respiratory failure. In addition, absorptive atelectasis results as a physiological phenomenon with increasing levels of inspiratory oxygen. Hyperoxia-induced vasoconstriction can be beneficial during vasodilatory shock, but hemodynamic changes may also impose risk when organ perfusion is impaired. In this context, oxygen may be recognized as a multifaceted agent, a modifiable risk factor, and a feasible target for intervention. Although most clinical outcomes are still under extensive investigation, careful titration of oxygen supply is warranted in order to secure adequate tissue oxygenation while preventing hyperoxic harm.

Association Between Arterial Hyperoxia and Outcome in Subsets of Critical Illness: A Systematic Review, Meta-Analysis, and Meta-Regression of Cohort Studies.

OBJECTIVE: Oxygen is vital during critical illness, but hyperoxia may harm patients. Our aim was to systematically evaluate the methodology and findings of cohort studies investigating the effects of hyperoxia in critically ill adults. DATA SOURCE: A meta-analysis and meta-regression analysis of cohort studies published between 2008 and 2015 was conducted. Electronic databases of MEDLINE, EMBASE, and Web of Science were systematically searched for the keywords hyperoxia and mortality or outcome. STUDY SELECTION: Publications assessing the effect of arterial hyperoxia on outcome in critically ill adults (≥ 18 yr) admitted to critical care units were eligible. We excluded studies in patients with chronic obstructive pulmonary disease, extracorporeal life support or hyperbaric oxygen therapy, and animal studies. Due to a lack of data, no studies dedicated to patients with acute lung injury, sepsis, shock, or multiple trauma could be included. DATA EXTRACTION: Studies were included independent of admission diagnosis and definition of hyperoxia. The primary outcome measure was in-hospital mortality, and results were stratified for relevant subgroups (cardiac arrest, traumatic brain injury, stroke, post-cardiac surgery, and any mechanical ventilation). The effects of arterial oxygenation on functional outcome, long-term mortality, and discharge variables were studied as secondary outcomes. DATA SYNTHESIS: Twenty-four studies were included of which five studies were only for a subset of the analyses. Nineteen studies were pooled for meta-analyses and showed that arterial hyperoxia during admission increases hospital mortality: adjusted odds ratio, 1.21 (95% CI, 1.08-1.37) (p = 0.001). Functional outcome measures were diverse and generally showed a more favorable outcome for normoxia. CONCLUSIONS: In various subsets of critically ill patients, arterial hyperoxia was associated with poor hospital outcome. Considering the substantial heterogeneity of included studies and the lack of a clinical definition, more evidence is needed to provide optimal oxygen targets to critical care physicians.

A systematic review of reliability and objective criterion-related validity of physical activity questionnaires.

Physical inactivity is one of the four leading risk factors for global mortality. Accurate measurement of physical activity (PA) and in particular by physical activity questionnaires (PAQs) remains a challenge. The aim of this paper is to provide an updated systematic review of the reliability and validity characteristics of existing and more recently developed PAQs and to quantitatively compare the performance between existing and newly developed PAQs.A literature search of electronic databases was performed for studies assessing reliability and validity data of PAQs using an objective criterion measurement of PA between January 1997 and December 2011. Articles meeting the inclusion criteria were screened and data were extracted to provide a systematic overview of measurement properties. Due to differences in reported outcomes and criterion methods a quantitative meta-analysis was not possible.In total, 31 studies testing 34 newly developed PAQs, and 65 studies examining 96 existing PAQs were included. Very few PAQs showed good results on both reliability and validity. Median reliability correlation coefficients were 0.62-0.71 for existing, and 0.74-0.76 for new PAQs. Median validity coefficients ranged from 0.30-0.39 for existing, and from 0.25-0.41 for new PAQs.Although the majority of PAQs appear to have acceptable reliability, the validity is moderate at best. Newly developed PAQs do not appear to perform substantially better than existing PAQs in terms of reliability and validity. Future PAQ studies should include measures of absolute validity and the error structure of the instrument.