Initial Risk Estimates Research Articles

Predictors of recurrence after total thyroidectomy in 1,611 patients with papillary thyroid carcinoma: postoperative stimulated serum thyroglobulin and ATA initial and dynamic risk assessment.

Despite a favorable prognosis, some patients with papillary thyroid carcinoma (PTC) develop recurrence. The objective of this study was to examine the impact of the combination of initial American Thyroid Association (ATA) risk stratification with serum level of postoperative stimulated thyroglobulin (s-Tg) in predicting recurrence in patients with PTC and compare the results with an assessment of response to initial therapy (dynamic risk stratification). We retrospectively analyzed 1,611 patients who had undergone total thyroidectomy for PTC, followed in most cases (87.3%) by radioactive iodine (RAI) administration. Clinicopathological features and s-Tg levels obtained 3 months postoperatively were evaluated. The patients were stratified according to ATA risk categories. Nonstimulated thyroglobulin levels and imaging studies obtained during the first year of follow-up were used to restage the patients based on response to initial therapy. After a mean follow-up of 61.5 months (range 12-246 months), tumor recurrence was diagnosed in 99 (6.1%) patients. According to ATA risk, recurrence was identified in 2.3% of the low-risk, 9% of the intermediate-risk, and 25% of the high-risk patients (p < 0.001). Using a receiver operating characteristic curve approach, a postoperative s-Tg level of 10 ng/mL emerged as the ideal cutoff value, with positive and negative predictive values of 24% and 97.8%, respectively (p < 0.001). Patients with low to intermediate ATA risk with postoperative s-Tg levels < 10 ng/mL and excellent response to treatment had a very low recurrence rate (<0.8%). In contrast, higher recurrence rates were observed in intermediate-riskto high-risk patients with postoperative s-Tg > 10 ng/mL and indeterminate response (25%) and in those with incomplete response regardless of ATA category or postoperative s-Tg value (38.5-87.5%). Using proportion of variance explained (PVE), the predicted recurrence using the ATA initial risk assessment alone was 12.7% and increased to 29.9% when postoperative s-Tg was added to the logistic regression model and 49.1% with dynamic risk stratification. The combination of ATA staging system and postoperative s-Tg can better predict the risk of PTC recurrence. Initial risk estimates can be refined based ondynamic risk assessment following response to therapy, thus providing a useful guide for follow-up recommendations.

Cancer risk algorithms in primary care: can they impact risk estimates and referral decisions?

Cancer risk algorithms were introduced to clinical practice in the last decade, but they remain underused. In two randomised controlled experiments, we tested the impact of an unnamed cancer risk algorithm (QCancer) on GPs' risk assessment and 2-week-wait referral decisions. We also tested the impact of algorithm information, 'social proof', and a visual explanation. We presented two different samples of GPs (total n=372) with vignettes depicting patients with possible colorectal (Experiment 1) or upper GI (Experiment 2) cancers and measured their risk estimates and inclination to refer both before and after seeing the algorithmic estimate. In Experiment 1, half of the participants read information about the algorithm. In Experiment 2, half of the participants read how Experiment 1 participants had found the algorithm useful ('social proof'). Half of the participants also saw an explanatory bar graph representing the relative contribution of symptoms to the risk estimate. Both experiments provided consistent results: after seeing the algorithm, GPs' inclination to refer changed on 26% of instances. 'Social proof' enhanced the algorithm's impact on both risk estimates and referrals. Neither information about the algorithm nor the explanatory graph impacted behaviour. In both experiments, learning took place, as GPs' initial risk estimates moved closer to QCancer over time. Cancer risk algorithms have the potential to impact risk assessment and decision making and may have a role as learning tools. Informing clinicians about their proven usefulness to colleagues may maximise impact.

Probability calibration-based prediction of recurrence rate in patients with diffuse large B-cell lymphoma

BackgroundAlthough many patients receive good prognoses with standard therapy, 30–50% of diffuse large B-cell lymphoma (DLBCL) cases may relapse after treatment. Statistical or computational intelligent models are powerful tools for assessing prognoses; however, many cannot generate accurate risk (probability) estimates. Thus, probability calibration-based versions of traditional machine learning algorithms are developed in this paper to predict the risk of relapse in patients with DLBCL.MethodsFive machine learning algorithms were assessed, namely, naïve Bayes (NB), logistic regression (LR), random forest (RF), support vector machine (SVM) and feedforward neural network (FFNN), and three methods were used to develop probability calibration-based versions of each of the above algorithms, namely, Platt scaling (Platt), isotonic regression (IsoReg) and shape-restricted polynomial regression (RPR). Performance comparisons were based on the average results of the stratified hold-out test, which was repeated 500 times. We used the AUC to evaluate the discrimination ability (i.e., classification ability) of the model and assessed the model calibration (i.e., risk prediction accuracy) using the H-L goodness-of-fit test, ECE, MCE and BS.ResultsSex, stage, IPI, KPS, GCB, CD10 and rituximab were significant factors predicting the 3-year recurrence rate of patients with DLBCL. For the 5 uncalibrated algorithms, the LR (ECE = 8.517, MCE = 20.100, BS = 0.188) and FFNN (ECE = 8.238, MCE = 20.150, BS = 0.184) models were well-calibrated. The errors of the initial risk estimate of the NB (ECE = 15.711, MCE = 34.350, BS = 0.212), RF (ECE = 12.740, MCE = 27.200, BS = 0.201) and SVM (ECE = 9.872, MCE = 23.800, BS = 0.194) models were large. With probability calibration, the biased NB, RF and SVM models were well-corrected. The calibration errors of the LR and FFNN models were not further improved regardless of the probability calibration method. Among the 3 calibration methods, RPR achieved the best calibration for both the RF and SVM models. The power of IsoReg was not obvious for the NB, RF or SVM models.ConclusionsAlthough these algorithms all have good classification ability, several cannot generate accurate risk estimates. Probability calibration is an effective method of improving the accuracy of these poorly calibrated algorithms. Our risk model of DLBCL demonstrates good discrimination and calibration ability and has the potential to help clinicians make optimal therapeutic decisions to achieve precision medicine.

Comparison of the abilities of staging and risk stratification systems to predict the long-term structural recurrence in patients with differentiated thyroid carcinoma after total thyroidectomy and radioactive iodine remnant ablation.

In patients with differentiated thyroid carcinoma (DTC), various staging and risk stratification systems have been applied to estimate long-term recurrence, which is a major issue during the postoperative follow-up period. However, the efficacy of these systems remains unclear in this context. The present historical cohort study included 510 patients with DTC who underwent a total thyroidectomy followed by radioactive iodine (RAI) remnant ablation. Enrolled patients were categorized according to the 8th edition of American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) Tumor Node Metastasis (TNM) staging system, the 2015 American Thyroid Association (ATA) initial risk stratification system, and the dynamic risk stratification (DRS) system. The ability of each system to predict long-term structural recurrence was compared using proportion of variance explained (PVE) by logistic regression models. The median follow-up period was 108 months. Structural recurrence occurred in 7.6% of the patients (n=39/510). Disease-free survival (DFS) curves of the patients within each category in the TNM staging system, the ATA initial risk stratification system, and the DRS system were significantly different (P<0.001). The PVE of the DRS system (20.7%) was higher than those of the TNM staging system and the ATA initial risk estimates. The DRS system may effectively predict long-term structural recurrence and guide long-term management and follow-up strategies in patients with DTC undergoing total thyroidectomy and RAI remnant ablation.

Optimal Timing of Initiating Dynamic Risk Stratification During the Early Postoperative Period in Patients with Differentiated Thyroid Carcinoma After Thyroidectomy and Radioactive Iodine Remnant Ablation.

This study investigated the optimal timing to initiate assessment of the response to initial therapy during the early postoperative period in patients with differentiated thyroid carcinoma (DTC) using dynamic risk stratification (DRS). This historical cohort study included 510 patients with DTC who underwent a total thyroidectomy followed by radioactive iodine (RAI) remnant ablation. DRS for these patients was categorized into subgroups according to the time into the follow-up period at which the response to initial therapy was assessed. The ability of each DRS subgroup to predict the long-term structural recurrence of cancer was compared using the proportion of variance explained (PVE) from logistic regression models. The median follow-up period was 108 months. Structural recurrence occurred in 7.6% of patients (n=39/510). The PVE for long-term structural recurrence was higher among DRS subgroups (28.8-34.19%) compared with the American Joint Committee on Cancer/Union for International Cancer Control tumor-node-metastasis staging system (both the 7th and 8th editions; 4.01% and 6.13%, respectively) and the American Thyroid Association initial risk estimate (4.59%). Among the DRS subgroups, DRS assessed between 2 and 3years after the initial surgery was associated with the highest PVE (34.19%). The first assessment of DRS optimally predicts long-term structural recurrence in patients with DTC who underwent a total thyroidectomy and subsequent RAI remnant ablation at that 2- to 3-year postoperative period.

Assessment of the impact of 2015 American Thyroid Association guidelines in management of differentiated thyroid cancer patients.

A total of 138 DTC patients were stratified according to ATA 2009 and 2015 guidelines into low (LR), intermediate (IR) and high (HR) risk groups. Change in RS and in intention of RAI use was calculated. Deviation in administered RAI dosage from the guidelines was assessed. 1-year follow-up data was audited to assess how the DRS modified the initial risk estimate. A total of 11.6% of patients changed their RS categories in 2015 guidelines. A total of 10.1% got upstaged to HR, and 1.4% got downstaged to LR. In 2.17% of patients' intention of RAI use changed to remnant ablation from adjuvant therapy and 65% of the LR patients won't require any RAI therapy. A total of 26.7% of patients had received significantly more RAI dosage according to ATA 2015. At 1-year follow-up according to DRS 84% of LR, 75% of IR and 44% of HR patients showed excellent response (ER). More patients changed RS to HR than to LR. Intention of RAI use changed in only a small number of patients. Significantly higher dosage of RAI is being administered to patients in current practice. The effect of DRS in modifying the initial RS was most prominent in IR, with most showing ER to initial therapy.

Fluoroquinolones and the risk of tendon injury: a systematic review and meta-analysis.

Tendinopathy is a known adverse reaction associated to fluoroquinolones, but a meta-analysis was not yet published. The aim of this study was to conduct a systematic review and a meta-analysis of the scientific evidence evaluating the risk of tendon injury associated with fluoroquinolones. A literature search was conducted to identify observational studies which reported results on the risk of Achilles tendon rupture (ATR), risk of Achilles tendinitis (AT), or risk of any tendon disorders (ATD). A meta-analysis was performed by pooling odds ratios (ORs) with their 95% confidence intervals (CIs). Fifteen studies were included in the meta-analysis. Treatment with fluoroquinolones was associated with an increased risk of ATR (OR 2.52 (95% CI 1.81-3.52), p < 0.001, I2 = 76.7%), an increased risk of AT (OR 3.95 (95% CI 3.11-5.01), p < 0.001, I2 = 0%), and increased risk of ATD (OR 1.98 (95% CI 1.62-2.43), p < 0.001, I2 = 84.5%). The initial risk estimates remained statistically significant among patients aged ≥ 60years old. Risk estimates did not significantly change after depending on the concomitant use of corticosteroids or studies methodological quality assessment. The analysis according to the type of fluoroquinolones was only possible for ATR, which were ofloxacin and norfloxacin were found to increase the risk of this outcome, but not ciprofloxacin and levofloxacin. The results of this meta-analysis confirm the risk of tendon injuries associated with fluoroquinolones. Older age and concomitant use of corticosteroids seem to be additional risk factors for tendinopathy.

Sonographically Estimated Risks of Malignancy for Thyroid Nodules Computed with Five Standard Classification Systems: Changes over Time and Their Relation to Malignancy.

Over 50% of newly diagnosed thyroid nodules are either cytologically benign or presumed to be benign on the basis of low-suspicion sonographic findings. The strategies used for their long-term surveillance are based mainly on the estimated residual risk of malignancy calculated with various ultrasonographic classification systems (e.g., Thyroid Image Reporting and Data Systems [TIRADS]). We conducted a longitudinal study to evaluate the temporal stability of the initial risk estimates computed with five widely used systems and to determine whether risk class increases during follow-up are indeed predictive of malignancy. We re-analyzed data prospectively collected at a single academic referral center on 232 patients (age: 54.1 ± 13.7 years) with 432 asymptomatic, sonographically or cytologically benign thyroid nodules at baseline (T0) and 122 new nodules that were present five years later (T5). At both time points, the sonographically estimated risk of malignancy was calculated as recommended by the American Association of Clinical Endocrinologists/American College of Endocrinology/Associazione Medici Endocrinologi, the American College of Radiologists' TIRADS, the American Thyroid Association's 2015 practice guidelines, the European Thyroid Association's TIRADS (EU-TIRADS), and the TIRADS of the Korean Society of Thyroid Radiology (K-TIRADS). For 57 to 127 (13.2-29.4%) of the original nodules, depending on the system used, the estimated malignancy risk increased over the 5-year interval. Of the nodules whose baseline risk had not warranted cytological assessment, very few (6.3-8.3%) met the criteria for cytology at the 5-year evaluation. Biopsy was indicated for only 4 to 8 (3.3-6.6%) of the new nodules based on T5 risk estimates. Despite these changes, none of the 232 patients was ever diagnosed with a cancer. Ultrasound-based risk classes of presumably benign thyroid nodules remain fairly stable over time, and changes warranting biopsy are rare indeed. The appearance of new nodules is a frequent event, but very few (<5%) are classified as high risk, and only the 3-7% meet the criteria for cytological assessment. Collectively, these findings support the view that patients with presumably benign thyroid nodules can be safely followed with less intensive protocols.

Influence of vmPFC on dmPFC Predicts Valence-Guided Belief Formation.

When updating beliefs about their future prospects, people tend to disregard bad news. By combining fMRI with computational and dynamic causal modeling, we identified neurocircuitry mechanisms underlying this optimism bias to test for valence-guided belief formation. In each trial of the fMRI task, participants (n = 24, 10 male) estimated the base rate (eBR) and their risks of experiencing negative future events, were confronted with the actual BR, and finally had the opportunity to update their initial self-related risk estimate. We demonstrated an optimism bias by revealing greater belief updates in response to good over bad news (i.e., learning that the actual BR is lower or higher than expected) while controlling for confounds (estimation error and personal relevance of the new information). Updating was favorable when the final belief about risks improved (or at least did not worsen) relative to the initial risk estimate. This valence of updating was encoded by the ventromedial prefrontal cortex (vmPFC) associated with the valuation of rewards. Within the updating circuit, the vmPFC filtered the incoming signal in a valence-dependent manner and influenced the dorsomedial prefrontal cortex (dmPFC). Both the valence-encoding activity in the vmPFC and its influence on the dmPFC predicted individual magnitudes of the optimism bias. Our results indicate that updating was biased by the motivation to maximize desirable beliefs, mediated by the influence of the valuation system on further cognitive processing. Therefore, although it provides the very basis for human reasoning, belief formation is essentially distorted to promote desired conclusions.SIGNIFICANCE STATEMENT The question of whether human reasoning is biased by desires and goals is crucial for everyday social, professional, and economic decisions. How much our belief formation is influenced by what we want to believe is, however, still debated. Our study confirms that belief updates are indeed optimistically biased. Critically, the bias depends on the recruitment of the brain valuation system and the influence of this system on neural regions involved in reasoning. These neurocircuit interactions support the notion that the motivation to maximize pleasant beliefs reinforces those cognitive processes that are most likely to yield the desired conclusion.

Does Race Influence Risk Assessment and Recommendations for Lung Resection? A Randomized Trial

Racial disparities in use of surgical therapy for lung cancer exist in the United States. Videos of standardized patients (SPs) can help identify factors that influence physicians' surgical risk estimation. We hypothesized that physician race and SP race in videos influence surgeon decision making. Four race-neutral clinical vignettes representing lung resection candidates were paired with risk-level concordant short silent videos of SPs. Vignette/video combinations were classified as low or high risk. Trainees and practicing thoracic surgeons read a race-neutral vignette, provided an initial estimate of the percentage risk of major surgical complications, viewed a video randomized to a black or white SP, provided a final estimate of risk, and scored the likelihood that they would recommend operative therapy. Changes in risk estimates were assessed. Participants included 113 surgeons (38 practicing surgeons, 75 trainees); of these, 76 were white non-Hispanic (67%), and 37 were other self-identified racial categories. Percentage changes between initial and final risk estimates were not significantly related to patient race (p= 0.11) or surgeon race (white versus other; p= 0.52). Videos of black SPs were associated with a similar likelihood of recommending an operation compared with that of videos of white SPs (p= 0.90). Physician race (white versus other) was not related to the likelihood of recommending surgical intervention (p= 0.79). Neither patient nor physician race was significantly associated with risk estimation or surgical recommendations. These findings do not provide an explanation for documented racial disparities in lung cancer therapy. Further investigation is needed to identify the mechanism underlying these disparities.

Dynamic Risk Estimates of Outcome in Chinese Patients with Well-Differentiated Thyroid Cancer After Total Thyroidectomy and Radioactive Iodine Remnant Ablation.

This study was conducted to compare the staging systems for the prediction of long-term disease status in patients with well-differentiated thyroid carcinoma (WDTC), and to find out the earliest postoperative period predictor of long-term persistence/recurrence of disease. Patients with WDTC (n = 356; Mage = 41.5 ± 12.7 years) followed for at least five years (12.3 ± 5.0 years) after thyroidectomy and 131I remnant ablation at a tertiary regional hospital in Taiwan were retrospectively studied. Each patient was risk stratified using the American Joint Cancer Committee (stage I-IV) and American Thyroid Association (low, intermediate, and high risk) staging systems after operation and first 131I remnant ablation and using response to initial therapy reclassification (RTR; excellent, indeterminate, biochemical incomplete, and structural incomplete response) system, which is determined 6-24 months after the first 131I ablation. The clinical outcome was defined as no evidence of disease (NED; suppressed thyroglobulin [Tg] <0.5 ng/mL, stimulated Tg <1 ng/mL, and no structural detectable disease), biochemical persistent disease (BPD; suppressed Tg ≥0.5 ng/mL or stimulated Tg ≥1 ng/mL in the absence of structural disease), structural persistent disease (SPD; locoregional or distant metastases with any Tg level), or recurrent disease (RD; biochemical or structural disease identified after a period of NED). At the time of final follow-up, 78.4% (n = 279) of the patients had NED, 9.3% (n = 33) had BPD, 10.1% (n = 36) had SPD, and 2.2% (n = 8) developed RD. All three systems could predict the increasing trend of SPD and the decreasing trend of NED with advancing stage of disease. However, the ATA risk estimates could be significantly refined by the RTR system, especially for the ATA high-risk group, in which 29.2% developed SPD/RD during follow-up. The RTR system reduced the likelihood of finding SPD/RD to 3.7% in those demonstrating an excellent response to therapy, and increased the likelihood to 78.6% in those demonstrating a structural incomplete response. Among the earliest postoperative factors, only the Tg level at the first 131I ablation could predict long-term persistence/recurrence. The results highly support incorporating the RTR system to modify the initial risk estimate during follow-up among Chinese patients with WDTC.

Dynamic Risk Stratification in Patients with Differentiated Thyroid Cancer Treated Without Radioactive Iodine.

Although response to therapy assessment is a validated tool for dynamic risk stratification in patients with differentiated thyroid cancer (DTC) treated with total thyroidectomy (TT) and radioactive iodine therapy (RAI), it has not been well studied in patients treated with lobectomy or TT without RAI. Because these responses to therapy definitions are heavily dependent on serum thyroglobulin (Tg) levels, modifications of the original definitions were needed to appropriately classify patients treated without RAI. This study aimed to validate the response to therapy assessment in patients with DTC treated with lobectomy or TT without RAI. This was a retrospective study, which took place at a referral center. A total of 507 adults with DTC were treated with lobectomy (n = 187) or TT (n = 320) without RAI. They had a median age of 43.7 y, 88% were female, 85.4% had low risk, and 14.6% intermediate risk. Main outcome measured was recurrent/persistent structural evidence of disease (SED) during a median followup period of 100.5 months (24-510). Recurrent/persistent SED was observed in 0% of the patients with excellent response to therapy (nonstimulated Tg for TT < 0.2 ng/mL and for lobectomy < 30 ng/mL, undetectable Tg antibodies [TgAb] and negative imaging; n = 326); 1.3% with indeterminate response (nonstimulated Tg for TT 0.2-5 ng/mL, stable or declining TgAb and/or nonspecific imaging findings; n = 2/152); 31.6% of the patients with biochemical incomplete response (nonstimulated Tg for TT > 5 ng/mL and for lobectomy > 30 ng/mL and/or increasing Tg with similar TSH levels and/or increasing TgAb and negative imaging; n = 6/19) and all (100%) patients with structural incomplete response (n = 10/10) (P < .0001). Initial American Thyroid Association risk estimates were significantly modified based on response to therapy assessment. Our data validate the newly proposed response to therapy assessment in patients with DTC treated with lobectomy or TT without RAI as an effective tool to modify initial risk estimates of recurrent/persistent SED and better tailor followup and future therapeutic approaches. This study provides further evidence to support a selective use of RAI in DTC.

Evaluating nonindigenous species management in a Bayesian networks derived relative risk framework for Padilla Bay, WA, USA.

Many coastal regions are encountering issues with the spread of nonindigenous species (NIS). In this study, we conducted a regional risk assessment using a Bayesian network relative risk model (BN-RRM) to analyze multiple vectors of NIS introductions to Padilla Bay, Washington, a National Estuarine Research Reserve. We had 3 objectives in this study. The 1st objective was to determine whether the BN-RRM could be used to calculate risk from NIS introductions for Padilla Bay. Our 2nd objective was to determine which regions and endpoints were at greatest risk from NIS introductions. Our 3rd objective was to incorporate a management option into the model and predict endpoint risk if it were to be implemented. Eradication can occur at different stages of NIS invasions, such as the elimination of these species before being introduced to the habitat or removal of the species after settlement. We incorporated the ballast water treatment management scenario into the model, observed the risk to the endpoints, and compared this risk with the initial risk estimates. The model results indicated that the southern portion of the bay was at greatest risk because of NIS. Changes in community composition, Dungeness crab, and eelgrass were the endpoints most at risk from NIS introductions. The currents node, which controls the exposure of NIS to the bay from the surrounding marine environment, was the parameter that had the greatest influence on risk. The ballast water management scenario displayed an approximate 1% reduction in risk in this Padilla Bay case study. The models we developed provide an adaptable template for decision makers interested in managing NIS in other coastal regions and large bodies of water.

The Impact of a Frailty Education Module on Surgical Resident Estimates of Lobectomy Risk

Frailty is a risk factor for adverse events after surgery. Residents' ability to recognize frailty is underdeveloped. We assessed the influence of a frailty education module on surgical residents' estimates of lobectomy risk. Traditional track cardiothoracic surgery residents were randomly allocated to take an online short course on frailty (experimental group) or to receive no training (control group). Residents read a clinical vignette, made an initial risk estimate of major complications for lobectomy, and rated clinical factors on their importance to their estimates. They viewed a video of a standardized patient portraying the patient in the vignette, randomly selected to exhibit either vigorous or frail behavior, and provided a final risk estimate. After rating five vignettes, they completed a test on their frailty knowledge. Forty-one residents participated (20 in the experimental group). Initial risk estimates were similar between the groups. The experimental group rated clinical factors as "very important" in their initial risk estimates more often than did the control group (47.6% versus 38.5%; p < 0.001). Viewing videos resulted in a significant change from initial to final risk estimates (frail 50% ± 75% increase, p = 0.008; vigorous 14% ± 32% decrease, p = 0.043). The magnitude of change in risk estimates was greater for the experimental group (10.0 ± 8.1 versus 5.1 ± 7.7; p < 0.001). The experimental group answered more frailty test questions correctly (93.7% versus 75.2%; p < 0.001). A frailty education module improved resident knowledge of frailty and influenced surgical risk estimates. Training in frailty may help educate residents in frailty recognition and surgical risk assessment.

The Impact of Perceived Frailty on Surgeons' Estimates of Surgical Risk

Physicians are only moderately accurate in estimating surgical risk based on clinical vignettes. We assessed the impact of perceived frailty by measuring the influence of a short video of a standardized patient on surgical risk estimates. Thoracic surgeons and cardiothoracic trainees estimated the risk of major complications for lobectomy based on clinical vignettes of varied risk categories (low, average, high). After each vignette, subjects viewed a randomly selected video of a standardized patient exhibiting either vigorous or frail behavior, then reestimated risk. Subjects were asked to rate 5 vignettes paired with 5 different standardized patients. Seventy-one physicians participated. Initial risk estimates varied according to the vignette risk category: low 15.2%±11.2% risk; average 23.7%±16.1%; high 37.3%±18.9% (p<0.001 by analysis of variance). Concordant information in vignettes and videos moderately altered estimates (high risk vignette, frail video 10.6%±27.5% increase in estimate, p=0.006; low risk vignette, vigorous video 14.5%±45.0% decrease, p=0.009). Discordant findings influenced risk estimates more substantially (high risk vignette, vigorous video 21.2%±23.5% decrease in second risk estimate, p<0.001; low risk vignette, frail video 151.9%±209.8% increase, p<0.001). Surgeons differentiated relative risk of lobectomy based on clinical vignettes. The effect of viewing videos was small when vignettes and videos were concordant; the effect was more substantial when vignettes and videos were discordant. The information will be helpful in training future surgeons in frailty recognition and risk estimation.

Optimal management of a biochemical incomplete response to therapy in differentiated thyroid cancer: aggressive treatment or cautious observation?

The last 10 years has seen a renewed interest in a risk adapted management approach to differentiated thyroid cancer. We now view risk stratification as an ongoing, dynamic process that begins with initial estimates of the risk of death from thyroid cancer and risk of recurrent/ persistent disease for each patient [1]. These initial risk estimates are used to guide early management decisions and plan follow-up studies that allow us to define the response to initial therapy for each patient. As information is accumulated during follow-up, we actively modify the initial risk estimates based on the clinical course of the disease and the patient’s individual response to therapy. To facilitate classification and communication, we have previously proposed a nomenclature that can be used to describe response to therapy as either [1–3]

Perceived risk following melanoma genetic testing: a 2-year prospective study distinguishing subjective estimates from recall.

A major goal of predictive genetic testing is to alert people to their risk before illness onset; however, little is known about how risk perceptions change following genetic testing and whether information is recalled accurately over time. In the United States, a CDKN2A/p16 mutation confers 76% lifetime risk of melanoma. Following genetic counseling and test reporting, subjective risk estimates and recall of counselor-provided risk estimates were assessed 5 times over the next 2years among 60 adult members of 2 extended CDKN2A/p16 kindreds. No sustained changes from baseline in risk perceptions were reported. Unaffected carriers (n = 15) consistently reported significantly lower subjective risk estimates (46%) than they were actually given (76%, p < 0.001) or recalled having been given (60%, p < 0.001). Noncarriers' (n = 27) risk estimates decreased following results disclosure, but rebounded, with both subjective and recalled estimates subsequently exceeding what they were told by the counselor (both ps < 0.001). Affected carriers' (n = 18) risk estimates for developing a new melanoma corresponded well to counselor-provided information (p = 0.362). For all 3 patient groups, results were consistent across multiple risk measures and remained similar when demographic, phenotypic, and baseline behavioral contributors to melanoma risk were statistically controlled. These findings are consistent with other studies of risk perception, but additional studies of more diverse populations are needed to understand the reasons behind both the persistence of initial risk estimates and their divergence from information provided by the counselor during genetic counseling. Additionally, determining whether holding subjective risk perceptions that differ from counselor-provided information ultimately affects adherence to management recommendations will help guide the presentation of risk information in genetic counseling practice.

Structure–activity relationships for perfluoroalkane-induced in vitro interference with rat liver mitochondrial respiration

Perfluorinated alkyl acids (PFAAs) represent a broad class of commercial products designed primarily for the coatings industry. However, detection of residues globally in a variety of species led to the discontinuation of production in the U.S. Although PFAAs cause activation of the PPARα and CAR nuclear receptors, interference with mitochondrial bioenergetics has been implicated as an alternative mechanism of cytotoxicity. Although the mechanisms by which the eight carbon chain PFAAs interfere with mitochondrial bioenergetics are fairly well described, the activities of the more highly substituted or shorter chain PFAAs are far less well characterized. The current investigation was designed to explore structure–activity relationships by which PFAAs interfere with mitochondrial respiration in vitro. Freshly isolated rat liver mitochondria were incubated with one of 16 different PFAAs, including perfluorinated carboxylic, acetic, and sulfonic acids, sulfonamides and sulfamido acetates, and alcohols. The effect on mitochondrial respiration was measured at five concentrations and dose–response curves were generated to describe the effects on state 3 and 4 respiration and respiratory control. With the exception of PFOS, all PFAAs at sufficiently high concentrations (>20μM) stimulated state 4 and inhibited state 3 respiration. Stimulation of state 4 respiration was most pronounced for the carboxylic acids and the sulfonamides, which supports prior evidence that the perfluorinated carboxylic and acetic acids induce the mitochondrial permeability transition, whereas the sulfonamides are protonophoric uncouplers of oxidative phosphorylation. In both cases, potency increased with increasing carbon number, with a prominent inflection point between the six and eight carbon congeners. The results provide a foundation for classifying PFAAs according to specific modes of mitochondrial activity and, in combination with toxicokinetic considerations, establishing structure–activity-based boundaries for initial estimates of risk for noncancer endpoints for PFAAs for which minimal in vivo toxicity testing currently exists.

Risk stratification in medullary thyroid cancer: Moving beyond static anatomic staging

Much progress has been made over the last 10 years with regard to risk estimation in non-medullary differentiated thyroid cancer with risk of recurrence systems and response to therapy re-evaluation approaches being used to augment initial risk estimates obtained using standard anatomic staging systems. Furthermore, risk stratification is being increasingly viewed as an active, evolving, dynamic process that requires re-evaluation during follow-up rather than a single static risk estimate predicted by initial staging. As with differentiated thyroid cancer, multiple clinico-pathologic factors have been demonstrated to correlate with the risk of disease specific mortality, risk of death, likelihood of disease progression, likelihood of cure with initial therapy, and likelihood of cure with additional therapy in medullary thyroid cancer. In this review, we re-examine the clinically important initial risk factors in medullary thyroid cancer and then re-evaluate how some of these risk factors can be used to alter risk estimates over time as they reflect the response to therapy and the clinical course of the disease. We demonstrate that the same response to therapy nomenclature that we have proposed and validated in differentiated thyroid cancer (excellent response, biochemical incomplete response, structural incomplete response, indeterminant response) can be easily applied to medullary cancer and used to guide on-going clinical management.

Saving a million species: extinction risk from climate change

The research paper Extinction Risk from Climate Change published in the journal Nature in January 2004 created front-page headlines around the world. The notion that climate change could drive more than a million species to extinction captured both the popular imagination and the attention of policymakers, and provoked an unprecedented round of scientific critique. Saving a Million Species reconsiders the central question of that paper: How many species may perish as a result of climate change and associated threats? Leaders from a range of disciplines synthesize the literature, refine the original estimates, and elaborate the conservation and policy implications. This book examines the initial extinction risk estimates of the original paper, subsequent critiques, and the media and policy impact of this unique study. It presents evidence of extinctions from climate change from different time frames in the past. It explores extinctions documented in the contemporary record. It sets forth new risk estimates for future climate change. It considers the conservation and policy implications of the estimates. Saving a Million Species offers a clear explanation of the science behind the headline-grabbing estimates for conservationists, researchers, teachers, students, and policymakers. It is a critical resource for helping those working to conserve biodiversity takes on the rapidly advancing and evolving global stressor of climate change - the most important issue in conservation biology today, and the one for which we are least prepared.