Long-acting porcine ACTH stimulated salivary cortisol reduces the overdiagnosis of adrenal insufficiency compared to serum cortisol in cirrhosis liver.

BACKGROUND: There are no reliable methods in clinical practice to diagnose adrenal insufficiency (AI) in patients with cirrhosis owing to variable cortisol-binding protein levels. This leads to unreliable results in ACTH stimulated serum cortisol test. We aimed to estimate the long-acting porcine (LA)ACTH-stimulated serum and salivary cortisol levels of patients at different stages of cirrhosis using second generation electrochemiluminescence and to determine the prevalence of true adrenal insufficiency in these patients. DESIGN, PATIENTS AND MEASUREMENTS: We included 135 noncritical patients with cirrhosis (45 each from CHILD A, B and C) and 45 healthy controls. Serum and salivary samples were collected at baseline in the morning and at 1 and 2 h after LA-ACTH injection. RESULTS: In healthy subjects, the 2.5th centile of 2 h ACTH stimulated serum and salivary cortisol were 19.8 and 0.97 µg/dL, which were used as cut-offs for defining AI based on serum and saliva respectively. The median (interquartile-range) 2-h stimulated salivary cortisol in Child A, B, C categories and controls were 1.36(1.23-2.38), 1.46(1.18-2.22), 1.72(1.2-2.2) and 2.12(1.42-2.72) µg/dL respectively. Six subjects (4.4%) were diagnosed to have AI based on stimulated salivary cortisol cut-off, whereas 39 (28.9%) cirrhosis subjects had inadequately stimulated serum cortisol. Three patients (symptomatic) required steroid replacement therapy. Hypoalbuminemia was identified as a major risk factor for the misdiagnosis of adrenal insufficiency by serum cortisol-based testing. CONCLUSIONS: Long-acting porcine ACTH stimulated salivary cortisol reduces the overdiagnosis of adrenal insufficiency compared to serum cortisol in cirrhosis liver. Stimulated salivary cortisol is a promising investigation for evaluation of adrenal function in cirrhosis and more studies are required for its further validation before clinical use.

The tele-liver frailty index (TeLeFI): development of a novel frailty tool in patients with cirrhosis via telemedicine.

Frailty is a critical determinant of outcomes in cirrhosis patients. The increasing use of telemedicine has created an unmet need for virtual frailty assessment. We aimed to develop a telemedicine-enabled frailty tool (tele-liver frailty index). Adults with cirrhosis in the liver transplant setting underwent ambulatory frailty testing with the liver frailty index (LFI) in-person, then virtual administration of (1) validated surveys (eg, SARC-F and Duke Activity Status Index [DASI]), (2) chair stands, and (3) balance. Two models were selected and internally validated for predicting LFI ≥4.4 using: (1) Bayesian information criterion (BIC), (2) C-statistics, and (3) ease of use. Of 145 patients, the median (interquartile range) LFI was 3.7 (3.3-4.2); 15% were frail. Frail (vs not frail) patients reported significantly greater impairment on all virtually assessed instruments. We selected 2 parsimonious models: (1) DASI + chair/bed transfer (SARC-F) (BIC 255, C-statistics 0.78), and (2) DASI + chair/bed transfer (SARC-F) + virtually assessed chair stands (BIC 244, C-statistics 0.79). Both models had high C-statistics (0.76-0.78) for predicting frailty. In conclusion, the tele-liver frailty index is a novel tool to screen frailty in liver transplant patients via telemedicine pragmatically and may be used to identify patients who require in-person frailty assessment, more frequent follow-up, or frailty intervention.

Learning the full impact of migraine through patient voices: A qualitative study.

OBJECTIVE: To better characterize the ways that migraine affects multiple domains of life. BACKGROUND: Further understanding of migraine burden is needed. METHODS: Adults with migraine randomized to mindfulness-based stress reduction or headache education arms (n = 81) in two separate randomized clinical trials participated in semistructured in-person qualitative interviews conducted after the interventions. Interviews queried participants on migraine impact on life and were audio-recorded, transcribed, and summarized into a framework matrix. A master codebook was created until meaning saturation was reached and magnitude coding established code frequency. Themes and subthemes were identified using a constructivist grounded theory approach. RESULTS: Despite most participants being treated with acute and/or prophylactic medications, 90% (73/81) reported migraine had a negative impact on overall life, with 68% (55/81) endorsing specific domains of life impacted and 52% (42/81) describing impact on emotional health. Six main themes of migraine impact emerged: (1) global negative impact on overall life; (2) impact on emotional health; (3) impact on cognitive function; (4) impact on specific domains of life (work/career, family, social); (5) fear and avoidance (pain catastrophizing and anticipatory anxiety); and (6) internalized and externalized stigma. Participants reported how migraine (a) controls life, (b) makes life difficult, and (c) causes disability during attacks, with participants (d) experiencing a lack of control and/or (e) attempting to push through despite migraine. Emotional health was affected through (a) isolation, (b) anxiety, (c) frustration/anger, (d) guilt, (e) mood changes/irritability, and (f) depression/hopelessness. Cognitive function was affected through concentration and communication difficulties. CONCLUSIONS: Migraine has a global negative impact on overall life, cognitive and emotional health, work, family, and social life. Migraine contributes to isolation, frustration, guilt, fear, avoidance behavior, and stigma. A greater understanding of the deep burden of this chronic neurological disease is needed to effectively target and treat what is most important to those living with migraine.

Long-acting porcine ACTH stimulated salivary cortisol in the diagnosis of adrenal insufficiency.

BACKGROUND: Synacthen stimulated salivary cortisol has been previously evaluated and found beneficial in the diagnosis of adrenal insufficiency (AI), especially in situations with altered cortisol-binding protein (CBG) levels. Unfortunately, Synacthen is not marketed in many parts of the world whereas porcine sequence corticotrophin (Acton Prolongatum) is readily available. This study aimed to find the diagnostic accuracy of Acton prolongatum stimulated salivary cortisol test (APSST) compared to the short synacthen test (SST). METHODS: Consecutive outpatients with suspected AI underwent SST initially, followed by APSST after 3 days. For APSST, saliva was collected at 0, 60 and 120 minutes after administering 30 units Acton Prolongatum intramuscularly. Serum and salivary cortisol were estimated using electrochemiluminescence assay. (Cobas e 411, Elecsys Cortisol II kits) RESULTS: Sixty-seven patients with clinically suspected AI were enrolled for the study. Based on SST, 35 patients were classified as having AI [primary AI (n=19) and secondary AI (n=16)] whereas 32 had normal glucocorticoid reserve. The area under receiver operator curve of 0.99 and 0.98 was observed for salivary cortisol values at 60 and 120 minutes, respectively, for APSST. A cut-off value of 18.5 nmol/L (0.67 µg/dL) and 29.3 nmol/L (1.06 µg/dL) at 60 and 120 minutes, respectively, had a sensitivity as well as specificity of 93%-100% in diagnosing AI. CONCLUSION: Salivary cortisol estimation following stimulation using intramuscular porcine ACTH (Adrenocorticotrophic hormone) (30 units) is an economical and accurate alternative to SST in the diagnosis of AI, m and its level of 30 nmol/L or more at 2 hours confirms adrenal sufficiency.

A Multicenter Prospective Non-Randomized Study Comparing Ferguson Hemorrhoidectomy and Transanal Hemorrhoidal Dearterialization for Prolapsed, Nonincarcerated, Reducible Hemorrhoids: A Study Protocol.

INTRODUCTION: Current evidence suggests that transanal hemorrhoidal dearterialization (THD) is associated with less postoperative pain and faster recovery than Ferguson hemorrhoidectomy. However, there is some uncertainty regarding the durability of the therapeutic effect in terms of recurrent disease. Objective and significance: The aim of this study will be to evaluate the outcome of THD compared to Ferguson hemorrhoidectomy in terms of recurrence rate at 1-year follow-up. METHODS: This is a multicenter, parallel-arm, non-randomized prospective study comparing Ferguson hemorrhoidectomy and THD in terms of recurrence rate at one year. The primary endpoint is recurrence rate at one year defined as prolapsing internal hemorrhoids at physical examination. Secondary endpoints include the following postoperative complications: urinary retention, constipation (requiring laxative or emergency room visit), dysuria, pruritis ani, anal pain, anal stenosis, unhealed wound, fissure, fecal urgency, and flatus or stool incontinence. Adults older than 18 years with prolapsed, non-incarcerated, reducible hemorrhoids in at least 3 columns at physical examination will be included in one of the study arms: Ferguson hemorrhoidectomy and THD. Surgeons with proven expertise in hemorrhoids surgery will enroll patients undergoing Ferguson hemorrhoidectomy and THD (not both). Each participating surgeon will enroll a maximum of 10 patients. Ethics and Dissemination: This study was approved by the Institutional Review Boards of Stony Brook University (previously) and New York Medical College (currently), and registered in ClinicalTrials.gov (NCT03245086). The findings of the study will be published in a peer-reviewed journal.

Independent Predictors of Venous Thromboembolism in Patients Undergoing Reconstructive Breast Cancer Surgery.

INTRODUCTION: Breast cancer is a hypercoagulable state and predisposes patients to venous thromboembolism (VTE). We sought to determine independent risk factors for VTE post-surgical treatment for breast cancer using a national risk adjusted database. METHODS: Participant Use Data Files in the National Surgical Quality Improvement Program database from 2012 to 2016 were studied. Female patients with invasive and in situ breast cancer that underwent either mastectomy with immediate breast reconstruction, autologous or implant-based, or lumpectomy were identified with current procedural terminology and International Classification of Diseases-9 codes. Venous thromboembolism was defined as occurrence of deep vein thrombosis or pulmonary embolism. Non-VTE and VTE groups were compared and statistical differences were addressed through propensity score weighting. The balance of the model was checked with comparing standardized differences before and after weighting. Multivariate logistic regression was used to determine independent predictors of VTE. RESULTS: A total of 137 449 procedures were identified. After applying exclusion criteria, 40 986 lumpectomies and 35 909 mastectomies remained for the analysis (n = 76 895). Venous thromboembolism was found in 172/76 895 patients (0.2%). In the weighted data set, mastectomy, BMI> 35 and length of stay >3 days were predictors of VTE. The greatest odds ratio (OR) was observed with mastectomy with immediate autologous breast reconstruction (OR = 8.792, P < .001; 95% CI: 3.618-21.367). CONCLUSION: Autologous breast reconstruction was associated with highest risk of VTE. Hospital LOS >3 days, BMI >35, and general anesthesia also increase odds of developing VTE. These variables are predisposing factors that need to be considered in patients undergoing surgical treatment for breast cancer.

INTRODUCTION: Le cancer du sein est un état d'hypercoagulabilité qui prédispose les patients à une thromboembolie veineuse (TEV). Les chercheurs se sont attachés à déterminer les facteurs de risque indépendants de TEV après un traitement chirurgical du cancer du sein en fonction d'une base de données nationale pondérée par le risque. MÉTHODOLOGIE: Les chercheurs ont étudié les fichiers de données d'utilisation par les participants dans la base de données du NSQIP entre 2012 et 2016. Ils ont extrait les patientes atteintes d'un cancer invasif et in situ qui ont subi une mastectomie suivie d'une reconstruction mammaire immédiate, autologue ou par implant, ou une lumpectomie, à l'aide des codes de la terminologie procédurale actuelle et de la Classification internationale des maladies, 9e révision. La TEV désignait une occurrence de thrombose veineuse profonde ou d'embolie pulmonaire. Les chercheurs ont comparé les groupes sans TEV et atteints d'une TEV et évalué les différences statistiques d'après une pondération du score de propension. Ils ont vérifié le reste du modèle en comparant les différences standardisées avant et après la pondération. Ils ont utilisé la régression logistique multivariée pour déterminer les prédicteurs indépendants de TEV. RÉSULTATS: Au total, les chercheurs ont recensé 137 449 interventions. Une fois les critères d'exclusion appliqués, ils ont pu analyser 40 986 lumpectomies et 35 909 mastectomies (n=76 895). Ainsi, 176 des 76 895 patients (0,2 %) ont souffert d'une TEV. Dans la base de données pondérée, la mastectomie, un IMC supérieur à 35 et une hospitalisation de plus de trois jours étaient prédictifs d'une TEV. Le rapport de cotes (RC) le plus marqué a été observé après une mastectomie suivie d'une reconstruction mammaire autologue immédiate (RC 8,792, P<0,001; IC à 95 %, 3,618 à 21,367). CONCLUSION: La reconstruction mammaire autologue était liée au plus fort risque de TEV. Une hospitalisation de plus de trois jours, un IMC supérieur à 35 et une anesthésie générale accroissaient également le risque de TEV. Ces variables sont des facteurs prédisposants dont il faut tenir compte chez les patients qui subissent un traitement chirurgical du cancer du sein.

NSQIP Impacts Patient Experience.

National Quality Improvement Project (NSQIP) semiannual reports (SARs) revealed high observed to expected ratios for venous thromboembolic events (VTEs) on the surgical service. Press Ganey scores identified an area of particular weakness in shared decision-making in patient care. Patients reported little to no participation in shared decision-making. A performance improvement project was developed with a 2-fold objective: decrease the percentages of patients sustaining VTE through adequate screening and prophylaxis (VTEP) and to engage patients in shared decision-making to accept VTEP through enhanced patient-centered discussions and education on the risks and benefits of VTEP. A clinical pathway was developed to implement VTEP using a standardized risk assessment tool. Patient-centered discussion introduced VTEP and impact on perioperative safety. Results included telephone survey, NSQIP SARs, and Press Ganey patient experience survey. Using NSQIP data and a pathway developed for both VTE risk assessment and patient engagement, the authors observe immediate improvements in patient experience and decreased rates of VTE.

Late-Night Salivary Cortisol in Healthy, Community-Dwelling Asian Indians Assessed by Second-Generation ECLIA.

BACKGROUND: Late-night salivary cortisol (LNSC) is used as a screening test for Cushing syndrome (CS), but there is no community-derived normative data for the normal upper limit in the South Asian population. This study aimed to determine the upper limit of normal (97.5th percentile) for LNSC in an Asian Indian population using a commercially available second-generation electrochemiluminiscence immunoassay (ECLIA). METHODS: LNSC in apparently healthy community-dwelling individuals was assessed by multistage cluster sampling. Healthy individuals age 18 to 60 years from 8 urban and 8 rural clusters of Thiruvananthapuram district were studied. Thirty people from an approximate population of 1000 individuals from each cluster participated in the study. A saliva sample was collected between 11 PM and 12 midnight and analyzed using Roche COBAS-e-411 and ultrasensitive Cortisol II kits the next day. RESULTS: Cortisol values from 474 salivary samples were available for final analysis after exclusion of improperly collected samples. The 97.5th percentile of the LNSC concentrations was 0.25 µg/dL (6.89 nmol/L) (90% CI, 0.23-0.27 µg/dL; ie, 6.34-7.45 nmol/L). In postmenopausal women, median LNSC was significantly higher but the 90% CI for the upper limit of their LNSC (0.28µg/dL or 7.72 nmol/L) overlapped with that of premenopausal women. CONCLUSIONS: This study establishes the normal value of LNSC estimated by second-generation ECLIA in healthy community-dwelling Asian Indian individuals for the first time. Salivary cortisol at 11 pm to 12 am is less than 0.25µg/dL (6.89 nmol/L) in the general Asian Indian population. Menopause causes a significant increase in LNSC and may lead to overdiagnosis of CS if not interpreted carefully.

Slipped Capital Femoral Epiphysis in Primary Hyperparathyroidism - Case Report with Literature Review.

Primary hyperparathyroidism is not common in children and adolescents. Association of slipped capital femoral epiphysis and hyperparathyroidism is rare. We report the case of a 15-year-old boy who presented with pain in both hips and limping. He was diagnosed to have bilateral slipped capital femoral epiphysis (SCFE) and underwent cancellous screw fixation of both hips. He had proximal myopathy and pain at multiple points over the chest. Examination revealed an emaciated patient with genu valgum, rachitic rosary, Harrison's sulcus, and bony tenderness over the ribs. Investigations showed PTH-dependent hypercalcemia with serum calcium levels reaching >17 mg/dL and electrocardiography showing QTc shortening. Imaging revealed parathyroid adenoma. The work up for multiple endocrine neoplasia syndromes (MEN) was negative. Serum calcium was controlled by medical management and patient underwent expedited surgery. Postoperatively serum calcium levels normalized and patient became better biochemically and clinically including resolution of skeletal changes on follow-up. Only 12 cases of SCFE associated with primary hyperparathyroidism have been reported worldwide till date including the current case. The literature has been reviewed and it indicates that SCFE is associated with late adolescent age and severe hyperparathyroidism (severe bone disease, higher parathormone, serum calcium, and alkaline phosphatase levels).

Long acting porcine sequence ACTH in the diagnosis of adrenal insufficiency.

OBJECTIVES: Injectable tetracosactide hexa-acetate, ACTH 1-24 (Synacthen), is not marketed in many countries including India, whereas Injectable long acting porcine sequence, ACTH 1-39 (Acton Prolongatum®) is easily available and much cheaper. This study aimed to find the diagnostic accuracy of ACTH stimulation test using i.m. Acton Prolongatum® (acton prolongatum stimulation test, APST) in comparison with Synacthen (short synacthen test, SST) for the diagnosis of glucocorticoid insufficiency. METHODS: Subjects with a suspicion of adrenal insufficiency based on clinical features underwent a SST with 250 µg Synacthen followed by APST using 30 units of Acton Prolongatum®. Serum cortisol levels were measured at 60 and 120 min following injection of Acton Prolongatum®. Stimulated peak cortisol of less than 18 µg/dL on SST was considered as adrenal insufficiency. RESULTS: Forty seven patients with mean age of 36.7 ± 14.4 years were enrolled for the study. Based on SST, twenty (n = 20) persons were classified as having adrenal insufficiency, whereas twenty-seven (n = 27) were found to be normal. Area under the curve of APST (at 120 min) was 0.986 when compared to SST, thus proving its high accuracy. A serum cortisol cut off value of 19.5 µg/dL at 120-min following stimulation with Acton Prolongatum® showed a sensitivity of 100% and specificity of 88%. CONCLUSION: ACTH stimulation test using Acton Prolongatum® is an economical and accurate alternative to the short Synacthen test.

Implementing Daily Leadership Safety Huddles in a Public Hospital: Bridging the Gap.

BACKGROUND: A Leadership Safety Huddle was instituted in efforts to improve communication and make safety culture a priority at our institution. The Huddle is a transparent, regularly recurring forum of clinical and administrative hospital leaders, in which safety issues and concerns are identified, shared, and swiftly addressed. METHODS: Metrics regarding huddle effectiveness in 3 areas are studied: information technology (IT) services ticket resolution time, bladder catheterization, and one-to-one inpatient monitoring. RESULTS: Analysis revealed effectiveness of the huddle on quality of inpatient care and cost savings. Survey revealed 75% or higher favorable responses to huddle improving communication, transparency, time to resolution of issues, ability to voice concerns, and patient safety. As a result of huddle implementation, metrics showed 46% reduction in IT ticket turnaround time (P = .0001), 28% reduction in non-intensive care unit bladder catheter days (P = .011), and 10% decrease in continuous observations (P = .008), allowing a 24% reduction in cost (P = .001) with quarterly savings of $139 107.00. CONCLUSION: These metrics demonstrate how huddles are instrumental in infusing and sustaining a culture of patient safety in hospitals.

A comparative evaluation of the staining capacity of microhybrid and nanohybrid resin-based composite to indian spices and food colorants: An In vitro study.

INTRODUCTION: Resin composite restorative materials can mimic the natural color and shade of the tooth. However, exogenous colorants from food and drinks can stain them due to adsorption. The influence of Indian food colorants and spices on resin composite restorations has not been evaluated extensively. AIM: This study aims to evaluate the staining capacity of microhybrid and nanohybrid resin-based composites, to saffron extract, tandoori powder, and turmeric powder. SUBJECTS AND METHODS: Forty samples of microhybrid (Kulzer Charisma) and nanohybrid (3M Filtek Z350) resin composites were prepared using an acrylic template of dimension 5 mm × 3 mm. They were randomly divided into four groups and immersed into solutions of saffron extract, tandoori powder, and turmeric powder. Distilled water was used as the control group. Color values (LFNx01, aFNx01, bFNx01) were measured by colorimeter using the CIE LFNx01aFNx01bFNx01 system before and after 72 h of immersion. Color differences ΔEFNx01ab were statistically analyzed. STATISTICAL ANALYSIS USED: Two-way ANOVA and post-hoc Tukey (honest significant difference) test were done using IBM SPSS Statistics for Windows, Version 19.0. Armonk, NY: IBM Corp. RESULTS AND DISCUSSION: : All the immersion media changed the color of the resin composites to varying degrees. However, turmeric solution showed the maximum mean color variation ΔEFNx01ab of 14.8 ± 2.57 in microhybrid resin composites and 16.8 ± 3.50 in nanohybrid resin composites. CONCLUSION: Microhybrid and nanohybrid resin composites tend to stain to Indian food colorants, especially to turmeric powder.

Prevalence and Associations of Hypothyroidism in Indian Patients with Type 2 Diabetes Mellitus.

Both type 2 diabetes and hypothyroidism are highly prevalent disorders in the community. The existing data regarding prevalence of hypothyroidism in patients with diabetes comes mostly from small studies. There are only two studies with a sample size of more than 1000 diabetic patients, none of which have been done in South Asians. The present study evaluated patients with type 2 diabetes for presence of hypothyroidism and the clinical factors associated with it. The demographic, anthropometric, clinical, and biochemical parameters of consecutively enrolled patients with diabetes were systematically collected and analyzed. A total of 1152 middle aged patients with type 2 diabetes with a mean duration of diabetes of around 10 years were enrolled. Nearly 40 percent of the patients were obese and overweight, respectively, for South Asian standards and abdominal obesity was seen in around 90% patients. Clinical hypothyroidism (TSH>10 mIU/ml) was present in 113 of patients (9.83%) and another 68 patients (5.9%) had subclinical hypothyroidism (TSH 5-10 mIU/ml). Anemia (odds ratio : 2.19), overweight/obese status (odds ratio 2.07), and known dyslipidemia (odds ratio : 1.99) were found to have independent association with clinical hypothyroidism. HbA1c, abdominal obesity, poor control of hypertension, lipid parameters, microalbuminuria, and renal dysfunction showed no difference among patients with hypothyroidism when compared with euthyroid patients. Subclinical hypothyroid patients had no difference in any of the above analyzed parameters when compared to the euthyroid patients. This study shows that a significant proportion of type 2 diabetes patients suffer from clinical or subclinical hypothyroidism and screening for the same may be appropriate.

Phase I Trial of Consolidative Radiotherapy with Concurrent Bevacizumab, Erlotinib and Capecitabine for Unresectable Pancreatic Cancer.

PURPOSE: To determine the safety, tolerability and maximum tolerated dose (MTD) of addition of erlotinib to bevacizumab and capecitabine-based definitive chemoradiation (CRT) in unresectable pancreatic cancer. METHODS: Seventeen patients with CT-staged, biopsy-proven unresectable pancreatic cancer were enrolled between 3/2008 and 10/2010. Prior chemotherapy was permitted. Two patients each were enrolled at dose levels (DLs) 1-4 and 9 patients at DL 5. All patients received 50.4 Gy (GTV only) in 28 fractions with concurrent capecitabine, bevacizumab and erlotinib. Dose of each drug was escalated in 5 DLs using the continual reassessment method. Bevacizumab was escalated from 5mg/Kg q2weeks (DLs 1-4) to 10mg/Kg q2weeks (DL 5); daily erlotinib from 100mg/day (DLs 1-2) to 150 mg/Kg (DLs 3-5); and capecitabine from 400mg/m2 twice daily on days of radiation (DL 1) to 650mg/m2 (DLs 2-3) to 825 mg/m2 (DLs 4-5). Reassessment for potential resection was performed 6-8 weeks later. RESULTS: Sixteen patients received gemcitabine-based chemotherapy prior to CRT. With a median clinical follow-up of 10 months, no grade 3 toxicities were observed in DLs 1-4. Three (33%) patients at DL 5 developed a grade 3 acute toxicity (2 diarrhea, 1 rash). No grade 4 or 5 toxicities were seen. DL 4 was selected as the MTD; therefore, the recommended doses in combination with radiation are: bevacizumab, 5mg/Kg q2weeks; erlotinib, 150 mg/Kg daily; and capecitabine, 825mg/m2 BID. Median survival was 17.4 months. Of the five patients who underwent resection, 4 were originally deemed locally advanced and 1 was borderline resectable. Three patients had excellent pathological response (2 complete response and 20% viable tumor) at surgery, and the 2 patients with complete response are still alive at 61 and 67 months of follow up with no local or distant failures. CONCLUSIONS: This chemoradiation regimen at the recommended dose levels is safe and tolerable for patients with unresectable pancreatic cancer and merits further evaluation.