Ternary Chalcogenides GeSb2Se3 and Ge3Sb4Se7 Containing a ∞1[Sb2Se2]2- 1D Chain and a 2D Structure Related to SnSe.

Ternary chalcogenides, GeSb2Se3 and Ge3Sb4Se7, were synthesized and characterized. These chalcogenides are the first ternary selenides in a ternary Ge-Sb-Se system that feature a layer structure related to black phosphorus and SnSe-type structures. Both compounds contain a ∞1[Sb2Se2]2- unit with Sb+ cations in a zigzag Sb-Sb chain structure, and Sb3+ cations in a distorted NaCl100-type of ∞1[Gen-2Sb2Sen]2+ unit (n = 4, 5). These materials exhibit n-type semiconducting properties with thermal conductivity significantly lower than that of GeSe and Sb2Se3, which could be correlated to the 1D Sb+ chain and disordered sites with different Ge/Sb compositions. It is anticipated that these newly discovered ternary chalcogenides may provide unique properties with enhanced thermoelectric properties.

Natural History of Persistent Pulmonary Subsolid Nodules: Long-Term Observation of Different Interval Growth.

BACKGROUND: The long-term natural course and outcomes of subsolid nodules (SSNs) in terms of true growth, substantial growth, and stage shift need to be clarified. METHODS: Between 2002 and 2016, 128 subjects with persistent SSNs of 3cm or smaller were enrolled. The baseline and interval changes in the series computed tomography (CT) findings during the follow-up period were subsequently reviewed. RESULTS: The mean follow-up period was 3.57±2.93years. The cumulative percentage of growth nodules of the part-solid nodule (PSN) group was significantly higher than that of the ground-glass nodule (GGN) group by Kaplan-Meier estimation (all p<0.0001). For true SSN growth, GGNs usually take a median follow-up of 7 years to grow; PSNs usually take a median follow-up of 3 years to grow. For substantial SSN growth, GGNs usually take a median follow-up of 9 years to grow; PSNs usually take a median follow-up of 3 years to grow. For stage shift, GGNs usually take a median follow-up of 12 years to grow; PSNs usually take a median follow-up of 9 years to grow. CONCLUSIONS: The natural course in terms of true growth, substantial growth, and stage shift differed significantly according to their nodule type, which could contribute to the development of follow-up guidelines and management strategy of pulmonary SSNs.

New approach to assess bioequivalence parameters using generalized gamma mixed-effect model (model-based asymptotic bioequivalence test).

In the pharmacokinetic (PK) study under a 2x2 crossover design that involves both the test and reference drugs, we propose a mixed-effects model for the drug concentration-time profiles obtained from subjects who receive different drugs at different periods. In the proposed model, the drug concentrations repeatedly measured from the same subject at different time points are distributed according to a multivariate generalized gamma distribution, and the drug concentration-time profiles are described by a compartmental PK model with between-subject and within-subject variations. We then suggest a bioequivalence test based on the estimated bioavailability parameters in the proposed mixed-effects model. The results of a Monte Carlo study further show that the proposed model-based bioequivalence test is not only better on maintaining its level but also more powerful for detecting the bioequivalence of the two drugs than the conventional bioequivalence test based on a non-compartmental analysis or the one based on a mixed-effects model with a normal error variable. The application of the proposed model and test is finally illustrated by using data sets in two PK studies.

Ba3TM2Se9 (TM = Nb, Ta): synthesis and characterization of new polyselenides.

New ternary polyselenides Ba3TM2Se9 (TM = Nb, Ta) were synthesized through a solid-state reaction, and their structures were characterized using single-crystal X-ray diffraction. These compounds crystallized into a new structural type with a monoclinic space group P21/c. The structures were constructed from distorted, close-packed layers of ∞3[BaSe3]3.33­ that incorporated TM atoms at octahedral sites and contained [(TM5+)2(Se2­)7(Se22­)] units. Diffuse reflectance spectra and electronic resistivity measurements indicated semiconducting properties and optical band gaps of 1.3 eV for Ba3Nb2Se9 and 1.6 eV for Ba3Ta2Se9. Raman spectra were used to investigate the interatomic interactions. Calculations of the electronic structure verified the semiconducting behavior and bonding interaction of short Se­Se contacts.

Prediction of the stage shift growth of early-stage lung adenocarcinomas by volume-doubling time.

Background: Prediction of subsolid nodule (SSN) interval growth is crucial for clinical management and decision making in lung cancer screening program. To the best of our knowledge, no study has investigated whether volume doubling time (VDT) is an independent factor for predicting SSN interval growth, or whether its predictive power is better than that of traditional semantic methods, such as nodular diameter or type. This study aimed to investigate whether VDT could provide added value in predicting the long-term natural course of SSNs (<3 cm) regarding stage shift. Methods: This retrospective study enrolled 132 patients with spectrum lesions of lung adenocarcinoma who underwent two consecutive computed tomography (CT) examinations before surgical tissue proofing between 2012 and 2021 in Kaohsiung Veterans General Hospital. The VDTs were manually calculated from the volumetric segmentation using Schwartz's approximation formula. We utilized logistic regression to identify predictors associated with stage shift progression based on the VDT parameter. Results: The average duration of follow-up period was 3.629 years. A VDT-based nomogram model (model 2) based on CT semantic features, clinical characteristics, and the VDT parameter yielded an area under the curve (AUC) of 0.877 [95% confidence interval (CI): 0.807-0.928]. Compared with model 1 (CT semantic features and clinical characteristics), model 2 exhibited the better predictive performance for stage shift (AUC model 1: 0.833 versus AUC model 2: 0.877, P=0.047). In model 2, significant predictors of stage shift growth included initial nodule size [odds ratio (OR) =4.074, 95% CI: 1.368-12.135; P=0.012], SSN classification (OR =0.042; 95% CI: 0.006-0.288; P=0.001), follow-up period (OR =1.692, 95% CI: 1.337-2.140; P<0.001), and VDT classification (OR =2.327, 95% CI: 1.368-3.958; P=0.002). For the stage shift, the mean progression time for the VDT (>400 d) group was 7.595 years, and median progression time was 7.430 years. Additionally, a VDT ≤400 d is an important prognostic factor associated with aggressive growth behavior with a stage shift. Conclusions: VDT is crucial for predicting SSN stage shift growth irrespective of clinical and CT semantic features. This highlights its significance in informing follow-up protocols and surgical planning, emphasizing its prognostic value in predicting SSN growth.

A Retrospective Analysis: Investigating Factors Linked to High Lung-RADS Scores in a Nonsmoking, Non-Family History Population.

Low-dose computed tomography screening for lung cancer is currently targeted at heavy smokers or those with a family history of lung cancer. This study aimed to identify risk factors for lung cancer in individuals who do not meet the current lung cancer screening criteria as stipulated by the Taiwan Health Promotion Agency's low-dose computed tomography (LDCT) screening policy. A cohort analysis was conducted on 12,542 asymptomatic healthy subjects aged 20-80 years old who voluntarily underwent LDCT scans from January 2016 to December 2021. Logistic regression demonstrated that several factors, including age over 55 years, female gender, a body mass index (BMI) less than 23, a previous history of respiratory diseases such as tuberculosis or obstructive respiratory diseases (chronic obstructive pulmonary disease [COPD], asthma), and previous respiratory symptoms such as cough or dyspnea, were associated with high-risk lung radiology scores according to LDCT scans. These findings indicate that risk-based assessments using primary data and questionnaires to identify risk factors other than heavy smoking and a family history of lung cancer may improve the efficiency of lung cancer screening.

Highly bright broadband red light produced by fluorescence polymer/InGaN hybrid light-emitting diodes.

The fabrication of fluorescence polymer/InGaN hybrid light-emitting diodes (LEDs) that emit highly bright broadband red light is presented in this Letter. The absorption peak of the fluorescence polymer was 455 nm, and the emission peak was 640 nm. The light output power and external quantum efficiency of hybrid LEDs at a driving current of 100 mA were 46.6 mW and 24.1%, respectively. The emission spectrum of hybrid LEDs was located at a wavelength of 641 nm, with a broadband FWHM of 106 nm. Thus this study offers potential methods for enhancing the output power of commercial white-light-emitting devices.

Prediction of Interval Growth of Lung Adenocarcinomas Manifesting as Persistent Subsolid Nodules ≤3 cm Based on Radiomic Features.

RATIONALES AND OBJECTIVES: To investigate the prognostic value of the radiomic-based prediction model in predicting the interval growth rate of persistent subsolid nodules (SSNs) with an initial size of ≤ 3 cm manifesting as lung adenocarcinomas. MATERIALS AND METHODS: A total of 133 patients (mean age, 59.02 years; male, 37.6%) with 133 SSNs who underwent a series of CT examinations at our hospital between 2012 and 2022 were included in this study. Forty-one radiomic features were extracted from each volumetric region of interest. Radiomic features combined with conventional clinical and semantic parameters were then selected for radiomic-based model building. To investigate the model performance in terms of substantial SSN growth and stage shift growth, the model performance was compared by the area under the curve (AUC) obtained by receiver operating characteristic analysis. RESULTS: The mean follow-up period was 3.62 years. For substantial SSN growth, a radiomic-based model (Model 2) based on clinical characteristics, CT semantic features, and radiomic features yielded an AUCs of 0.869 (95% CI: 0.799-0.922). In comparison with Model 1 (clinical characteristics and CT semantic features), Model 2 performed better than Model 1 for substantial SSN growth (AUC model 1:0.793 versus AUC model 2:0.869, p = 0.028). A radiomic-based nomogram combining sex, follow-up period, and three radiomic features was built for substantial SSN growth prediction. For the stage shift growth, a radiomic-based model (Model 4) based on clinical characteristics, CT semantic features, and radiomic features yielded an AUCs of 0.883 (95% CI: 0.815-0.933). Compared with Model 3 (clinical characteristics and CT semantic features), Model 4 performed better than the model 3 for stage shift growth (AUC model 1: 0.769 versus AUC model 2: 0.883, p = 0.006). A radiomic-based nomogram combining the initial nodule size, SSN classification, follow-up period, and three radiomic features was built to predict the stage shift growth. CONCLUSION: Radiomic-based models have superior utility in estimating the prognostic interval growth of patients with early lung adenocarcinomas (≤ 3 cm) than conventional clinical-semantic models in terms of substantial interval growth and stage shift growth, potentially guiding clinical decision-making with follow-up strategies of SSNs in personalized precision medicine.

Managing Persistent Subsolid Nodules in Lung Cancer: Education, Decision Making, and Impact of Interval Growth Patterns.

With the popularization of lung cancer screening, many persistent subsolid nodules (SSNs) have been identified clinically, especially in Asian non-smokers. However, many studies have found that SSNs exhibit heterogeneous growth trends during long-term follow ups. This article adopted a narrative approach to extensively review the available literature on the topic to explore the definitions, rationale, and clinical application of different interval growths of subsolid pulmonary nodule management and follow-up strategies. The development of SSN growth thresholds with different growth patterns could support clinical decision making with follow-up guidelines to reduce over- and delayed diagnoses. In conclusion, using different SSN growth thresholds could optimize the follow-up management and clinical decision making of SSNs in lung cancer screening programs. This could further reduce the lung cancer mortality rate and potential harm from overdiagnosis and over management.

Mineralocorticoid receptor antagonist treatment improved arterial stiffness in patients with primary aldosteronism: a cohort study compared with adrenalectomy.

Background: Elevated arterial stiffness in patients with primary aldosteronism (PA) can be reversed after adrenalectomy; however, the effect of medical treatment with mineralocorticoid receptor antagonist (MRAs) is unknown. Objectives: The aim of this study was to evaluate the effect of MRAs and compare both treatment strategies on arterial stiffness in PA patients. Design: Prospective cohort study. Methods: We prospectively enrolled PA patients from 2006 to 2019 who received either adrenalectomy or MRA treatment (spironolactone). We compared their baseline and 1-year post-treatment biochemistry characteristics and arterial pulse wave velocity (PWV) to verify the effects of treatment and related determinant factors. Results: A total 459 PA patients were enrolled. After 1:1 propensity score matching for age, sex and blood pressure (BP), each group had 176 patients. The major determinant factors of baseline PWV were age and baseline BP. The adrenalectomy group had greater improvements in BP, serum potassium level, plasma aldosterone concentration, and aldosterone-to-renin ratio. The MRA group had a significant improvement in PWV after 1 year of treatment (1706.2 ± 340.05 to 1613.6 ± 349.51 cm/s, p < 0.001). There were no significant differences in post-treatment PWV (p = 0.173) and improvement in PWV (p = 0.579) between the adrenalectomy and MRA groups. The determinant factors for an improvement in PWV after treatment were hypertension duration, baseline PWV, and the decrease in BP. Conclusion: The PA patients who received medical treatment with MRAs had a significant improvement in arterial stiffness. There was no significant difference in the improvement in arterial stiffness between the two treatment strategies.

Multinary selenides with unusual coordination environment of bismuth.

New multinary selenides Ae3SnPn2Se8 (Ae = Sr, Ba; Pn = Sb, Bi), Sr8.01Ge2.04Bi7.95Se24, and Sr8YGe2Bi7Se24 were synthesized by solid-state reaction, and their structures were determined by single-crystal X-ray diffraction. These compounds crystallize in orthorhombic space group Pnma (no. 62) for Ae3SnPn2Se8 (Ae = Sr, Ba; Pn = Sb, Bi) and in Pna21 (no. 33) for Sr8.01Ge2.04Bi7.95Se24 and Sr8YGe2Bi7Se24. The structures feature one-dimensional corner sharing tetrahedral (∞)(1)[MSe3] units, and one-dimensional edge sharing octahedral ∞1[M4Se10], packed with the alkaline earth or rare earth cations. Sr8.01Ge2.04Bi7.95Se24 and Sr8YGe2Bi7Se24 contain a triple cell superlattice structure derived from a special arrangement of Bi and Ge in the tetrahedrally coordinated ∞1[MSe3] chain. Diffuse reflectance spectra and electronic resistivity measurements indicate semiconducting behaviors; the Sr8YGe2Bi7Se24 Seebeck coefficient is −180 µV/K at 303 K. Electronic structure calculations confirm that the electron count for Sr8YGe2Bi7Se24 is optimal for interatomic bonding in the ionic network.

Impact of Smoking Status on Lung Cancer Characteristics and Mortality Rates between Screened and Non-Screened Lung Cancer Cohorts: Real-World Knowledge Translation and Education.

This was a retrospective hospital-based cohort study of participants diagnosed with lung cancer in the lung cancer register database, and our goal was to evaluate the impact of smoking and screening status on lung cancer characteristics and clinical outcomes. According to the hospital-based lung cancer register database, a total of 2883 lung cancers were diagnosed in 2883 patients between January 2007 and September 2017, which were divided into four groups according to smoking and screening status. A comparison was performed in terms of clinical characteristics and outcomes of lung cancer between the four groups. For non-smokers, age, gender, screened status, tumor size, targeted therapy, and curative surgery were independent prognostic factors of overall survival for lung cancer subjects. However, screened status and gender were not significant prognostic factors for lung cancer survival in smokers with lung cancer. For the non-smoker group, about 4.9% of lung cancer subjects (N = 81) were detected by screening. However, only 0.97% of lung cancer subjects (N = 12) were detected by screening in smokers. This could be attributed to smokers' negative attitudes and low socioeconomic status preventing LDCT lung cancer screening. In summary, our real-world data suggest that effectively encouraging smokers to be more willing to participate in lung cancer screening programs with screening allowance and educational training in the future is an important issue.

Diabetes mellitus is associated with worse baseline and less post-treatment recovery of arterial stiffness in patients with primary aldosteronism.

BACKGROUND: Aldosterone excess in primary aldosteronism (PA) has been linked to insulin resistance, and diabetes mellitus has been associated with increased arterial stiffness and worse cardiovascular outcomes. However, the impact of diabetes on baseline and post-treatment arterial stiffness in patients with PA is unknown. METHODS: This study prospectively enrolled 1071 PA patients, of whom 177 had diabetes and 894 did not. Clinical, biochemical, and brachial-ankle pulse wave velocity (baPWV) data were analyzed at baseline and 1 year after PA-specific treatment. After propensity score matching of age, sex, body mass index, systolic and diastolic blood pressure, hypertension duration, and number of antihypertensive medications, 144 patients with diabetes and 320 without diabetes were included for further analysis. RESULTS: After propensity score matching, the baseline characteristics were balanced between the diabetes and nondiabetes groups except for fasting glucose, HbA1c, and lipid profiles. The patients with diabetes had significantly worse baseline baPWV compared with those without diabetes. After multivariable linear regression, the presence of diabetes mellitus remained a significant predictor of worse baseline mean baPWV (ß: 46.3, 95% confidence interval: 2.9-89.7, p = 0.037). After 1 year of PA-specific treatment, only the nondiabetes group had significant recovery of mean baPWV (1661.8 ± 332.3 to 1565.0 ± 329.2 cm/s, p < 0.001; Δ = -96.8 ± 254.6 cm/s). In contrast, the diabetes group had less improvement (1771.2 ± 353.8 cm/s to 1742.0 ± 377.2 cm/s, p = 0.259; Δ = -29.2 ± 263.2 cm/s) even though the systolic and diastolic blood pressure significantly improved in both groups. CONCLUSION: The presence of diabetes mellitus in PA patients was associated with worse baseline and less post-treatment recovery of arterial stiffness.

[Modulation of Toll-like signal path of allergic asthma by CpG-ODNs from Bordetella pertussis].

This study focused on prevention and treatment of acute and chronic asthma by oligonucleotides containing unmethylated CpG motifs (CpG-ODNs). Acute and chronic asthma models of mice were made by sensitizing and inhaling ovalbumin (OVA); The number of white blood cells (WBC) and eosnophils (EOS) in bronchoalveolar lavage fluid (BALF) was counted and the concentration of cytokines and vascular endothelial growth factor (VEGF) was examined in BALF by ELISA kit. After that, TLR-9 mRNA was detected in mice spleen cells by reverse transcription polymerase chain reaction (RT-PCR) and TLR-9 protein was determined in mice lung tissues by Western blotting. Compared with acute asthma models of mice, WBC in BALF decreased obviously in the groups of Bordetella pertussis, CpG-ODNs and seq A to seq I which were administrated by both of intragastric (ig) and intraperitoneal (ip) injection group, EOS decreased obviously in Bordetella pertussis, CpG+ and seq A to seq D ig groups, and in all ip administrating groups, although it was not effective in the groups of seq E to seq I. In chronic asthma models of mice, IFN-gamma increased ((1) control: 176.45 +/- 23.46 pg x mL(-1); (2) model: 174.11 +/- 22.71 pg x mL(-1); (3) CpG+ ip: 220.56 +/- 15.42 pg x mL(-1); (4) seq A ip: 225.23 +/- 21.60 pg x mL(-1)) and IL-4 decreased obviously (1) control: 66.91 +/- 5.81 pg x mL(-1); (2) model: 81.02 +/- 11.24 pg x mL(-1); (3) CpG+ ip: 63.99 +/- 6.09 pg x mL(-1); (4) seq A ip: 62.75 +/- 10.03 pg x mL(-1)) in the BALF of CpG+ and seq A ip group, although VEGF was not changed in this research. And also, TLR-9 mRNA in spleen cells (TLR-9/GAPDH: (1) control: 0.62 +/- 0.13; (2) model: 0.66 +/- 0.17; (3) CpG+ ip: 1.46 +/- 0.26; (4) seq A ip: 1.42 +/- 0.34) and TLR-9 protein in lung tissues (TLR-9/beta-actin: (1) control: 0.63 +/- 0.16; (2) model: 0.61 +/- 0.07; (3) CpG+ ip: 1.15 +/- 0.25; (4) seq A ip: 1.03 +/- 0.29) both increased in ip groups, but the change was not significant in ig group. The study confirms that CpG-ODNs and seq A could inhibit airway inflammation remarkably, this mechanism might be related with regulating Th1/Th2 balance and controlling the expression of TLR-9.

Prognostic effect of implementation of the mass low-dose computed tomography lung cancer screening program: a hospital-based cohort study.

Low-dose computed tomography lung cancer screening aims to detect early-stage lung cancers in order to decrease the incidence of advanced-stage lung cancers and to reduce lung cancer mortality. We analyzed the time trends of lung cancer stage distribution and mortality rates after the gradual implementation of the low-dose computed tomography lung cancer screening in a hospital-based cohort. Using the hospital-based cancer registry data on lung cancer number and death from 2007 to 2014, we aim to evaluate the trends in stage distribution and mortality rate after the gradual implementation of low-dose computed tomography lung cancer screening program over recent years. From 2007 to 2014, overall 2542 cases of lung cancers were diagnosed according to hospital-based cancer registry. For the 1-year mortality rate, the mortality rate decreased gradually from 48.16 to 37.04% between 2007 and 2014. For the 5-year mortality rate, the mortality rate decreased gradually from 88.49 to 69.44% between 2007 and 2014. There was a gradual decrease in stage IV lung cancer with the corresponding sharp increase in stage I early lung cancer after following the implementation of the large volume of the low-dose computed tomography examination between the years 2011 and 2014. In conclusion, these results suggest that the gradual implementation of low-dose computed tomography lung screening program could lead to a remarkable decrease in lung cancer mortality and a remarkable stage shift in the trend over time in this hospital-based cohort.

Malignant Pleural PEComa: A Previously Undocumented Site.

Perivascular epithelioid cell (PEC) tumors are rare tumors of mesenchymal origin and can affect many anatomic regions. Although these tumors are usually benign, malignant variants exist. We document for the first time a malignant PEComa arising from the pleura of a 43-year-old Malay woman. The pathology of the tumor as well as differential diagnoses is discussed.

Multiple testing for bioequivalence with pharmacokinetic data in 2 x 2 crossover designs.

To evaluate globally the average bioequivalence of a test drug to a reference drug in a pharmacokinetic (PK) study under a 2 x 2 crossover design, we consider directly comparing the associated drug concentration-time curves. Statistical models for the drug concentrations are suggested when the concentrations measured at different time points are distributed according to a generalized gamma distribution and the mean concentrations over time is described by a one-compartment PK model. A multiple test based on the supreme distance between the two curves over the time interval under study is then proposed for testing the equivalence of the two drug concentration-time curves. The results of a Monte Carlo study suggest that, comparative to the conventional univariate and bivariate tests, the proposed test is more powerful for detecting the global bioequivalence and superior on maintaining its level when the global bioequivalence is violated. The application of the proposed tests is finally illustrated by using the data in a PK study involving two brands of benzbromarone tablets for reducing the uric acid.

Synthesis and phase width of quaternary selenides Pb4In(x)M(6-x)Se13 (M = Bi, x = 2.1-2.8; Sb, x = 2).

Quaternary selenides of Pb(4)In(x)M(6-x)Se(13) (M = Bi, x = 2.1-2.8; Sb, x = 2) were synthesized by solid-state methods, and their structures were determined from X-ray diffraction of single crystals. These compounds are isostructural with Pb(4)In(2)Bi(4)S(13) and crystallize in orthorhombic space group Pbam (No. 55) with Z = 4; the structure features a three-dimensional framework consisting of Z-shaped ribbon units and corner-sharing infinite one-dimensional [InSe(4)](infinity) chains running parallel to the c-axis, which are connected by Pb atoms to form a three-dimensional structure. Calculations of the band structure and measurements of Seebeck coefficient, electrical conductivity, and diffuse reflectance spectra confirm that these compounds are semiconductors with a narrow band gap. All compounds show semiconducting properties; the Seebeck coefficient of Pb(4)In(2.5)Bi(3.5)Se(13) is -180 microV/K at 295 K.

Differences in lung cancer characteristics and mortality rate between screened and non-screened cohorts.

Screening programs for lung cancer aim to allow diagnosis at the early stage, and therefore the decline in mortality rates. Thus, the aim of this retrospective cohort study was to the comparison of screened and non-screened lung cancer in terms of lung cancer characteristics, overdiagnosis and survival rate. A retrospective study in which 2883 patients with 2883 lung cancer diagnosed according to the hospital-based lung cancer register database between 2007 and 2017. A comparison was performed in term of clinical characteristics and outcomes of lung cancer between the screened and non-screening patient groups. 2883 subjects were identified (93 screened and 2790 non-screened). Screened group patients were younger (59.91 ± 8.14 versus 67.58 ± 12.95; p < 0.0001), and were more likely to be female than non-screened group (61.3% versus 36.8%; p < 0.0001). The screened group showed significantly better outcomes in overall mortality than the non-screened group (10.75% versus 79.06%; <0.0001). In a Cox proportional hazard model, lung cancer in the screened group proved to be an independent prognostic factor in lung cancer subjects. Our findings point to the improved survival outcome in the screened group and might underline the benefit of low-dose computed tomography (LDCT) screening program in Asian populations with the high prevalence of non-smoking-related lung cancer. Further study aimed at the LDCT mass screening program targeting at light smokers and non-smoker outside of existing screening criteria is warranted.