New regulatory thinking is needed for AI-based personalised drug and cell therapies in precision oncology.

Until recently the application of artificial intelligence (AI) in precision oncology was confined to activities in drug development and had limited impact on the personalisation of therapy. Now, a number of approaches have been proposed for the personalisation of drug and cell therapies with AI applied to therapy design, planning and delivery at the patient's bedside. Some drug and cell-based therapies are already tuneable to the individual to optimise efficacy, to reduce toxicity, to adapt the dosing regime, to design combination therapy approaches and, preclinically, even to personalise the receptor design of cell therapies. Developments in AI-based healthcare are accelerating through the adoption of foundation models, and generalist medical AI models have been proposed. The application of these approaches in therapy design is already being explored and realistic short-term advances include the application to the personalised design and delivery of drugs and cell therapies. With this pace of development, the limiting step to adoption will likely be the capacity and appropriateness of regulatory frameworks. This article explores emerging concepts and new ideas for the regulation of AI-enabled personalised cancer therapies in the context of existing and in development governance frameworks.

Assessment of a Digital Symptom Checker Tool's Accuracy in Suggesting Reproductive Health Conditions: Clinical Vignettes Study.

BACKGROUND: Reproductive health conditions such as endometriosis, uterine fibroids, and polycystic ovary syndrome (PCOS) affect a large proportion of women and people who menstruate worldwide. Prevalence estimates for these conditions range from 5% to 40% of women of reproductive age. Long diagnostic delays, up to 12 years, are common and contribute to health complications and increased health care costs. Symptom checker apps provide users with information and tools to better understand their symptoms and thus have the potential to reduce the time to diagnosis for reproductive health conditions. OBJECTIVE: This study aimed to evaluate the agreement between clinicians and 3 symptom checkers (developed by Flo Health UK Limited) in assessing symptoms of endometriosis, uterine fibroids, and PCOS using vignettes. We also aimed to present a robust example of vignette case creation, review, and classification in the context of predeployment testing and validation of digital health symptom checker tools. METHODS: Independent general practitioners were recruited to create clinical case vignettes of simulated users for the purpose of testing each condition symptom checker; vignettes created for each condition contained a mixture of condition-positive and condition-negative outcomes. A second panel of general practitioners then reviewed, approved, and modified (if necessary) each vignette. A third group of general practitioners reviewed each vignette case and designated a final classification. Vignettes were then entered into the symptom checkers by a fourth, different group of general practitioners. The outcomes of each symptom checker were then compared with the final classification of each vignette to produce accuracy metrics including percent agreement, sensitivity, specificity, positive predictive value, and negative predictive value. RESULTS: A total of 24 cases were created per condition. Overall, exact matches between the vignette general practitioner classification and the symptom checker outcome were 83% (n=20) for endometriosis, 83% (n=20) for uterine fibroids, and 88% (n=21) for PCOS. For each symptom checker, sensitivity was reported as 81.8% for endometriosis, 84.6% for uterine fibroids, and 100% for PCOS; specificity was reported as 84.6% for endometriosis, 81.8% for uterine fibroids, and 75% for PCOS; positive predictive value was reported as 81.8% for endometriosis, 84.6% for uterine fibroids, 80% for PCOS; and negative predictive value was reported as 84.6% for endometriosis, 81.8% for uterine fibroids, and 100% for PCOS. CONCLUSIONS: The single-condition symptom checkers have high levels of agreement with general practitioner classification for endometriosis, uterine fibroids, and PCOS. Given long delays in diagnosis for many reproductive health conditions, which lead to increased medical costs and potential health complications for individuals and health care providers, innovative health apps and symptom checkers hold the potential to improve care pathways.

Spinal cord stimulation for low back pain.

BACKGROUND: Spinal cord stimulation (SCS) is a surgical intervention used to treat persistent low back pain. SCS is thought to modulate pain by sending electrical signals via implanted electrodes into the spinal cord. The long term benefits and harms of SCS for people with low back pain are uncertain. OBJECTIVES: To assess the effects, including benefits and harms, of SCS for people with low back pain. SEARCH METHODS: On 10 June 2022, we searched CENTRAL, MEDLINE, Embase, and one other database for published trials. We also searched three clinical trials registers for ongoing trials. SELECTION CRITERIA: We included all randomised controlled trials and cross-over trials comparing SCS with placebo or no treatment for low back pain. The primary comparison was SCS versus placebo, at the longest time point measured in the trials. Major outcomes were mean low back pain intensity, function, health-related quality of life, global assessment of efficacy, withdrawals due to adverse events, adverse events, and serious adverse events. Our primary time point was long-term follow-up (≥ 12 months). DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included 13 studies with 699 participants: 55% of participants were female; mean age ranged from 47 to 59 years; and all participants had chronic low back pain with mean duration of symptoms ranging from five to 12 years. Ten cross-over trials compared SCS with placebo. Three parallel-group trials assessed the addition of SCS to medical management. Most studies were at risk of performance and detection bias from inadequate blinding and selective reporting bias. The placebo-controlled trials had other important biases, including lack of accounting for period and carryover effects. Two of the three parallel trials assessing SCS as an addition to medical management were at risk of attrition bias, and all three had substantial cross-over to the SCS group for time points beyond six months. In the parallel-group trials, we considered the lack of placebo control to be an important source of bias. None of our included studies evaluated the impact of SCS on mean low back pain intensity in the long term (≥ 12 months). The studies most often assessed outcomes in the immediate term (less than one month). At six months, the only available evidence was from a single cross-over trial (50 participants). There was moderate-certainty evidence that SCS probably does not improve back or leg pain, function, or quality of life compared with placebo. Pain was 61 points (on a 0- to 100-point scale, 0 = no pain) at six months with placebo, and 4 points better (8.2 points better to 0.2 points worse) with SCS. Function was 35.4 points (on a 0- to 100-point scale, 0 = no disability or best function) at six months with placebo, and 1.3 points better (3.9 points better to 1.3 points worse) with SCS. Health-related quality of life was 0.44 points out of 1 (0 to 1 index, 0 = worst quality of life) at six months with placebo, and 0.04 points better (0.16 points better to 0.08 points worse) with SCS. In that same study, nine participants (18%) experienced adverse events and four (8%) required revision surgery. Serious adverse events with SCS included infections, neurological damage, and lead migration requiring repeated surgery. We could not provide effect estimates of the relative risks as events were not reported for the placebo period. In parallel trials assessing SCS as an addition to medical management, it is uncertain whether, in the medium or long term, SCS can reduce low back pain, leg pain, or health-related quality of life, or if it increases the number of people reporting a 50% improvement or better, because the certainty of the evidence was very low. Low-certainty evidence suggests that adding SCS to medical management may slightly improve function and slightly reduce opioid use. In the medium term, mean function (0- to 100-point scale; lower is better) was 16.2 points better with the addition of SCS to medical management compared with medical management alone (95% confidence interval (CI) 19.4 points better to 13.0 points better; I2 = 95%; 3 studies, 430 participants; low-certainty evidence). The number of participants reporting opioid medicine use was 15% lower with the addition of SCS to medical management (95% CI 27% lower to 0% lower; I2 = 0%; 2 studies, 290 participants; low-certainty evidence). Adverse events with SCS were poorly reported but included infection and lead migration. One study found that, at 24 months, 13 of 42 people (31%) receiving SCS required revision surgery. It is uncertain to what extent the addition of SCS to medical management increases the risk of withdrawals due to adverse events, adverse events, or serious adverse events, because the certainty of the evidence was very low. AUTHORS' CONCLUSIONS: Data in this review do not support the use of SCS to manage low back pain outside a clinical trial. Current evidence suggests SCS probably does not have sustained clinical benefits that would outweigh the costs and risks of this surgical intervention.

Improving Emergency Department Patient-Physician Conversation Through an Artificial Intelligence Symptom-Taking Tool: Mixed Methods Pilot Observational Study.

BACKGROUND: Establishing rapport and empathy between patients and their health care provider is important but challenging in the context of a busy and crowded emergency department (ED). OBJECTIVE: We explore the hypotheses that rapport building, documentation, and time efficiency might be improved in the ED by providing patients a digital tool that uses Bayesian reasoning-based techniques to gather relevant symptoms and history for handover to clinicians. METHODS: A 2-phase pilot evaluation was carried out in the ED of a German tertiary referral and major trauma hospital that treats an average of 120 patients daily. Phase 1 observations guided iterative improvement of the digital tool, which was then further evaluated in phase 2. All patients who were willing and able to provide consent were invited to participate, excluding those with severe injury or illness requiring immediate treatment, with traumatic injury, incapable of completing a health assessment, and aged <18 years. Over an 18-day period with 1699 patients presenting to the ED, 815 (47.96%) were eligible based on triage level. With available recruitment staff, 135 were approached, of whom 81 (60%) were included in the study. In a mixed methods evaluation, patients entered information into the tool, accessed by clinicians through a dashboard. All users completed evaluation Likert-scale questionnaires rating the tool's performance. The feasibility of a larger trial was evaluated through rates of recruitment and questionnaire completion. RESULTS: Respondents strongly endorsed the tool for facilitating conversation (61/81, 75% of patients, 57/78, 73% of physician ratings, and 10/10, 100% of nurse ratings). Most nurses judged the tool as potentially time saving, whereas most physicians only agreed for a subset of medical specialties (eg, surgery). Patients reported high usability and understood the tool's questions. The tool was recommended by most patients (63/81, 78%), in 53% (41/77) of physician ratings, and in 76% (61/80) of nurse ratings. Questionnaire completion rates were 100% (81/81) by patients and 96% (78/81 enrolled patients) by physicians. CONCLUSIONS: This pilot confirmed that a larger study in the setting would be feasible. The tool has clear potential to improve patient-health care provider interaction and could also contribute to ED efficiency savings. Future research and development will extend the range of patients for whom the history-taking tool has clinical utility. TRIAL REGISTRATION: German Clinical Trials Register DRKS00024115; https://drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00024115.

Recall, perceptions and determinants of receiving physical activity advice amongst cancer survivors: a mixed-methods survey.

PURPOSE: This study explored cancer survivors' views and experiences of receiving physical activity advice post-diagnosis. We also determined the influence of sociodemographic characteristics on the recall of physical activity advice and whether receiving advice was associated with meeting physical activity guidelines. METHODS: An anonymised, mixed-methods, 27-item survey was distributed to cancer survivors via online cancer communities in the UK. RESULTS: Of the 242 respondents, 52% recalled receiving physical activity advice. Of those who recalled receiving advice, only 30% received guidance on type of physical activity and 14% were referred to another source of information or exercise specialist. Advice was most often given after treatment cessation, with only 19% of respondents receiving advice during active treatment. Most respondents (56%) expressed a need for further information. There was no evidence of associations between sociodemographic characteristics and recall of physical activity advice. However, cancer survivors who perceived the physical activity advice they received as being appropriate (odds ratio [OR] 3.8, 95% confidence interval [95% CI]: 1.4-10.7) and those with a higher level of education (OR 3.2, 95% CI: 1.8-5.8) were more likely to meet aerobic exercise guidelines. Females were less likely to meet resistance exercise guidelines than males (OR 0.44, 95% CI: 0.21-0.90). CONCLUSION: There is scope to improve the provision of physical activity advice in cancer care by providing advice in a timely manner after diagnosis, referring patients to a suitable exercise or rehabilitation specialist when indicated, and using a tailored approach to ensure the advice is appropriate for specific sociodemographic groups.

Tunable Anion-Selective Transport through Monolayer Graphene and Hexagonal Boron Nitride.

Membranes that selectively filter for both anions and cations are central to technological applications from clean energy generation to desalination devices. 2D materials have immense potential as these ion-selective membranes due to their thinness, mechanical strength, and tunable surface chemistry; however, currently, only cation-selective membranes have been reported. Here we demonstrate the controllable cation and anion selectivity of both monolayer graphene and hexagonal boron nitride. In particular, we measure the ionic current through membranes grown by chemical vapor deposition containing well-known defects inherent to scalably produced and wet-transferred 2D materials. We observe a striking change from cation selectivity with monovalent ions to anion selectivity by controlling the concentration of multivalent ions and inducing charge inversion on the 2D membrane. Furthermore, we find good agreement between our experimental data and theoretical predictions from the Goldman-Hodgkin-Katz equation and use this model to extract selectivity ratios. These tunable selective membranes conduct up to 500 anions for each cation and thus show potential for osmotic power generation.

Arrhythmogenic Remodeling of the Left Ventricle in a Porcine Model of Repaired Tetralogy of Fallot.

BACKGROUND: Ventricular arrhythmias are frequent in patients with repaired tetralogy of Fallot (rTOF), but their origin and underlying mechanisms remain unclear. In this study, the involvement of left ventricular (LV) electrical and structural remodeling was assessed in an animal model mimicking rTOF sequelae. METHODS: Piglets underwent a tetralogy of Fallot repair-like surgery (n=6) or were sham operated (Sham, n=5). Twenty-three weeks post-surgery, cardiac function was assessed in vivo by magnetic resonance imaging. Electrophysiological properties were characterized by optical mapping. LV fibrosis and connexin-43 localization were assessed on histological sections and protein expression assessed by Western Blot. RESULTS: Right ventricular dysfunction was evident, whereas LV function remained unaltered in rTOF pigs. Optical mapping showed longer action potential duration on the rTOF LV epicardium and endocardium. Epicardial conduction velocity was significantly reduced in the longitudinal direction in rTOF LVs but not in the transverse direction compared with Sham. An elevated collagen content was found in LV basal and apical sections from rTOF pigs. Moreover, a trend for connexin-43 lateralization with no change in protein expression was found in the LV of rTOFs. Finally, rTOF LVs had a lower threshold for arrhythmia induction using incremental pacing protocols. CONCLUSIONS: We found an arrhythmogenic substrate with prolonged heterogeneous action potential duration and reduced conduction velocity in the LV of rTOF pigs. This remodeling precedes LV dysfunction and is likely to contribute to ventricular arrhythmias and sudden cardiac death in patients with rTOF.

Effects of a lifestyle intervention on endothelial function in men on long-term androgen deprivation therapy for prostate cancer.

BACKGROUND: Treatment of prostate cancer with androgen deprivation therapy (ADT) is associated with metabolic changes that have been linked to an increase in cardiovascular risk. METHODS: This randomised controlled trial investigated the effects of a 12-week lifestyle intervention that included supervised exercise training and dietary advice on markers of cardiovascular risk in 50 men on long-term ADT recruited to an on-going study investigating the effects of such a lifestyle intervention on quality of life. Participants were randomly allocated to receive the intervention or usual care. Cardiovascular outcomes included endothelial function (flow-mediated dilatation (FMD) of the brachial artery), blood pressure, body composition and serum lipids. Additional outcomes included treadmill walk time and exercise and dietary behaviours. Outcomes were assessed before randomisation (baseline), and 6, 12 and 24 weeks after randomisation. RESULTS: At 12 weeks, the difference in mean relative FMD was 2.2% (95% confidence interval (CI) 0.1-4.3, P=0.04) with an effect size of 0.60 (95% CI <0.01-1.18) favouring the intervention group. Improvements in skeletal muscle mass, treadmill walk time and exercise behaviour also occurred in the intervention group over that duration (P<0.05). At 24 weeks, only the difference in treadmill walk time was maintained. CONCLUSIONS: This study demonstrates that lifestyle changes can improve endothelial function in men on long-term ADT for prostate cancer. The implications for cardiovascular health need further investigation in larger studies over longer duration.

Identification of Region-Specific Myocardial Gene Expression Patterns in a Chronic Swine Model of Repaired Tetralogy of Fallot.

Surgical repair of Tetralogy of Fallot (TOF) is highly successful but may be complicated in adulthood by arrhythmias, sudden death, and right ventricular or biventricular dysfunction. To better understand the molecular and cellular mechanisms of these delayed cardiac events, a chronic animal model of postoperative TOF was studied using microarrays to perform cardiac transcriptomic studies. The experimental study included 12 piglets (7 rTOF and 5 controls) that underwent surgery at age 2 months and were further studied after 23 (+/- 1) weeks of postoperative recovery. Two distinct regions (endocardium and epicardium) from both ventricles were analyzed. Expression levels from each localization were compared in order to decipher mechanisms and signaling pathways leading to ventricular dysfunction and arrhythmias in surgically repaired TOF. Several genes were confirmed to participate in ventricular remodeling and cardiac failure and some new candidate genes were described. In particular, these data pointed out FRZB as a heart failure marker. Moreover, calcium handling and contractile function genes (SLN, ACTC1, PLCD4, PLCZ), potential arrhythmia-related genes (MYO5B, KCNA5), and cytoskeleton and cellular organization-related genes (XIRP2, COL8A1, KCNA6) were among the most deregulated genes in rTOF ventricles. To our knowledge, this is the first comprehensive report on global gene expression profiling in the heart of a long-term swine model of repaired TOF.

Lifestyle changes for improving disease-specific quality of life in sedentary men on long-term androgen-deprivation therapy for advanced prostate cancer: a randomised controlled trial.

BACKGROUND: Prostate cancer is a key driver of cancer-related global disability-adjusted life-years. Androgen-deprivation therapy (ADT) for advanced disease is linked to fatigue, reduced physical function, and quality of life (QoL). OBJECTIVE: To evaluate the effect of a lifestyle intervention on disease-specific QoL, diastolic blood pressure, and cancer-related fatigue in sedentary men receiving long-term ADT for advanced prostate cancer. DESIGN, SETTING, AND PARTICIPANTS: A total of 100 hundred sedentary men with locally advanced or metastatic prostate cancer on long-term ADT were randomised to an intervention or usual care group. INTERVENTION: A 12-wk lifestyle intervention consisting of aerobic and resistance exercise with parallel dietary advice. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Disease-specific QoL was measured using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) and Functional Assessment of Cancer Therapy-Fatigue (FACT-F) questionnaires at 12 wk postintervention and at 6 mo following withdrawal of support. Analysis of covariance and mixed regression were conducted. RESULTS AND LIMITATIONS: Clinically relevant improvements in FACT-P were seen at 12 wk in the intervention group compared with controls (mean difference: 8.9 points; 95% confidence interval [CI], 3.7-14.2; adjusted p=0.001). No difference was apparent at 6 mo (mean difference: 3.3 points; 95% CI, -2.6 to 9.3; adjusted p=0.27). No difference in diastolic blood pressure was seen at either follow-up (all p > 0.05). Clinically relevant improvements in FACT-F were seen at 12 wk (mean difference: 5.3 points; 95% CI, 2.7-7.9; adjusted p<0.001) and maintained following withdrawal of supervision (mean difference: 3.9 points; 95% CI, 1.1-6.8; adjusted p=0.007). Improvements in exercise tolerance and behaviour were maintained at 6 mo (adjusted p<0.001 and 0.038). CONCLUSIONS: A lifestyle intervention resulted in a clinically meaningful improvement in disease-specific QoL that was not maintained postintervention. No effect on blood pressure occurred. Durability of response was seen in fatigue and exercise behaviour. Further evaluation of support structures is essential. TRIAL REGISTRATION: ISRCTN88605738.

Assessment of endothelial dysfunction by flow-mediated dilatation in men on long-term androgen deprivation therapy for prostate cancer.

NEW FINDINGS: What is the central question of this study? Androgen deprivation therapy (ADT) for prostate cancer has been linked with increased cardiovascular risk, but the mechanisms are unclear. Is there evidence that endothelial dysfunction, as evidenced by reduced flow-mediated dilatation (FMD), is associated with ADT? What is the main finding and its importance? Reduction in FMD with preservation of glyceryl trinitrate-mediated dilatation indicates endothelial dysfunction in men with prostate cancer on long-term ADT compared with well-matched control subjects. Vascular endothelial dysfunction associated with long-term ADT for prostate cancer might explain the observed epidemiological increases in adverse cardiovascular events. Assessment of FMD may be useful in the monitoring of cardiovascular risk in men with prostate cancer on ADT. Androgen deprivation therapy (ADT) in men with prostate cancer has been linked to an increased incidence of cardiovascular events and mortality, but the underpinning mechanisms are unclear. Endothelial dysfunction is considered a precursor for cardiovascular disease. Previous studies have reported variably on the association between ADT and endothelial function. This blinded case-control study examined endothelial function, using high-resolution ultrasound to measure flow-mediated dilatation (FMD) and glyceryl trinitrate (GTN)-mediated-dilatation in the brachial artery, in 20 men with prostate cancer (69 ± 7 years old) treated by ADT (median duration 22 months, range 6-133 months) and 20 men without prostate cancer (69 ± 5 years old) matched for age, physical activity, coexistent cardiovascular disease and body mass index. The magnitude of dilatation was calculated traditionally and allometrically scaled, adjusting for baseline diameter. There were no differences between groups for resting vascular measures (means ± SD). Flow-mediated dilatation was lower in men on ADT than in control subjects (3.9 ± 2.1 versus 5.9 ± 3.8% for traditional, P = 0.047; 3.7 ± 2.7 versus 6.0 ± 2.7% for allometrically scaled, P = 0.023). Response to GTN was similar in both groups (12.2 ± 4.2 versus 14.8 ± 5.7% for traditional, P = 0.113; 12.3 ± 4.6 versus 14.4 ± 4.6% for allometrically scaled, P = 0.163). The magnitude of difference in mean FMD between groups was marginally altered to 2.4% (95% confidence interval 0.3-4.5) after adjustment for the difference in body fat mass and concomitant cardiovascular medication, with the difference in FMD remaining significant (P = 0.029). There is evidence of endothelial dysfunction in men with prostate cancer on long-term ADT. Although a causal relationship is unproven, the findings are consistent with observational reports of adverse cardiovascular outcomes associated with long-term ADT for prostate cancer.

Cardiac arrhythmia mechanisms in rats with heart failure induced by pulmonary hypertension.

Pulmonary hypertension provokes right heart failure and arrhythmias. Better understanding of the mechanisms underlying these arrhythmias is needed to facilitate new therapeutic approaches for the hypertensive, failing right ventricle (RV). The aim of our study was to identify the mechanisms generating arrhythmias in a model of RV failure induced by pulmonary hypertension. Rats were injected with monocrotaline to induce either RV hypertrophy or failure or with saline (control). ECGs were measured in conscious, unrestrained animals by telemetry. In isolated hearts, electrical activity was measured by optical mapping and myofiber orientation by diffusion tensor-MRI. Sarcoplasmic reticular Ca(2+) handling was studied in single myocytes. Compared with control animals, the T-wave of the ECG was prolonged and in three of seven heart failure animals, prominent T-wave alternans occurred. Discordant action potential (AP) alternans occurred in isolated failing hearts and Ca(2+) transient alternans in failing myocytes. In failing hearts, AP duration and dispersion were increased; conduction velocity and AP restitution were steeper. The latter was intrinsic to failing single myocytes. Failing hearts had greater fiber angle disarray; this correlated with AP duration. Failing myocytes had reduced sarco(endo)plasmic reticular Ca(2+)-ATPase activity, increased sarcoplasmic reticular Ca(2+)-release fraction, and increased Ca(2+) spark leak. In hypertrophied hearts and myocytes, dysfunctional adaptation had begun, but alternans did not develop. We conclude that increased electrical and structural heterogeneity and dysfunctional sarcoplasmic reticular Ca(2+) handling increased the probability of alternans, a proarrhythmic predictor of sudden cardiac death. These mechanisms are potential therapeutic targets for the correction of arrhythmias in hypertensive, failing RVs.

The potential role of MRI in veterinary clinical cardiology.

Over the last decade, magnetic resonance imaging (MRI) has become established as a useful referral diagnostic method in veterinary medicine that is widely used in small animal brain and spinal diseases, aural, nasal and orbital disorders, planning soft tissue surgery, oncology and small animal and equine orthopaedics. The use of MRI in these disciplines has grown due to its unparalleled capability to image soft tissue structures. This has been exploited in human cardiology where, despite the inherent difficulties in imaging a moving, contractile structure, cardiac MRI (CMRI) has become the optimal technique for the morphological assessment and quantification of ventricular function. Both CMRI hardware and software systems have developed rapidly in the last 10 years but although several preliminary veterinary CMRI studies have been reported, the technique's growth has been limited and is currently used primarily in clinical research. A review of published studies is presented with a description of CMRI technology and the potential of CMRI is discussed along with some of the reasons for its limited usage.

A Monte Carlo maximum likelihood method for estimating uncertainty arising from shared errors in exposures in epidemiological studies of nuclear workers.

Errors in the estimation of exposures or doses are a major source of uncertainty in epidemiological studies of cancer among nuclear workers. This paper presents a Monte Carlo maximum likelihood method that can be used for estimating a confidence interval that reflects both statistical sampling error and uncertainty in the measurement of exposures. The method is illustrated by application to an analysis of all cancer (excluding leukemia) mortality in a study of nuclear workers at the Oak Ridge National Laboratory (ORNL). Monte Carlo methods were used to generate 10,000 data sets with a simulated corrected dose estimate for each member of the cohort based on the estimated distribution of errors in doses. A Cox proportional hazards model was applied to each of these simulated data sets. A partial likelihood, averaged over all of the simulations, was generated; the central risk estimate and confidence interval were estimated from this partial likelihood. The conventional unsimulated analysis of the ORNL study yielded an excess relative risk (ERR) of 5.38 per Sv (90% confidence interval 0.54-12.58). The Monte Carlo maximum likelihood method yielded a slightly lower ERR (4.82 per Sv) and wider confidence interval (0.41-13.31).

Regional localisation of left ventricular sheet structure: integration with current models of cardiac fibre, sheet and band structure.

The architecture of the heart remains controversial despite extensive effort and recent advances in imaging techniques. Several opposing and non-mutually compatible models have been proposed to explain cardiac structure, and these models, although limited, have advanced the study and understanding of heart structure, function and development. We describe key areas of similarity and difference, highlight areas of contention and point to the important limitations of these models. Recent research in animal models on the nature, geometry and interaction of cardiac sheet structure allows unification of some seemingly conflicting features of the structural models. Intriguingly, evidence points to significant inter-individual structural variability (within constrained limits) in the canine, leading to the concept of a continuum (or distribution) of cardiac structures. This variability in heart structure partly explains the ongoing debate on myocardial architecture. These developments are used to construct an integrated description of cardiac structure unifying features of fibre, sheet and band architecture that provides a basis for (i) explaining cardiac electromechanics, (ii) computational simulations of cardiac physiology and (iii) designing interventions.

Role of the two-component regulator CpxAR in the virulence of Salmonella enterica serotype Typhimurium.

The CpxAR (Cpx) two-component regulator controls the expression of genes in response to a variety of environmental cues. The Cpx regulator has been implicated in the virulence of several gram-negative pathogens, although a role for Cpx in vivo has not been demonstrated directly. Here we investigate whether positive or negative control of gene expression by Cpx is important for the pathogenesis of Salmonella enterica serotype Typhimurium. The Cpx signal pathway in serotype Typhimurium was disrupted by insertional inactivation of the cpxA and cpxR genes. We also constitutively activated the Cpx pathway by making an internal in-frame deletion in cpxA (a cpxA* mutation). Activation of the Cpx pathway inhibited induction of the envelope stress response pathway controlled by the alternative sigma factor sigma(E) (encoded by rpoE). Conversely, the Cpx pathway was highly up-regulated (>40-fold) in a serotype Typhimurium rpoE mutant. The cpxA* mutation, but not the cpxA or the cpxR mutation, significantly reduced the capacity of serotype Typhimurium to adhere to and invade eucaryotic cells, although intracellular replication was not affected. The cpxA and cpxA* mutations significantly impaired the ability of serotype Typhimurium to grow in vivo in mice. To our knowledge, this is the first demonstration that the Cpx system is important for a bacterial pathogen in vivo.

Evaluation of the risk of noise-induced hearing loss among unscreened male industrial workers.

Variability in background risk and distribution of various risk factors for hearing loss may explain some of the diversity in excess risk of noise-induced hearing loss (NIHL). This paper examines the impact of various risk factors on excess risk estimates of NIHL using data from the 1968-1972 NIOSH Occupational Noise and Hearing Survey (ONHS). Previous analyses of a subset of these data focused on 1172 highly "screened" workers. In the current analysis, an additional 894 white males (609 noise-exposed and 285 controls), who were excluded for various reasons (i.e., nonoccupational noise exposure, otologic or medical conditions affecting hearing, prior occupational noise exposure) have been added 2066) to assess excess risk of noise-induced material impairment in an unscreened population. Data are analyzed by age, duration of exposure, and sound level (8-h TWA) for four different definitions of noise-induced hearing impairment, defined as the binaural pure-tone average (PTA) hearing threshold level greater than 25 dB for the following frequencies: (a) 1-4 kHz (PTA1234), (b) 1-3 kHz (PTA123), (c) 0.5, 1, and 2 kHz (PTA512), and (d) 3, 4, and 6 kHz (PTA346). Results indicate that populations with higher background risks of hearing loss may show lower excess risks attributable to noise relative to highly screened populations. Estimates of lifetime excess risk of hearing impairment were found to be significantly different between screened and unscreened population for noise levels greater than 90 dBA. Predicted age-related risk of material hearing impairment in the ONHS unscreened population was similar to that predicted from Annex B and C of ANSI S3.44 for ages less than 60 years. Results underscore the importance of understanding differential risk patterns for hearing loss and the use of appropriate reference (control) populations when evaluating risk of noise-induced hearing impairment among contemporary industrial populations.

An alternate characterization of hazard in occupational epidemiology: years of life lost per years worked.

BACKGROUND: Standardized mortality ratios (SMRs) and other measures of relative risk by themselves may not suffice as descriptors of occupational hazards for many audiences including decision-makers and those at direct risk from hazardous work. To explore other approaches, we calculated excess years of potential life lost and excess lifetime risk for both lung diseases and fatal injuries in a cohort of uranium miners with historical records of exposure to radon gas. METHODS: We used relatively simple life table (SMR) methods and also analyzed lung cancer mortality with Poisson regression methods permitting control for smoking. RESULTS: Among uranium miners hired after 1950, whose all-cause SMR was 1.5, 28 percent would experience premature death from lung diseases or injury in a lifetime of uranium mining. On average, each miner lost 1.5 yr of potential life due to mining-related lung cancer, or almost 3 months of life for each year employed in uranium mining. As a consequence of all excess lung disease and injury risks combined, a year of mining was associated with 5.9 months loss of potential life. For each year actually working underground, miners lost more than 8 months of potential life. When controlled for smoking (and healthy worker effect) with Poisson regression, the estimates for radon-related lung cancer effects were slightly larger. Although chronic disease deaths dominated in excess years of life lost (due to radon, silica and possibly other exposures), more years were lost on average per individual injury death (38 yr), than per excess lung cancer (20 yr) or other lung disease death (18 yr). Fatal-injury dominated the potential years of life lost up to about age 40. CONCLUSIONS: Years of life lost per years employed provides another, more intuitive summary of occupational mortality risk.