Modulation by Withania somnifera of stress-induced anxiogenesis and airway inflammation in rats.

OBJECTIVES: Stress is an aversive stimulus which disrupts the biological milieu of the organism and a variety of emotional and environmental stressors are known to influence allergic and immunological disorders like bronchial asthma but the pharmacological basis of such interactions is not clearly defined. Withania somnifera (ashwagandha) is a potent anti-stress agent used widely in Indian traditional medicine and the present experimental study evaluated the effects of W. somnifera extract (WSE) on chronic stress-induced neurobehavioral and immunological responses in an experimental model of allergic asthma in rats. METHODS: Wistar rats (200-250 g) were immunized and challenged with ovalbumin (OVA) and exposed to restraint stress (RS) and WSE treatments for 15 days. Following this, anxiety behavior was assessed by the elevated plus maze (EPM) test, and blood and BAL fluid samples were collected for measuring of inflammatory/immune markers by ELISA and biochemical assay. The data of the various treatment groups were analyzed by ANOVA and Tukey's test. RESULTS: Restraint stress (RS) induced anxiogenic behavior in the (EPM) test in OVA immunized rats, and this was attenuated by WSE (200 and 400 mg/kg), in a dose related manner. Examination of blood and BAL fluid in these RS exposed rats also resulted in elevations in IgE, TNF-α and IL-4 levels, which were also attenuated by WSE pretreatments. Further, WSE pretreatment neutralized the such RS induced changes in oxidative stress markers viz. elevated MDA and reduced GSH levels. CONCLUSIONS: The data pharmacologically validates role of stress in asthma and suggests that adaptogens like WSE could be a potential complementary agent for reducing anxiety as well as airway inflammation by a multi-targeted and holistic approach. The study also highlights the significance of integration of traditional and modern medical concepts in such chronic disorders.

Assessment of the Prevalence of Infections in Pediatric Patients With Acute Lymphoblastic Leukemia.

Infections cause notable treatment-related morbidity during pediatric acute lymphoblastic leukemia/lymphoma (ALL/LLy) therapy. Infections are the most critical cause of morbidity and mortality in children undergoing treatment for acute lymphoblastic leukemia (ALL). Children with ALL, who are frequently underweight, are at increased risk of community-acquired pathogens, nosocomial multidrug-resistant pathogens, and opportunistic microorganisms. A weakened immune system from ALL itself and chemotherapy's side effects further worsen the prognosis. PubMed and Google Scholar articles were curated in a Google document with shared access. Discussion and development of the paper were achieved over Zoom meetings. This narrative review aims to analyze and summarize various pathogens responsible for infections in children receiving treatment for ALL and their treatment regimen and prophylaxis. The incidence of viral infection is higher in ALL patients, followed by bacterial and fungal infections. Prevention via prophylaxis and timely initiation of treatment is essential for positive outcomes.

Efficacy and Safety of RET-Specific Kinase Inhibitors in RET-Altered Cancers: A Systematic Review.

RET proto-oncogene encodes receptor tyrosine kinase. Selpercatinib and pralsetinib are the only RET-specific tyrosine kinase inhibitors approved by FDA in RET-altered tumors. We searched PubMed, Embase, Cochrane, WOS, and Clinicaltrials.gov. Objective-response, complete-response, and partial-response were 60-89%, 0-11%, and 55-89%, respectively, with the use of RET-specific drugs. ≥Grade 3 adverse events were seen in 28-53% of the patients, with hypertension, change in ALT, QT prolongation, neutropenia, and pneumonitis among the common side effects. Hence, selpercatinib and pralsetinib were effective and well tolerated by most of the patients with RET-altered tumors.

Efficacy and toxicity of surufatinib in neuroendocrine tumors: A systematic review and meta-analysis.

The incidence and prevalence of neuroendocrine neoplasms (NENs) has increased in the US in recent decades. These are well-vascularized tumors, but no antiangiogenic drug has been approved for treatment of extra-pancreatic NENs. The aim is to assess efficacy and safety of surufatinib in pancreatic and extra-pancreatic NETs. We searched PubMed, Embase, Cochrane Library, Web of Science and Clinicaltrials.gov. Clinical trials and observational studies that provided safety and efficacy data in clinical terms were included. Characteristics of the study, baseline characteristics of participants, treatment drugs, measures of efficacy, and toxicity (≥grade 3 adverse effects) were extracted. The meta-analysis was performed using the "R" programming language. Risk ratio (RR) of objective response (OR)/partial response (PR) was 8.55 (95% CI: 1.68-43.66, I2  = 0) in favor of surufatinib. The hazard ratio (HR) of progression-free survival (PFS) was 0.48 (95% CI: 0.25-0.92, I2  = 77%) in favor of surufatinib. The risk of ≥grade 3 adverse effects: diarrhea, hypertension, hypertriglyceridemia, proteinuria, and vomiting were high with the use of surufatinib. Quality of life (QoL) was similar in surufatinib and placebo groups except for the diarrhea that was high with surufatinib. Lack of randomized clinical trials in non-Chinese population. Surufatinib is well tolerated and is more effective than placebo in both pancreatic and extra-pancreatic NETs. More multicenter randomized, double-blinded clinical trials are needed to confirm these results.

Current Status of Monoclonal Antibodies-Based Therapies in Castration-Resistant Prostate Cancer: A Systematic Review and Meta-Analysis of Clinical Trials.

Background Multiple patients with prostate cancer become resistant to castration therapies, which is termed castration-resistant prostate cancer (CRPC). Purpose The purpose of this review is to assess the status of efficacy (≥50% decline in prostate-specific antigen (PSA), progression-free survival (PFS), and overall survival (OS)) and safety (grade 3-4 adverse effects) of monoclonal antibodies in CRPC. Data source We searched databases including PubMed, Embase, Cochrane, Web of Science, and ClinicalTrials.gov. Results Hazard ratios of PFS and OS were 0.77 (95% CI = 0.69-0.87, I2 = 53%) and 0.98 (95% CI = 0.86-1.11, I2 = 40%), respectively, in the favor of monoclonal antibodies as compared to placebo. Risk ratio (RR) of >50% decline in PSA was 1.99 (95% CI = 0.97-4.08, I2 = 53%) in favor of monoclonal antibodies. Pooled incidence of >50% decline in PSA levels was 15% (95% CI = 0.1-0.23, I2 = 83%), 29% (95% CI = 0.14-0.51, I2 = 93%), 63% (95% CI = 0.49-0.76, I2 = 77%), and 88% (95% CI = 0.81-0.93, I2 = 0%) in single, two, three, and four-drug regimens, respectively. Conclusion Monoclonal antibodies are well tolerated and showed better PFS as compared to placebo. However, OS was only improved with ipilimumab. Denosumab delayed skeletal-related adverse events as compared to zoledronic acid. More multicenter double-blind clinical trials may be needed to confirm these results.

Periostin: A Potential Biomarker and Therapeutic Target in Pulmonary Diseases.

Periostin is a matricellular, nonstructural protein belonging to the fasciclin family and is encoded by the POSTN gene in humans. Periostin plays an important role in maintaining a normal tissue matrix in the lungs. Despite the vital role as a structural mediator in tissue growth and repair, periostin is involved in the pathogenic mechanism during tissue remodeling and fibrosis. Periostin is a chemoattractant mediator, promotes eosinophil recruitment and adhesion on the airways sub-epithelial membrane of asthmatic patients. POSTN gene was identified as one of the highly expressed genes induced by interleukins IL-13, IL-5 and IL-4 - the key cytokines of Th2 immune responses in the bronchial tissues of asthmatic patients. This review highlights the potential role of periostin as a validated biomarker in respiratory disease progression and its candidacy to predict the response to treatments targeting Th-2 cytokines in bronchial asthma. In addition, its potential role in COPD, IPF, lung cancer and lung infection, is also speculated.   Keywords Periostin, Asthma, Pneumonia, COPD, Idiopathic pulmonary fibrosis, Biomarker.

Imaging Spectrum of Infections in the Setting of Immunotherapy and Molecular Targeted Therapy.

Advances in genomics and immunology are revolutionizing our understanding and treatment of cancer with improved treatment outcomes and patient quality of life. With the increasing use of immunotherapy and molecular targeted therapy, a variety of unusual and/or opportunistic infections are also observed. A variety of factors including use of immunosuppression for immune-mediated adverse effects play an important role for increasing the likelihood of these infections and form the basis of this case-based review. Imaging features of infections arising in patients undergoing immunotherapy regimens have not been previously highlighted. Prompt recognition of the spectrum of mycobacterial, bacterial, invasive fungal and viral pathogens can potentially lead to reduction in the high morbidity and mortality in this patient population.

Primary Mediastinal B-Cell Lymphoma: A 2021 Update on Genetics, Diagnosis, and Novel Therapeutics.

Primary mediastinal large B-cell lymphoma (PMBCL) is an aggressive B-cell lymphoma arising from thymic B-cells having clinicopathologic features distinct from systemic diffuse large B-cell lymphoma (DLBCL). PMBCL comprises 2% to 4% of all non-Hodgkin lymphomas (NHL), 7% of DLBCL and seen predominantly in young females with a median age of 35 years at diagnosis. The annual incidence of PMBCL is 0.4 per million with a 5-year survival rate exceeding 70% with improving supportive care and genetic characterization of the disease. Pathogenesis involves dysregulation of Janus kinase-signal transducer and activator of transcription (JAK-STAT), nuclear factor-kB (NF-kB) pathways and amplification of the 9p24.1 region of chromosome 9. PMBCL patients have a prolonged life expectancy necessitating the need for treatment approaches that are based on maximizing cure with minimal long-term toxicity. Due to rarity and its recognition as a distinct entity, therapeutic decisions are guided by clinical presentation, clinician and center experience, and analysis of patients with PMBCL within DLBCL registries. Historically R-CHOP has been the usual first line treatment for PMBCL followed by involved site radiotherapy (ISRT), however clinical practice varies across centers with emerging consensus to avoid upfront RT by utilizing dose intense regimens (DA-EPOCH-R) in younger and fit patients. Prognosis of relapsed refractory PMBCL not responding to salvage chemotherapy is dismal, however there are many emerging options including Brentuximab Vedotin, immune check point inhibitors and chimeric antigen receptor T-cell therapy. In this article, we focus on the pathogenesis, current and evolving treatments, and provide recommendations for optimal management of patients with PMBCL.

Pharmacological treatment during CoViD-19 and mental health issues.

Infection outbreak has been prevalent since previous decades. The impact of infection outbreak not merely limited to physical suffering but grounded for massive mental health issues. The fear of getting contagion and persistent exposure to diverse medication and vaccination contribute enormously to develop mental health issues among people. During previous infection treatment with diverse vaccination and antiviral agent, the common mental health issues found to be a mood disorder, delirium, schizophrenia, and psychotic symptoms. Cumbersomely, it is almost impossible to treat mental health issues during the pandemic with the help of only pharmacological availability. Hence psychological intervention is also important to ameliorate better consequences. The current study highlights the impact of CoViD-19 related diverse medication and vaccination on the mental health of the people.

Effect of Cadmium Toxicity on Growth, Oxidative Damage, Antioxidant Defense System and Cadmium Accumulation in Two Sorghum Cultivars.

Heavy metal stress is a leading environmental issue reducing crop growth and productivity, particularly in arid and semi-arid agro-ecological zones. Cadmium (Cd), a non-redox heavy metal, can indirectly increase the production of reactive oxygen species (ROS), inducing cell death. A pot experiment was conducted to investigate the effects of different concentrations of Cd (0, 5, 25, 50, 100 µM) on physiological and biochemical parameters in two sorghum (Sorghum bicolor L.) cultivars: JS-2002 and Chakwal Sorghum. The results showed that various concentrations of Cd significantly increased the Cd uptake in both cultivars; however, the uptake was higher in JS-2002 compared to Chakwal Sorghum in leaf, stem and root. Regardless of the cultivars, there was a higher accumulation of the Cd in roots than in shoots. The Cd stress significantly reduced the growth and increased the electrolyte leakage (EL), hydrogen peroxide (H2O2) concentration and malondialdehyde (MDA) content in both cultivars, but the Chakwal Sorghum showed more pronounced oxidative damage than the JS-2002, as reflected by higher H2O2, MDA and EL. Moreover, Cd stress, particularly 50 µM and 100 µM, decreased the activity of different antioxidant enzymes, including superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT). However, the JS-2002 exhibited higher SOD, POD and CAT activities than the Chakwal Sorghum under different Cd-levels. These findings revealed that JS-2002 had a stronger Cd enrichment capacity and also exhibited a better tolerance to Cd stress due to its efficient antioxidant defense system than Chakwal Sorghum. The present study provides the available information about Cd enrichment and tolerance in S. bicolor, which is used as an important agricultural crop for livestock feed in arid and semi-arid regions.

Long-term Impact of E-cigarette and Vaping Product Use-associated Lung Injury on Diffusing Capacity for Carbon Monoxide Values: A Case Series.

There has been an outbreak of lung injury associated with e-cigarettes and vaping in the United States since early 2019. We present two cases who were admitted to the hospital with shortness of breath and cough. Chest imaging showed they had interstitial changes. They were diagnosed with e-cigarette and vaping product use-associated lung injury (EVALI) and treated with steroids and supportive management. With an improvement in symptoms, they were discharged home. On follow-up in the clinic, both patients were asymptomatic and had complete resolution of radiographic abnormalities. However, pulmonary function testing showed reduced diffusion capacity for carbon monoxide (DLCO). Total lung capacity (TLC), forced vital capacity (FVC), forced expiratory volume in the first one second (FEV-1), and the FEV-1/FVC ratio were normal.

Chemical analysis of Dalbergia sissoo (Roxb.) pod oil by (GC-MS) / GC-FID and evaluation of antioxidant potential.

Dalbergia sissoo (Roxb.) is one of the important plant species having extensive commercial and medicinal uses. The current study aims to assess the chemical constituents in pod oil of Dalbergia sissoo (Roxb.) by using two spectroscopic techniques i.e. GC-FID (Gas Chromatography Flame Ionization Detection) and GC-MS (Gas Chromatography Mass Spectroscopy). In GC-FID technique, nine fatty acids were identified with their respective composition, capric acid (1) (1.496%) lauric acid (2) (5.695%), myristic acid (3) (4.925%), palmitic acid (4) (10.130%), palmitoleic acid (5) (2.166%), stearic acid (6) (2.862%), oleic acid (7) (10.232%), linoleic acid (8) (22.350%) and behenic acid (9) (9.283%). In second technique, i.e. GC-MS, a series of hydrocarbons (10-37) along with two triterpenoids (38-39) were found in pod oil of the plant used. Important structure indices such as Iodine value and Saponification values were also determined. These findings can be helpful to understand the important medicinal and commercial aspects of seeds oil of the plant, like fuel value, degree of unsaturation and oxidative stability. Antioxidant testing (DPPH-Radical Scavenging Assay) was also performed on pods oil but no any significant activity was found.

The dawn of phage therapy.

Bacteriophages or phages, being the most abundant entities on earth, represent a potential solution to a diverse range of problems. Phages are successful antibacterial agents whose use in therapeutics was hindered by the discovery of antibiotics. Eventually, because of the development and spread of antibiotic resistance among most bacterial species, interest in phage as therapeutic entities has returned, because their noninfectious nature to humans should make them safe for human nanomedicine. This review highlights the most recent advances and progress in phage therapy and bacterial hosts against which phage research is currently being conducted with respect to food, human, and marine pathogens. Bacterial immunity against phages and tactics of phage revenge to defeat bacterial defense systems are also summarized. We have also discussed approved phage-based products (whole phage-based products and phage proteins) and shed light on their influence on the eukaryotic host with respect to host safety and induction of immune response against phage preparations. Moreover, creation of phages with desirable qualities and their uses in cancer treatment, vaccine production, and other therapies are also reviewed to bring together evidence from the scientific literature about the potentials and possible utility of phage and phage encoded proteins in the field of therapeutics and industrial biotechnology.

Stereotactic Body Radiotherapy for Early-Stage Multiple Primary Lung Cancers.

BACKGROUND: Patients with multiple primary lung cancers increasingly receive multiple courses of stereotactic body radiotherapy (SBRT). We aimed to clarify the efficacy and safety of such treatments. PATIENTS AND METHODS: We reviewed a prospective lung SBRT database of patients treated for stage I non-small-cell lung cancer between June 2004 and December 2015. RESULTS: A total of 374 patients received a single course of SBRT, 14 received synchronous SBRT, 48 received metachronous SBRT alone, and 108 received surgery and metachronous SBRT. Median follow-up was 37.0 months for survivors. Patients who received a single course had a 3-year overall survival (OS) of 54.2% (95% confidence interval [CI], 48.8-59.3), 3-year freedom from progression (FFP) of 67.3% (95% CI, 60.9-72.9), and grade 3 or higher toxicity of 3.5%. Compared to single-course patients, patients receiving metachronous SBRT alone and patients receiving surgery and metachronous SBRT had improved OS (79.7% [95% CI, 64.4-88.9%], P < .0001 and 95.4% [95% CI, 89.2-98.0%], P < .0001, respectively) and FFP (85.8% [95% CI, 70.7-93.5], P = .03 and 95.4% [95% CI, 89.2-98.0%], P < .0001, respectively). Patients receiving synchronous SBRT had similar OS (46.4% [95% CI, 19.3-69.9%], P = .75) and similar FFP (57.5% [95% CI, 25.3-80.0%], P = .17) as single-course patients. There were no significant differences in rates of grade 3 or higher toxicity or of grade 1 or higher toxicity between single-course patients and the other groups. CONCLUSION: Patients who received either synchronous or metachronous SBRT had no significant detriment in OS or toxicity compared to single-course patients. This supports the use of SBRT in patients with multiple primary lung cancers.

Defining Optimal Comorbidity Measures for Patients With Early-Stage Non-small cell lung cancer Treated With Stereotactic Body Radiation Therapy.

PURPOSE: Comparison of overall survival (OS) between stereotactic body radiation therapy (SBRT) and other treatments for early-stage non-small cell lung cancer is confounded by differences in age, performance status, and medical comorbidity. We sought to define the most robust measurement for this population among 5 indices: age, Eastern Cooperative Oncology Group performance status, Adult Comorbidity Evaluation 27, Charlson Comorbidity Index (CCI), and age-adjusted CCI (CCIa). METHODS AND MATERIALS: A total of 548 patients with stage I non-small cell lung cancer treated with SBRT were analyzed. Patients were divided into high- and low-risk groups for OS for each index using the log-rank test. Continuous and dichotomized models were compared via Akaike information criterion and the Vuong test. Multivariate Cox regression modeling was used with demographic information to determine the independent prognostic value of the continuous and dichotomized versions of the indices. The best was used to stratify the patients into as many significantly different cohorts as possible. RESULTS: Optimal cut-points between high-risk and low-risk OS groups for age, Eastern Cooperative Oncology Group status, Adult Comorbidity Evaluation 27, CCI, and CCIa were ≥75 years, ≥1, ≥3, ≥3, and ≥6 with hazard ratios for death of 1.23 (95% confidence interval, 1.00-1.50), 1.66 (1.28-2.15), 1.37 (1.12-1.67), 1.43 (1.17-1.76), and 1.47 (1.20-1.80), respectively. Dichotomizing did not result in a significant loss of prognostic power. Although there was no significant difference in prognostic power among the indices, CCIa best predicted OS. CCIa divided the patients into 3 cohorts with median OS of 42 months, 33 months, and 23 months for scores of ≤5, 6 to 7, and ≥8, respectively. CONCLUSIONS: CCIa was the best indicator of OS in every model employed with no loss of prognostic power with dichotomization. Dichotomization of CCIa (≥6) could be implemented in future comparisons of SBRT with OS. No cohort could be identified with a median survival of less than a year, for which treatment could be deemed futile.

Stereotactic Body Radiation Therapy for Central Early-Stage NSCLC: Results of a Prospective Phase I/II Trial.

INTRODUCTION: We report results from a prospective phase I/II trial for patients with centrally located, early-stage NSCLC receiving stereotactic body radiation therapy. METHODS: Eligible patients were medically inoperable with biopsy-proven NSCLC within 2 cm of the proximal bronchial tree or 5 mm of the mediastinal pleura or parietal pericardium. Phase I had four dose levels using 5 fractions: 9, 10, 11, and 12 Gy per fraction. The primary phase II objective was to determine if the maximum tolerated dose in phase I achieved local control greater than 80% at 2 years. RESULTS: Seventy-four patients were enrolled; 23 to phase I and 51 to phase II. Two phase I patients treated with 10 Gy × 5 fractions developed unrelated acute grade 3 lung toxicities which resolved. The phase II dose level selected was 11 Gy × 5 fractions. The median follow-up for living phase II patients was 27 months (range, 9 to 58 months). Two-year local control using 11 Gy × 5 fractions was 85% (95% confidence interval [CI]: 62%-95%). Two-year overall survival was 43% (95% CI: 28%-57%). Three patients (6%, 95% CI: 1%-17%) experienced acute grade 3 and 4 cardiac or pulmonary toxicities. Of the 41 patients evaluable for late cardiac and pulmonary toxicity, 11 (27%, 95% CI: 14%-43%) developed grade 3, 5 (12%, 95% CI: 4%-26%) developed grade 4, and 1 (4%, 95% CI: 0%-13%) died of grade 5 toxicity. CONCLUSION: Stereotactic body radiation therapy for central NSCLC using 11 Gy × 5 fractions is tolerable and has excellent local control, but is associated severe late toxicity in some patients.

Local control for clinical stage I non-small cell lung cancer treated with 5-fraction stereotactic body radiation therapy is not associated with treatment schedule.

PURPOSE: Clinical concern remains regarding the relationship between consecutive (QD) versus nonconsecutive (QoD) lung stereotactic body radiation therapy (SBRT) treatment schedules and outcomes for clinical stage I non-small cell lung cancer (NSCLC). We examined a multi-institutional series of patients receiving 5-fraction lung SBRT to compare the local failure rates and overall survival between patients receiving QD versus QoD treatment. METHODS AND MATERIALS: Lung SBRT databases from 2 high-volume institutions were combined, and patients receiving 5-fraction SBRT for a solitary stage I NSCLC were identified. QD treatment was defined as completing SBRT in ≤7 days, whereas QoD treatment was defined as completing treatment in >7 days. To control for patient characteristics between the 2 institutions, a 1:1 propensity-matched analysis was performed. Multivariable logistic regression was performed to identify variables independently associated with local failure, and Cox proportional hazards modeling to identify variables independently associated with increased mortality. RESULTS: From 2005 through 2016, 245 clinical stage I NSCLC patients receiving 5-fraction SBRT were identified. A total of 117 (47.8%) patients received QD treatment and 128 (52.2%) patients received QoD treatment. On propensity-matched analysis, no association was seen between QD treatment and local failure (odds ratio [OR] for QD treatment, 0.48; 95% confidence interval [CI], 0.12-1.99; P = .5). On multivariable logistic regression, central tumors were independently associated with increased likelihood of local recurrence (OR, 5.2; 95% CI, 1.11-24.2; P = .04). Kaplan-Meier analysis identified no difference in median overall survival between QD versus QoD treatments (38.0 vs 38.0 months, log-rank P = .7), respectively. QD treatment was not associated with an increased mortality hazard (hazard ratio, 1.08; 95% CI, 0.67-1.75; P = .75). CONCLUSIONS: This analysis demonstrated no association between QD versus QoD treatment scheduling and local control or overall survival for early-stage NSCLC.

Magnetic resonance imaging metal artifact reduction for eye plaque patient with dental braces.

PURPOSE: To determine if metal artifact reduction can minimize magnetic susceptibility artifacts in the orbits for an eye plaque brachytherapy patient with metallic dental braces. MATERIAL AND METHODS: A 62-year-old female patient with a choroidal melanoma in the right eye received a 1.5 T magnetic resonance imaging (MRI) simulation for 3D eye plaque brachytherapy planning. The protocol included conventional 3D T1-weighted and 2D T2-weighted MRIs. A vendor-supplied T2-weighted metal artifact reduction sequence was added to the protocol to reduce magnetic susceptibility artifacts from the metallic dental braces. The metal artifact reduction sequence combined turbo spin echo acquisitions, high RF excitation and readout bandwidths, and view angle tilting and slice encoding for metal artifact correction with z-shimming to correct in-plane and through-plane image distortions, respectively. RESULTS: Dental braces caused significant signal loss and image distortion in the orbits on the conventional T1-weighted and T2-weighted MRIs, and the MRIs were unusable for treatment planning. The metal artifact reduction sequence with 13 z-phase encodes minimized distortion and signal loss in the orbits, allowing the tumor to be clearly delineated. CONCLUSIONS: T2-weighted MRI with metal artifact reduction was successfully applied to minimize artifacts in the orbits resulting from the dental braces, thus allowing the MRIs to be used in 3D brachytherapy treatment planning.