Dose-Dense Docetaxel-Cyclophosphamide and Epirubicin-Cisplatin(ddDCEP): Analysis of an Alternative Platinum-Containing Regimen in 116 Patients with Early Triple Negative Breast Cancer.

We assessed the efficacy, tolerability, and cost-effectiveness of a novel neoadjuvant regimen comprising docetaxel-cyclophosphamide alternating with epirubicin-cisplatin (ddDCEP) administered biweekly for 16 weeks in 116 patients with early triple-negative breast cancer. This regimen achieved a high pathological complete response (ypT0/TisN0) rate of 55.2% and favorable survival outcomes (30-month event-free survival, 91.2%; overall survival, 97%). Febrile neutropenia was observed in 4.3% of patients, and 98% completed at least six of eight cycles. ddDCEP was more cost-effective than contemporary carboplatin-based regimens. This novel approach offers an economically viable and effective alternative to current chemoimmunotherapy regimens, and merits further investigation.

Microbial machinery dealing diverse aromatic compounds: Decoded from pelagic sediment ecogenomics in the gulfs of Kathiawar Peninsula and Arabian Sea.

Aromatic hydrocarbons are persistent pollutants in aquatic systems as endocrine disruptors, significantly impacting natural ecosystems and human health. Microbes perform as natural bioremediators to remove and regulate aromatic hydrocarbons in the marine ecosystem. The present study focuses upon the comparative diversity and abundance of various hydrocarbon-degrading enzymes and their pathways from deep sediments along the Gulf of Kathiawar Peninsula and Arabian Sea, India. The elucidation of large number of degradation pathways in the study area under the presence of a wide range of pollutants whose fate needs to be addressed. Sediment core samples were collected, and the whole microbiome was sequenced. Analysis of the predicted ORFs (open reading frames) against the AromaDeg database revealed 2946 aromatic hydrocarbon-degrading enzyme sequences. Statistical analysis portrayed that the Gulfs were more diverse in degradation pathways compared to the open sea, with the Gulf of Kutch being more prosperous and more diverse than the Gulf of Cambay. The vast majority of the annotated ORFs belonged to groups of dioxygenases that included catechol, gentisate, and benzene dioxygenases, along with Rieske (2Fe-2S) and vicinal oxygen chelate (VOC) family proteins. From the sampling sites, only 960 of the total predicted genes were given taxonomic annotations, which mention the presence of many under-explored marine microorganism-derived hydrocarbon degrading genes and pathways. Through the present study, we tried to unveil the array of catabolic pathways of aromatic hydrocarbon degradation and genes from a marine ecosystem that upholds economic and ecological significance in India. Thus, this study provides vast opportunities and strategies for microbial resource recovery in marine ecosystems, which can be investigated to explore aromatic hydrocarbon degradation and their potential mechanisms under various oxic or anoxic environments. Future studies should focus on aromatic hydrocarbon degradation by considering degradation pathways, biochemical analysis, enzymatic, metabolic, and genetic systems, and regulations.

MRI features of spinal chronic recurrent multifocal osteomyelitis/chronic non-bacterial osteomyelitis in children.

BACKGROUND: Spinal lesions in pediatric chronic recurrent multifocal osteomyelitis/chronic non-bacterial osteomyelitis (CRMO/CNO) can cause permanent sequelae; thus, early recognition of these is vital for management. OBJECTIVE: To characterize the MR imaging features and patterns of pediatric spinal CRMO/CNO. MATERIALS AND METHODS: This cross-section study received IRB approval. The first available MRI with documented spine involvement in children with CRMO/CNO was reviewed by a pediatric radiologist. Descriptive statistics were used to describe the characteristics of vertebral lesions, disc involvement, and soft tissue abnormality. RESULTS: Forty-two patients were included (F:M, 30:12); median age was 10 years (range 4-17). At diagnosis, 34/42 (81%) had spine involvement. Kyphosis in 9/42 (21%) and scoliosis in 4/42 (9.5%) patients were present at the time of spinal disease recognition. Vertebral involvement was multifocal in 25/42 (59.5%). Disc involvement was found in 11/42 (26%) patients, commonly in the thoracic spine and often with adjacent vertebrae height loss. Posterior element abnormalities were present in 18/42 patients (43%) and soft tissue involvement in 7/42 (17%). One hundred nineteen vertebrae were affected, commonly the thoracic vertebrae (69/119; 58%). Vertebral body edema was focal in 77/119 (65%) and frequently superior (42/77; 54%). Sclerosis and endplate abnormality were present in 15/119 (13%) and 31/119 (26%) vertebrae, respectively. Height loss was present in 41/119 (34%). CONCLUSION: Chronic non-bacterial osteomyelitis of spine is usually thoracic. Vertebral body edema is often focal at the superior vertebral body. Kyphosis and scoliosis occur in a quarter and vertebral height loss in a third of children at spinal disease recognition.

An Unguided, Computerized Cognitive Behavioral Therapy Intervention (TreadWill) in a Lower Middle-Income Country: Pragmatic Randomized Controlled Trial.

BACKGROUND: Globally, most individuals who are susceptible to depression do not receive adequate or timely treatment. Unguided computerized cognitive behavioral therapy (cCBT) has the potential to bridge this treatment gap. However, the real-world effectiveness of unguided cCBT interventions, particularly in low- and middle-income countries (LMICs), remains inconclusive. OBJECTIVE: In this study, we aimed to report the design and development of a new unguided cCBT-based multicomponent intervention, TreadWill, and its pragmatic evaluation. TreadWill was designed to be fully automated, engaging, easy to use, and accessible to LMICs. METHODS: To evaluate the effectiveness of TreadWill and the engagement level, we performed a double-blind, fully remote, and randomized controlled trial with 598 participants in India and analyzed the data using a completer's analysis. RESULTS: The users who completed at least half of the modules in TreadWill showed significant reduction in depression-related (P=.04) and anxiety-related (P=.02) symptoms compared with the waitlist control. Compared with a plain-text version with the same therapeutic content, the full-featured version of TreadWill showed significantly higher engagement (P=.01). CONCLUSIONS: Our study provides a new resource and evidence for the use of unguided cCBT as a scalable intervention in LMICs. TRIAL REGISTRATION: ClinicalTrials.gov NCT03445598; https://clinicaltrials.gov/ct2/show/NCT03445598.

Anemia requiring transfusion in breast cancer patients on dose-dense chemotherapy: Prevalence, risk factors, cost and effect on disease outcome.

PURPOSE: Dose-dense chemotherapy improves survival but with increased toxicity and treatment-related cost. We report the prevalence of anemia and the possible risk factors associated with chemotherapy-related anemia and determine the cost and time-delay associated with transfusion requirement in Indian patients with non-metastatic breast cancer on dose-dense preoperative chemotherapy. METHODS: In this study, triple-negative breast cancer (TNBC) patients were treated preoperatively with docetaxel and cyclophosphamide alternating with epirubicin and cisplatin every 2 weeks. Patients were evaluated for anemia pre- and post-chemotherapy. We examined trends in the red cell indices, transfusion requirement, time to transfusion, as well as risk factors associated with transfusion during treatment, along with delay in treatment due to anemia and the additional cost incurred. RESULTS: A total of 116 consecutive women with nonmetastatic TNBC were treated with preoperative chemotherapy. The median age was 44.5 years. 56.1% of patients had stage III disease. Anemia was detected at baseline in 54 (46.5%) patients with mild anemia (10-12 g/dl) in 42 (36.2%) patients and moderate anemia (8-10 g/dl) in 12 (10.3%) patients. During the course of treatment, all patients developed anemia. A total of 44 patients (37.9%) required transfusion during chemotherapy, with 55(47.4%) patients developing grade 1-2 anemia and 40 (34.5%) patients developing grade 3 anemia. The factors associated with anemia requiring transfusion were a steeper decline in hemoglobin after two cycles (OR 1.65, p = 0.02), low-grade tumor (OR 2.48, p = 0.03), and thrombocytopenia grade 3 or 4 (OR 4.35, p = 0.034), of which tumor grade and thrombocytopenia remained significant in multivariate analysis. Nearly one-fourth of the study population had a delay between two cycles of chemotherapy due to anemia. A median additional cost of INR 7000 was incurred among those requiring blood transfusion. CONCLUSION: Anemia is a common toxicity associated with dose-dense chemotherapy during curative breast cancer treatment leading to delay in treatment and increased cost. Low-grade tumor, grade 3 or 4 thrombocytopenia, and grade 2 or higher anemia after two cycles of chemotherapy are risk factors for blood transfusions during treatment.

S054: incidence and management of jejunojejunal intussusception after Roux-en-Y gastric bypass: a large case series.

INTRODUCTION: Jejunojejunal intussusception after Roux-en-Y gastric bypass (RYGBP) for morbid obesity is a rare but potentially catastrophic complication. There are limited data regarding the incidence of intussusception and the different surgical options for management of this disease. METHODS: This is a retrospective review of all patients that underwent RYGBP and subsequently developed intussusception at the jejunojejunostomy. Data were collected between 1/1/2008 and 5/31/2018 and included demographics, details related to the index procedure, presentation, and management of intussusception. Perioperative outcomes and complications were also collected. RESULTS: 665 patients underwent RYGBP. A total of 34 patients developed intussusception, with 31 (4.7%) of them having undergone RYGBP in our hospital. Demographics included age, gender, and BMI at both the index surgery and at the time of intussusception. The jejunojejunostomy was created during RYGBP using a linear stapler in all patients with 64.5% of them achieving a length of 90 mm. All intussuscepted patients presented acutely with abdominal pain. All but one patient required surgical intervention. 42.4% of the patients were found to have intraoperative intussusception which appeared to be retrograde in 78.6% of them. Reduction followed by enteropexy or just enteropexy was performed in 20 patients (60.6%) that required surgery. No immediate post-operative complications were noted but 8 patients (26.5%) had recurrence of intussusception requiring another surgical intervention. In the reoperated group, 75% of the patients were treated with reduction followed by enteropexy or just enteropexy. CONCLUSIONS: This is the largest case series describing jejunojejunal intussusception following RYGBP. All patients that developed intussusception had jejunojejunostomy length greater than 60 mm. The most commonly performed surgical repair was reduction of the intussuscepted segment (if present) followed by enteropexy. Jejunojejunostomy length greater than 60 mm might be associated with the occurrence of intussusception and could explain the higher incidence noted in our series. Minimal intervention with enteropexy can offer effective treatment for most patients.

Impact of various solid carriers and spray drying on pre/post compression properties of solid SNEDDS loaded with glimepiride: in vitro-ex vivo evaluation and cytotoxicity assessment.

Development of self-nanoemulsifying drug delivery systems (SNEDDS) of glimepiride is reported with the aim to achieve its oral delivery. Lauroglycol FCC, Tween-80, and ethanol were used as oil, surfactant, and co-surfactant, respectively as independent variables. The optimized composition of SNEDDS formulation (F1) was 10% v/v Lauroglycol FCC, 45% v/v Tween 80, 45% v/v ethanol, and 0.005% w/v glimepiride. Further, the optimized liquid SNEDDS were solidified through spray drying using various hydrophilic and hydrophobic carriers. Among the various carriers, Aerosil 200 was found to provide desirable flow, compression, dissolution, and diffusion. Both, liquid and solid-SNEDDS have shown release of more than 90% within 10 min. Results of permeation studies performed on Caco-2 cell showed that optimized SNEDDS exhibited 1.54 times higher drug permeation amount and 0.57 times lower drug excretion amount than that of market tablets at 4 hours (p < .01). Further, the cytotoxicity study performed on Caco-2 cell revealed that the cell viability was lower in SNEDDS (92.22% ± 4.18%) compared with the market tablets (95.54% ± 3.22%; p > .05, i.e. 0.74). The formulation was found stable with temperature variation and freeze thaw cycles in terms of droplet size, zeta potential, drug precipitation and phase separation. Crystalline glimepiride was observed in amorphous state in solid SNEDDS when characterized through DSC, PXRD, and FT-IR studies. The study revealed successful formulation of SNEDDS for glimepiride.

Surface ECG f Wave Analysis at Initial Onset of Paroxysmal and Persistent Atrial Fibrillation.

INTRODUCTION: Dominant frequency (DF) analysis of electrocardiograms (ECGs) from patients with paroxysmal (PAF) and persistent (PeAF) atrial fibrillation has identified higher DFs in PeAF. We therefore hypothesized that among patients initially presenting to the emergency department (ED) with new onset AF, surface ECG features could differentiate PeAF from PAF. METHODS AND RESULTS: Initial 12-lead ECGs from patients presenting to the ED with a first episode of symptomatic AF were analyzed. Following QRS-T subtraction, fast Fourier transform (FFT) analysis of the AF fibrillatory waves was performed to measure DF and organization index (OI). Median DF of all leads and the DF in the lead with maximum OI were determined. Maximum f wave amplitude and vector magnitudes were measured. One hundred sixty-one patients (age 59 ± 16 years, 68% men) were included in this analysis, of whom 96 (58%) spontaneously converted to sinus rhythm within 7 days (PAF group). The remaining 65 patients underwent cardioversion or remained in AF (PeAF group). ECG features (DF, OI, f wave amplitude, and vector magnitude) did not differ among PAF and PeAF patients. CONCLUSIONS: ECG features (DF, OI, amplitude, vector magnitude) do not differ among patients with PAF versus PeAF when the ECGs are obtained at the initial onset of symptoms. Thus, prior data showing higher DF in PeAF likely reflect electrophysiologic remodeling rather than a marker for any specific type of AF or extent of underlying substrate.

Stable Co-crystals of Glipizide with Enhanced Dissolution Profiles: Preparation and Characterization.

Present study deciphers preparation of co-crystals of lipophilic glipizide by using four different acids, oxalic, malonic, stearic, and benzoic acids, in order to achieve enhanced solubility and dissolution along with stability. All co-crystals were prepared by dissolving drug and individual acids in the ratio of 1:0.5 in acetonitrile at 60-70°C for 15 min, followed by cooling at room temperature for 24 h. FT-IR spectroscopy revealed no molecular interaction between acids and drug as the internal structure and their geometric configurations remain unchanged. Differential scanning calorimetry revealed closer melting points of raw glipizide and its co-crystals, which speculates absence of difference in crystallinity as well as intermolecular bonding of the co-crystals and drug. PXRD further revealed that all the co-crystals were having similar crystallinity as that of raw glipizide except glipizide-malonic acid co-crystals. This minor difference in the relative intensities of some of the diffraction peaks could be attributed to the crystal habit or crystal size modification. SEM revealed difference in the crystal morphology for all the co-crystals. Micromeritic, solubility, dissolution, and stability data revealed that among all the prepared co-crystals, glipizide-stearic acid co-crystals were found superior. Hence, it was concluded that glipizide-stearic acid co-crystals could offer an improved drug design strategy to overcome dissolution and bioavailability related challenges associated with lipophilic glipizide.

Look-alike, sound-alike (LASA) drugs in India.

Poor drug regulation in India is not a recent problem. The Indian drug market is full of look-alike, sound-alike (LASA) drugs which have not yet caught the attention of the media or the medical community. This viewpoint highlights the problem of LASA drugs and poor prescription practices and proposes solutions for involving all stakeholders in this unaddressed issue which is a huge public health problem in India.

Who drive the health policy agenda in India? Actors in National Health Committees since Independence.

Introduction: Health policies reflect the ideas and interests of the actors involved. The Indian Government constituted many health committees for policy recommendations on myriad issues concerning public health, ranging from tribal health to drug regulation. However, little is known about their composition and backgrounds. We reviewed these committees to map the actors and institutions. Methods: We elicited information on all relevant health committees available in the public domain. All were constituted post-independence, except two, with recommendations that remain pertinent to date. Data for chairpersons and members - their professions, gender, institutions, and location were extracted and analysed. Reliable online sources were used to collate the information. Results: We identified 23 national health committees from 1943 to 2020 with available reports. There were 25 chairpersons and 316 members. All except three chairpersons were men. Among members, only 11% were women. The majority (51%) had experience working in health systems; however, most were medical doctors, with negligible representation of other cadres. We noted the centralization of location, with 44% of members based in the national capital of Delhi. Government administrators were maximally represented (55%), followed by medical academia (19%). Post-2000, we have observed slightly improved diversity across some parameters like gender (15% women vs 9% earlier) and affiliation. However, the centralization of the location to the national capital had increased (55% post-2000 vs. 39% pre-2000). Conclusion: Indian health committees lack diversity in representation from multiple perspectives. Henceforth, health policymakers should prioritize including diverse social, geographical, and health systems actors to ensure equitable policymaking.

Local Sociocultural Practice Specific Financial Toxicity Assessment Tool for Cancer: An Emerging Need.

It is relevant to study the financial toxicity of cancer to address it. However, the existing tools fail to capture the financial destruction of cancer on patients and their families in resource-limited countries. The authors discuss the need for a new tool in this article.

A bleeding heart: case report and review of pericardial angiosarcoma.

Primary cardiac tumors are rare. The cardiac sarcomas are the most common malignant cardiac tumors. These tumors have a dismal prognosis with an overall median survival of 25 months. Clinical features include dyspnea, arrhythmias, pericardial effusions, heart failure, and sudden cardiac death. The diagnosis is often challenging. Therefore, the cardiac imaging workup plays a central role in addition to a high clinical suspicion in the setting of atypical presentations that do not respond to standard therapies. The echocardiography, computed tomography, and cardiac MRI are crucial in clinching the diagnosis. Multimodal treatment with surgery, chemotherapy, and radiotherapy has been shown to improve outcomes, as opposed to using either of these modalities alone. We describe the case of a 30-year-old gentleman with COVID-19 infection who developed recurrent hemorrhagic pericardial effusions refractory to standard treatment and was eventually diagnosed as a case of pericardial angiosarcoma after his biopsy revealed the diagnosis and staging was performed using PET-CT-FDG scan. Our case re-emphasizes the importance of considering a malignant etiology early in the course of the disease presentation, especially in recurrent hemorrhagic effusions despite an inflammatory cytologic diagnosis of fluid. It also highlights the place for cardiac CT and MRI to ascertain the location and spread and to plan the further course of treatment. If diagnosed early, the estimated survival time can be prolonged by instituting a multimodal approach.

How can TB Mukt Panchayat initiative contribute towards ending tuberculosis in India?

Community Engagement (CE) for disease control and health has been tested for a long time across the globe for various health programmes. Realizing the need for true multisectoral action and CE and ownership for ending TB on an accelerated timeline, the Government of India launched a nationwide campaign for 'TB Mukt Panchayat' (meaning 'TB free village council' in Hindi language) on 24 March 2023, banking on the system of local self-governments in the country. Though it is an initiative with huge potential to contribute to India's efforts to end the TB epidemic, it is not without a few shortcomings. We critically analyse the TB Mukt Panchayat initiative and suggest a few recommendations for the way forward.

Unveiling the phyto-restorative potential of ethereal distillates for atopic dermatitis: an advanced therapeutic approach.

Atopic dermatitis is acknowledged as a vital inflammatory disorder associated with the integumentary system of the body and is characterized by the formation of thick reddish-grey scars and erythema formation on skin, prevalent amidst the populace. Numerous synthetic drugs are available for treatment like antihistamines, immunosuppressants, glucocorticoids etc., but contrarily, essential oil therapy is exclusively lime lighted to favour the purpose. The utilization of available engineered drugs, possess the marked adverse effects owing to prolonged duration of therapy and therefore, essential oils are explored well and proved to exhibit the anti-eczematic, anti-inflammatory and antipruritic properties. Ethereal distillates own the assorted and selective therapeutic properties attributable to presence of bioactive compounds liable to treat this torturous and integumentary disorder, likely lavender oil, patchouli oil, frankincense oil etc., have been found to exert their pharmacological actions by impeding the liberation and action of inflammatory mediators and immunological hyperactivities that are engaged in exacerbating this idiopathic illness. The current attempt provided the update with the aim to bring forth the naturally originated treatment that is pertinent to provide the invulnerable therapy by circumventing the noxious symptoms i.e. erythema formation and inflamed lesions.

Frequency of Cerebellar Abnormalities Associated With the Differing Magnetic Resonance Imaging Patterns of Term Hypoxic-Ischemic Injury in Children.

BACKGROUND: We aimed to determine the frequency of cerebellar injury using delayed magnetic resonance imaging (MRI) in children with cerebral palsy, diagnosed with term hypoxic-ischemic injury (HII), and to characterize this for the different MRI patterns of HII. METHODS: We retrospectively reviewed delayed MRI scans in children with cerebral palsy, of whom 1175 had term HII. The pattern of HII was classified into basal ganglia-thalamus (BGT) pattern, watershed (WS) pattern, combined BGT/WS, and multicystic HII. Cerebellar location (hemisphere versus vermis) and the MRI characteristics were documented overall and for each of the different patterns of HII, as well as the association with thalamic injury. RESULTS: Cerebellar injury was found in 252 of 1175 (21.4%) (median age 6 years [interquartile range: 3 to 9 years]). Of these, 49% (124 of 252) were associated with a BGT pattern, 13% (32 of 252) with a WS pattern, 28% (72 of 252) with a combined BGT/WS pattern, and 10% (24 of 252) with a multicystic pattern. The vermis was abnormal in 83% (209 of 252), and the hemispheres were abnormal in 34% (86 of 252) (with 17% [43 of 252] showing both vermis and hemispheric abnormality). CONCLUSIONS: Over a fifth of patients with cerebral palsy due to HII had a cerebellar abnormality on delayed MRI, most commonly involving the vermis (83%), and as part of a BGT pattern of injury in just under half of these likely reflecting the association of cerebellar vermis injury with profound insults.

The data quality debate on Indian surveys should be more responsible.

Recently, the data quality of the National Sample Surveys (NSS) and the National Family Health Surveys (NFHS) has become the centre of discussion [1,2]. Two issues that have been raised include the overestimation of the rural population in these surveys and greater response rates in poorer wealth groups compared to the richer groups. Technically, there are concerns about the generalisability of these surveys. Politically, the argument is that together these issues bias the surveys toward depicting the country as worse off. In other words, the surveys do not capture the growth in urbanisation and accompanying wealth generation that has happened over the recent past.

Intramarrow penetration synergized with advanced platelet-rich fibrin in periodontal regeneration: A randomized controlled trial.

Background: Intramarrow penetration (IMP) is one of the recent treatment protocol where decortication is performed to stimulate osteogenic cells. IMP improves the blood supply and the inherent osteogenic properties of the vital bone and has the advantages of minimal surgical invasion, time, and cost. Incorporation of IMP in the regeneration of periodontal defects is very scarce. Hence, the present study aimed to evaluate the involvement of IMP and advanced platelet-rich fibrin (A-PRF) in the regenerative outcomes in the treatment of intrabony defects. Materials and Methods: In the present randomized controlled trial, 20 periodontitis patients with 20 defects were randomly allotted into two groups: group I open flap debridement (OFD) and A-PRF, group II OFD, intramarrow debridement, and A-PRF. Clinical parameters recorded were plaque index (PI), gingival index (GI), and clinical attachment level (CAL) probing depth. Radiographic parameters were defect depth, defect resolution, and change in alveolar crest height. Values were tabulated and subjected to statistical analysis. Paired and unpaired t-tests were performed for intra and intergroup comparisons. P <0.05 was set as statistically significant. Results: Intragroup comparisons showed a significant reduction (P < 0.05) in probing pocket depth, GI, PI, gain in CAL, and greater bone fill in both the groups from baseline to 6 months postoperative. Intergroup comparisons were not statistically significant (P > 0.05). Conclusion: Within limitations, both treatment modalities stand good, but utilization of IMP along with A-PRF results in effective regenerative outcome in intrabony defects because of its stimulation of osteogenic properties.

Anti-Amyloid-ß Immunotherapy: A Leading Novel Avenue for Alzheimer's Disease.

Alzheimer's disease or senile dementia is principally acknowledged by the gradual accumulation of neurotoxic amyloid- ß protein in the brain and is considered as the initial event of the phenomenon of this asymptomatic ailment. It prompts the decline in cognitive performance, standard psychiatric functioning, and neuronal transmission across the brain. Significant inferences were withdrawn by utilizing the recently introduced disease-modifying anti- amyloid- ß immunotherapy developed after performing the clinical and preclinical controlled trials to cure the neurodegenerative malady. This strategy is worthwhile because of the clinical relevance and specific targeted approach that exhibited the quenched immunotherapeutic effects and encouraged clinical findings. In vitro fabricated, anti- amyloid- ß recombinant monoclonal antibodies are passively employed to promote clearance and antagonize the aggregation and synthesis of neurotoxic and degenerative aggregates of amyloid-ß. Thus, passive immunotherapy has an adequate impact on treating this disorder, and currently, some other monoclonal pharmacological molecules are under clinical trials to defeat this severe exacerbation with more efficacy and clinical benefits. This review compendiously discusses the anti-amyloid-ß immunotherapy, which will provide a more proficient framework to be employed as a potential therapeutic approach.