Clinical biomarker-based biological age predicts deaths in Brazilian adults: the ELSA-Brasil study.

Biological age is a construct that seeks to evaluate the biological wear and tear process of the organism that cannot be observed by chronological age. We estimate individuals' biological age based on biomarkers from multiple systems and validate it through its association with mortality from natural causes. Biological age was estimated in 12,109 participants (6621 women and 5488 men) from the first visit of the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) who had valid data for the biomarkers used in the analyses. Biological age was estimated using the Klemera and Doubal method. The difference between chronological age and biological age (Δage) was computed. Cox proportional hazard models stratified by sex were used to assess whether Δage was associated with mortality risk after a median follow-up of 9.1 years. The accuracy of the models was estimated by the area under the curve (AUC). Δage had equal mean for men and women, with greater variability for men. Cox models showed that every 1-year increase in Δage was associated with increased mortality in men (HR (95% CI) 1.21; 1.17-1.25) and women (HR (95% CI) 1.24; 1.15-1.34), independently of chronological age. Results of the AUC demonstrated that the predictive power of models that only included chronological age (AUC chronological age = 0.7396) or Δage (AUC Δage = 0.6842) was lower than those that included both, chronological age and Δage (AUC chronological age + Δage = 0.802), in men. This difference was not observed in women. We demonstrate that biological age is strongly related to mortality in both genders and is a valid predictor of death in Brazilian adults, especially among men.

Healing and long-term prognosis of root-fractured permanent teeth: a retrospective longitudinal study.

AIM: The purpose of the present study was to evaluate permanent teeth with post-traumatic transversal root fractures, for their initial healing modality, the effect of candidate predictors and their long-term prognosis. METHODOLOGY: A retrospective longitudinal clinical study was conducted to evaluate records from patients bearing transversal root fractures in permanent teeth in order to radiographically assess short-term healing and non-healing events in the fracture line, their prognostic factors and their relationship with long term outcomes. The inter-fragmentary tissues were classified as healing: hard tissue (HT), connective tissue (CT) or connective tissue and bone (CT + B) and non-healing: interposition of granulation tissue (GT). A competing risk survival analysis was conducted to estimate the hazards of healing and non-healing events in the short-term and the effect of demographic, clinical, and treatment variables was assessed using the subdistribution regression model (Fine & Gray). RESULTS: Radiographic findings showed 61.4% of healing in the short-term being strongly influenced by the presence and type of concomitant injuries to the coronal fragment. Teeth with concomitant crown fractures (sHR 24.38, 95% CI [3.16-188.3], p = 0.0022), luxations with dislocations (sHR 10.58, 95% CI [1.37-81.9], p = 0.0240) and subluxations (HR 9.66, 95% CI [1.14-81.7], p = 0.0370) were more likely to present non-healing of root fractures in the short-term. The healing rate in the long-term was of 75.9%, most of them with interposition of bone and connective tissue. Kappa statistics demonstrated an overall agreement of 67.1% between short and long-term healing patterns, in special HT and CT + Bone modalities. CONCLUSION: Healing at the fracture site was the most frequent outcome, both in the short-term and in the long-term. Short-term healing modality was strongly influenced by the presence and type of concomitant injuries to the crown fragment, being the worst prognosis observed in root-fractured teeth with concomitant crown fractures, followed by concomitant luxations with dislocation. CLINICAL RELEVANCE: Post-traumatic transversal root fractures have a positive prognosis supporting therefore, a more conservative approach for these teeth before considering more radical treatments.

A retrospective cohort study of pulp prognosis in luxated permanent teeth: a competing risk analysis.

AIM: The present retrospective cohort study aimed to evaluate luxated permanent teeth for pulp prognosis and risk factors. METHODOLOGY: Case records and radiographs of 224 patients, involving 427 luxated permanent teeth, referred for treatment at the Dental Trauma Center-School of Dentistry, Universidade Federal de Minas Gerais, (DTC-SD-UFMG) from 2014 to 2022, were assessed for pulp prognosis classified as vitality, necrosis and pulp canal obliteration (PCO). A competing risk survival analysis estimated the hazards of the three outcomes, and the effect of demographic, clinical and treatment variables was tested using a cause specific Cox regression model. RESULTS: Pulp vitality was found in163 teeth (38.2%), pulp necrosis in 120 teeth (28.1%) and 55 teeth (12.9%) developed PCO. Pulp vitality decreased in the presence of concomitant crown fractures (HR 0.38 95% CI [0.2-0.8] p = 0.006). The risk of pulp necrosis (HR 0.62 95% CI [0.4-0.96] p = 0.03) was lower in cases with open apices but increased with concomitant crown fractures (HR 4.0 95% CI [2.6-6.1] p = 0.001) and intrusions (HR 2.3 95% CI [1.2-4.1] p = 0.007). Lateral or extrusive luxations (HR 3.0 95% CI [1.3-6.9] p = 0.001) and open apices (HR 2.4 95% CI [1.2-4.7] p = 0.01) showed higher rates of PCO. CONCLUSION: Type of luxation, the diameter of the apical foramen, and the presence of concomitant crown fractures were main determinants of pulp prognosis after luxation injuries in permanent teeth. CLINICAL RELEVANCE: Pulp prognosis after tooth luxation is dependent on the presence and direction of tooth displacement together with infection control. CLINICAL TRIAL REGISTRATION: Not applicable.

Skeletal muscle mass increases after viral eradication with direct-acting antivirals in patients with chronic hepatitis C: A longitudinal study.

BACKGROUND: Results of studies evaluating the effect of viral eradication following direct-acting antiviral (DDA) therapy on skeletal muscle mass of patients with chronic hepatitis C (CHC) are scarce. AIM: To assess the components of sarcopenia (low muscle mass, low muscle strength and low physical performance) in a cohort of CHC individuals before and after DAA therapy. METHODS: We performed a longitudinal study of patients with CHC who underwent body composition assessment before (T0), and at 12 (T1) and 48 (T2) weeks after DDA therapy. Bioelectrical Impedance Analysis was used to assess skeletal mass muscle (SM) and phase angle (PhA). SM index (SMI) was calculated by dividing the SM by squared height. Muscle function was evaluated by hand grip strength (HGS) and timed up-and-go (TUG) test. Mixed-effects linear regression models were fitted to SMI, HGS and physical performance and were used to test the effect of HCV eradication by DAA. RESULTS: 62 outpatients (mean age, 58.6 ± 10.8 years; 58% with compensated cirrhosis) were included. Significant decreases in liver fibrosis markers and an increase of 0.20 and 0.22 kg/m2 in the SMI were observed at T1 and T2. Following DAA therapy, an increase of one unit of PhA was associated with a reduction of 0.38 min in TUG. CONCLUSION: HCV eradication with DAA therapy was associated with a dynamic reduction of non-invasive markers of liver fibrosis and increased muscle mass in 62 patients with CHC who had an undetectable HCV load at 12 weeks after completion of antiviral treatment.

Agreement and diagnostic differences among three definitions of sarcopenia in patients with chronic hepatitis C.

BACKGROUND: There is neither a gold standard definition nor a universal consensus to diagnose sarcopenia in patients with chronic hepatitis C. Thus, we aimed to compare the prevalence of sarcopenia and the agreement and discrepancies between European Working Group on Sarcopenia in Older People (EWGSOP1), EWGSOP2, and Foundation for the National Institutes of Health Biomarkers Consortium Sarcopenia Project (FNIH) definitions in chronic hepatitis C. METHODS: Dual-energy x-ray absorptiometry was used to assess muscle mass by quantifying appendicular lean mass (ALM) adjusted for squared height (ALM/ht2) or for body mass index (ALMBMI). Muscle function was evaluated by handgrip strength. Subjective Global Assessment was used to assess the nutrition status. RESULTS: This cross-sectional study included 103 outpatients (mean age, 50.6 ± 11.3 years; 33.0% with compensated cirrhosis). Sarcopenia prevalence was 8.7%, 9.7%, and 9.7%, according to EWGSOP1, EWGSOP2, and FNIH definitions, respectively. There was neither a sex- nor a liver disease severity-specific difference in the prevalence of sarcopenia between the criteria applied. Sixteen (15.5%) patients fulfilled at least one of these criteria, and 3 out of 16 (18.8%) simultaneously had sarcopenia by consensus of the three criteria. Sarcopenic obesity was identified in 9 out of 16 (56.3%) patients, and 6 out of 9 (66.7%) of these only met FNIH consensus. CONCLUSIONS: In patients without cirrhosis or with compensated cirrhosis, and with chronic hepatitis C, the agreement between EWGSOP1 and EWGSOP2 classifications was substantial for sarcopenia diagnosis. Concerning EWGSOP and FNIH criteria, a fair agreement and limited overlap were found in these patients.

Effect of polypharmacy and Fall-Risk-Increasing Drugs (FRIDs) on falls among Brazilian older adults: The SABE cohort study.

Polypharmacy, considered as the use of multiple medications, has been one of the factors associated with a higher risk of falls among older adults. However, the association of this factor regardless of the use of Fall-Risk-Increasing Drugs (FRIDs) has not been extensively explored. OBJECTIVES: This study aimed to evaluate the longitudinal association of polypharmacy with falls and verify whether this association is independent of FRID use. METHODS: A longitudinal study was conducted with a representative sample of the urban population aged 60 years and over in the city of São Paulo, Brazil, from 2000 to 2006. The analysis of the association among polypharmacy, the use of FRIDs, and the occurrence of falls over the years was performed using Generalized Estimating Equation (GEE) models adjusted for covariates. RESULTS: The association between polypharmacy and falls was significantly attenuated after the adjustment for covariates and FRIDs. Users of two or more FRIDs had higher odds of falls (OR = 1.51; CI [1.16; 1.96]). CONCLUSION: FRID use was associated with the occurrence of falls among older adults. The number of medications must be kept to the minimum necessary, and FRIDs should be avoided in approaches to preventing falls among older adults.

Sarcopenia in chronic viral hepatitis: From concept to clinical relevance.

Although the frequency of metabolic risk factors for cirrhosis and hepatocellular carcinoma (HCC) is increasing, chronic hepatitis B (CHB) and chronic hepatitis C (CHC) remain the most relevant risk factors for advanced liver disease worldwide. In addition to liver damage, hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are associated with a myriad of extrahepatic manifestations including mixed cryoglobulinaemia, lymphoproliferative disorders, renal disease, insulin resistance, type 2 diabetes, sicca syndrome, rheumatoid arthritis-like polyarthritis, and autoantibody production. Recently, the list has grown to include sarcopenia. Loss of muscle mass or muscle function is a critical feature of malnutrition in cirrhotic patients and has been found in approximately 23.0%-60.0% of patients with advanced liver disease. Nonetheless, among published studies, there is significant heterogeneity in the aetiologies of hepatic diseases and measurement methods used to determine sarcopenia. In particular, the interaction between sarcopenia, CHB and CHC has not been completely clarified in a real-world setting. Sarcopenia can result from a complex and multifaceted virus-host-environment interplay in individuals chronically infected with HBV or HCV. Thus, in the present review, we provide an overview of the concept, prevalence, clinical relevance, and potential mechanisms of sarcopenia in patients with chronic viral hepatitis, with an emphasis on clinical outcomes, which have been associated with skeletal muscle loss in these patients. A comprehensive overview of sarcopenia in individuals chronically infected with HBV or HCV, independent of the stage of the liver disease, will reinforce the necessity of an integrated medical/nutritional/physical education approach in the daily clinical care of patients with CHB and CHC.

Association of preterm birth with poor metabolic outcomes in schoolchildren.

OBJECTIVE: To investigate, at school age, the metabolic profile of children born preterm. METHODS: A cross-sectional study of children 5 to 8 years old, born with gestational age (GA) < 34 weeks and/or weight ≤ 1,500 grams. Clinical and anthropometric data were assessed by a single trained pediatrician. Biochemical measurements were done at the organization's Central Laboratory using standard methods. Data on health conditions, eating, and daily life habits were retrieved from medical charts and through validated questionnaires. Binary logistic and linear regression models were built to identify the association between variables, weight excess, and GA. RESULTS: Out of 60 children (53.3% female), 6.8 ± 0.7 years old, 16.6% presented excess weight, 13.3% showed increased insulin resistance markers and 36.7% had abnormal blood pressure values. Those presenting excess weight had higher waist circumferences and higher HOMA-IR than normal-weight children (OR = 1.64; CI = 1.035-2.949). Eating and daily life habits were not different among overweight and normal-weight children. The small-for-gestational-age (SGA) and appropriate-for-gestational-age (AGA, 83.3%) birth weight children did not differ regarding clinical (body weight, blood pressure) or biochemical variables (serum lipids, blood glucose, HOMA-IR). CONCLUSION: Schoolchildren born preterm, regardless of being AGA or SGA, were overweight, and presented increased abdominal adiposity, reduced insulin sensitivity, and altered lipid profile, justifying longitudinal follow-up regarding adverse metabolic outcomes in the future.

Prevalence of traumatic dental injuries in emergency dental services: A systematic review and meta-analysis.

OBJECTIVES: This study aimed to perform a systematic review and meta-analysis regarding the prevalence of traumatic dental injuries (TDI) in emergency dental services. METHODS: Seven electronic and two grey literature databases were searched, up to December 2021, for studies that reported the TDI prevalence among dental emergencies. The Joanna Briggs Institute critical appraisal checklist for prevalence studies, and The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach were used to assess the risk of bias and quality of evidence respectively. The R software was used to perform a proportion meta-analysis on a random-effects model to estimate the pooled prevalence and respective 95% CI. RESULTS: From a total of 1476 studies identified after excluding duplicates, 38 met the inclusion criteria, and another five were identified through hand searching, summing 43 included observational studies with a total sample of 209099 individuals searching for emergency dental care. The overall pooled prevalence of TDI was 15.4% (95% CI: 11%-21%, I² = 100%). Paediatric dental emergency services and age group from 0 to 21 years presented the highest prevalence, 29% (95% CI: 22%-38%, I² = 99.5%) and 24% (95% CI: 15%-35%, I² = 98%) respectively. CONCLUSIONS: The overall pooled prevalence of TDI in emergency dental services was 15.4%, and 24% in the age group under 21 years. Considering the impact of prompt and correct emergency care in the long-term prognosis of TDI, such knowledge is relevant to organize emergency healthcare and support public policies in this area.

Association of preterm birth with poor metabolic outcomes in schoolchildren

Abstract Objective: To investigate, at school age, the metabolic profile of children born preterm. Methods: A cross-sectional study of children 5 to 8 years old, born with gestational age (GA) < 34 weeks and/or weight ≤ 1,500 grams. Clinical and anthropometric data were assessed by a single trained pediatrician. Biochemical measurements were done at the organization's Central Laboratory using standard methods. Data on health conditions, eating, and daily life habits were retrieved from medical charts and through validated questionnaires. Binary logistic and linear regression models were built to identify the association between variables, weight excess, and GA. Results: Out of 60 children (53.3% female), 6.8 ± 0.7 years old, 16.6% presented excess weight, 13.3% showed increased insulin resistance markers and 36.7% had abnormal blood pressure values. Those presenting excess weight had higher waist circumferences and higher HOMA-IR than normal-weight children (OR = 1.64; CI = 1.035-2.949). Eating and daily life habits were not different among overweight and normal-weight children. The small-for-gestational-age (SGA) and appropriate-for-gestational-age (AGA, 83.3%) birth weight children did not differ regarding clinical (body weight, blood pressure) or biochemical variables (serum lipids, blood glucose, HOMA-IR). Conclusion: Schoolchildren born preterm, regardless of being AGA or SGA, were overweight, and presented increased abdominal adiposity, reduced insulin sensitivity, and altered lipid profile, justifying longitudinal follow-up regarding adverse metabolic outcomes in the future.

Pharmacogenomic markers of glucocorticoid response in congenital adrenal hyperplasia.

Glucocorticoids (GC) replacement are the mainstay treatment for 21-hydroxylase deficiency (21-OHD), the most common cause of congenital adrenal hyperplasia (CAH), in its classical form. There are novel insights into the genetic basis of the GC action diversity that point to an important role for GC receptor (GR) gene polymorphisms, suggesting a possible modulation in occurrence of metabolic disorders, what may be relevant to clinical management of 21-OHD. The aim of this study was to investigate whether the five GR gene polymorphisms Tth111I, ER22, 23EK, BclI, 9ß (rs10052957, rs6189, rs6190, rs41423247, rs6198) and their combination into haplotypes are associated to different GC response in a cohort of classic 21-OHD subjects. GR genotype-phenotype associations were explored after a dexamethasone suppression test using very low-doses (VLD-DST), 20 and 40 µg/m². The final sample (n = 28) was selected based on the 102 individuals' previous genotypes classification, according to literature data of GC sensitivity or resistance. Thus, only patients with GC increased resistance (n = 18) or increased sensitivity (n = 10) profiles were selected. Out of 28 subjects aged 12 (2-34) years enrolled in this study, 75% were females, 75% presented the salt-wasting form (SW) and 25% the simple virilizing form (SV). Subjects who carried Tth111I and 9ß, associated or not to the ER22/23EK variants, showed an impaired DST response. Results did not differ significantly according to gender or body mass index. SV subjects with GC hypersensitivity-genotypes showed decreased average cortisol levels compared to those with GC resistance-genotypes (p = 0.0023). The Tth111I + 9ß/ Wild or Tth111I + ER22/23EK + 9ß/ Wild genotypes were associated to GC resistance in this population. This finding may be relevant given the challenges posed by therapeutic management with GC in CAH.

COVID-19 pandemic and the answer of science: a year in review.

The world is looking forward to a prompt response by the scientific community in order to overcome the first pandemic of the 21st century. This study aimed to provide an overview of scientific output on COVID-19 during its first year. We assembled information regarding 60,830 articles related to COVID-19 indexed in the WoS database from January 24 to December 13, 2020. Only 4 countries accounted for about 60% of the articles (USA, China, Italy, and England) and 12 countries accounted for about 95% of the world scientific output on COVID-19 (USA, China, Italy, England, India, Canada, Germany, Spain, Australia, Brazil, Iran, and Turkey). 25 research centers around the world contributed with more than 500 papers on COVID-19. Papers were scattered throughout 6,133 journals, with 12 journals with > 250 articles. 20 articles (0.03%) have already received more than the 1,000 citations. The response of the scientific endeavor to this acute global public health emergency has been fast and robust. The overview provided by the analysis of the scientific response to the pandemic may contribute to further studies aiming to evaluate the impact and changes in the scientific endeavor for the next years in light of the forthcoming new world framework.

Expression of matrix metalloproteinases 2 and 9 in replanted teeth with external root resorption: A cross-sectional study.

OBJECTIVE: To evaluate matrix metalloproteinase (MMP) expression in replanted permanent teeth with external root resorption (ERR). DESIGN: The present cross-sectional study included 42 patients with replanted permanent teeth, presenting with progressive forms of ERR, and referred for extraction according to the rehabilitation treatment plan or due to root fractures. The control group consisted of 12 healthy premolars, from 5 patients with good periodontal health and no radiographic evidence of root resorption, referred for extraction for orthodontic reasons. Root fragments were processed soon after extraction, and the supernatant was collected to measure matrix metalloproteinase 2/tissue inhibitor of metalloproteinase 2 (MMP-2/TIMP-2) and matrix metalloproteinase 9/tissue inhibitor of metalloproteinases 2 (MMP-9/TIMP-2) complexes through a double-ligand enzyme-linked immunosorbent assay (ELISA). RESULTS: Case groups with external inflammatory root resorption (EIRR) or external replacement root resorption (ERRR) showed significantly higher levels of MMP-2/TIMP-2 and MMP-9/TIMP-2 complexes than the control group. Additionally, comparisons between the case groups demonstrated that the MMP-2/TIMP-2 complex also had significantly higher levels in the ERRR group (p < 0.001). CONCLUSIONS: Our results suggest that MMP-2 and MMP-9 participate in the pathobiology of both types of ERR. In addition, the higher levels of MMP-2/TIMP-2 complex in the ERRR group support common modulation mechanisms with physiological bone turnover.

Pulp healing in immature replanted permanent teeth: A competing risk analysis.

BACKGROUND/AIM: Tooth displacement during avulsion causes total rupture of the pulp's neurovascular supply. Revascularization and pulp healing may occur in immature teeth, which gives rise to the recommendation that root canal treatment may not be required. The aim of this study was to evaluate the prognostic factors for the pulp's response after replantation of young permanent teeth. METHODS: Records from 117 patients with 133 replanted permanent immature teeth were reviewed, and pulp outcomes were classified as healing (hard tissue deposition on the dentinal walls followed by narrowing of the pulp lumen or ingrowth of bone-like tissue inside the pulp canal) or non-healing (pulp necrosis with infection). The effect of clinical and demographic co-variates on the hazards of both outcomes was assessed performing a competing risk model. RESULTS: Pulp necrosis with infection was diagnosed in 78.2% of the teeth, and healing was observed in 12.8% of the teeth. A total of 12 teeth (9.0%) were censored due to prophylactic removal of the pulp or severe external root resorption caused by eruption of adjacent canines. The cs-Cox model demonstrated that the hazards of pulp healing increased in teeth with extra-alveolar periods <15 min (csHR: 7.83, 95% CI 1.76-34.80, p = .01), while the hazards of pulp necrosis with infection decreased (csHR: 0.31, 95% CI: 0.10-0.92, p = .04). Teeth replanted with Moorrees' stages 4 and 5 of root development had higher hazards of pulp necrosis with infection than teeth with stage 2 of root development (csHR: 2.23, 95% CI 1.11-4.50, p = .03; csHR: 2.89, 95% CI: 1.40-5.95; p = .01). CONCLUSIONS: Pulp healing rarely occurred after replantation of young permanent teeth being associated with short extra-alveolar periods <15 min. Early stages of root development decreased the hazards of pulp necrosis with infection.

Interval-censored data with misclassification: a Bayesian approach.

Survival data involving silent events are often subject to interval censoring (the event is known to occur within a time interval) and classification errors if a test with no perfect sensitivity and specificity is applied. Considering the nature of this data plays an important role in estimating the time distribution until the occurrence of the event. In this context, we incorporate validation subsets into the parametric proportional hazard model, and show that this additional data, combined with Bayesian inference, compensate the lack of knowledge about test sensitivity and specificity improving the parameter estimates. The proposed model is evaluated through simulation studies, and Bayesian analysis is conducted within a Gibbs sampling procedure. The posterior estimates obtained under validation subset models present lower bias and standard deviation compared to the scenario with no validation subset or the model that assumes perfect sensitivity and specificity. Finally, we illustrate the usefulness of the new methodology with an analysis of real data about HIV acquisition in female sex workers that have been discussed in the literature.

Derivation and validation of a simple anthropometric equation to predict fat-free mass in patients with chronic hepatitis C.

BACKGROUND: Loss of skeletal muscle mass is very common in chronic liver diseases and affects 30.0-70.0% of the patients with cirrhosis. Given the relevance of muscle wasting in hepatic diseases, a practical screening tool for earlier detection of skeletal muscle mass loss is of utmost significance. AIMS: To develop and validate a simple anthropometric prediction equation for fat-free mass estimation by using Bioelectrical Impedance Analysis (BIA) as a reference method in patients with chronic hepatitis C (CHC). METHODS: We prospectively, included 209 CHC patients, randomly allocated into two groups, 158 patients in a development model (derivation sample) and 51 patients in a validation group (validation sample). Predictive equations were developed using backward stepwise multiple regression and the most adequate and simplest derived predictive equation was further explored for agreement and bias in the validation sample. The accuracy of the predictive equation was evaluated using the coefficient of determination (R2). RESULTS: The predictive equation with an optimal R2 was Fat-Free Mass (Kg) = Sex × 0.17 + Height (m) × 16.83 + Weight (Kg) × 0.62 + Waist Circumference (cm) × (-0.15) + Weight (Kg) × Sex × (-0.30) + Sex × Waist Circumference (cm) × 0.14-6.23; where sex = 1 for female and 0 for male. R2 = 0.93, standard error of the estimate = 2.6 Kg and coefficient of variation = 20.0%, p < 0.001. CONCLUSIONS: Our developed and cross-validated anthropometric prediction equation for fat-free mass estimation by using BIA attained a high coefficient of determination, a low standard error of the estimate, and lowermost coefficient of variation. This study indicates that predictive equations may be reliable and useful alternative methods for clinical evaluation of fat-free mass in patients with CHC.

Impact of incorporating echocardiographic screening into a clinical prediction model to optimise utilisation of echocardiography in primary care.

INTRODUCTION: Access to public subspecialty healthcare is limited in underserved areas of Brazil, including echocardiography (echo). Long waiting lines and lack of a prioritisation system lead to diagnostic lag and may contribute to poor outcomes. We developed a prioritisation tool for use in primary care, aimed at improving resource utilisation, by predicting those at highest risk of having an abnormal echo, and thus in highest need of referral. METHODS: All patients in the existing primary care waiting list for echo were invited for participation and underwent a clinical questionnaire, simplified 7-view echo screening by non-physicians with handheld devices, and standard echo by experts. Two derivation models were developed, one including only clinical variables and a second including clinical variables and findings of major heart disease (HD) on echo screening (cut point for high/low-risk). For validation, patients were risk-classified according to the clinical score. High-risk patients and a sample of low-risk underwent standard echo. Intermediate-risk patients first had screening echo, with a standard echo if HD was suspected. Discrimination and calibration of the two models were assessed to predict HD in standard echo. RESULTS: In derivation (N = 603), clinical variables associated with HD were female gender, body mass index, Chagas disease, prior cardiac surgery, coronary disease, valve disease, hypertension and heart failure, and this model was well calibrated with C-statistic = 0.781. Performance was improved with the addition of echo screening, with C-statistic = 0.871 after cross-validation. For validation (N = 1526), 227 (14.9%) patients were classified as low risk, 1082 (70.9%) as intermediate risk and 217 (14.2%) as high risk by the clinical model. The final model with two categories had high sensitivity (99%) and negative predictive value (97%) for HD in standard echo. Model performance was good with C-statistic = 0.720. CONCLUSION: The addition of screening echo to clinical variables significantly improves the performance of a score to predict major HD.

Firth adjusted score function for monotone likelihood in the mixture cure fraction model.

Models for situations where some individuals are long-term survivors, immune or non-susceptible to the event of interest, are extensively studied in biomedical research. Fitting a regression can be problematic in situations involving small sample sizes with high censoring rate, since the maximum likelihood estimates of some coefficients may be infinity. This phenomenon is called monotone likelihood, and it occurs in the presence of many categorical covariates, especially when one covariate level is not associated with any failure (in survival analysis) or when a categorical covariate perfectly predicts a binary response (in the logistic regression). A well known solution is an adaptation of the Firth method, originally created to reduce the estimation bias. The method provides a finite estimate by penalizing the likelihood function. Bias correction in the mixture cure model is a topic rarely discussed in the literature and it configures a central contribution of this work. In order to handle this point in such context, we propose to derive the adjusted score function based on the Firth method. An extensive Monte Carlo simulation study indicates good inference performance for the penalized maximum likelihood estimates. The analysis is illustrated through a real application involving patients with melanoma assisted at the Hospital das Clínicas/UFMG in Brazil. This is a relatively novel data set affected by the monotone likelihood issue and containing cured individuals.