Nonlinearity vs nonlocality with emphasis on bandwidth broadening in semiconductor-based 1d metamaterials.

The physics of nonlinear optical materials is incredibly versatile, with the design of novel materials and structures offering numerous degrees of freedom. Nevertheless, weak inherent nonlinearity of conventional optical materials continues to hinder the progress of a number of important applications. In this study, we delve into the realm of broadband enhancement of nonlinearity within one-dimensional (1d) plasmonic metamaterials, exploring its intricate connection with nonlocality. Specifically, we introduce a phenomenological framework for quantifying the effective third-order nonlinear susceptibility of 1d multiphase plasmonic nanostructures, utilizing heavily doped semiconductors, and subsequently applying this approach using realistic material parameters. Both direct and inverse problems of nonlinearity enhancement have been addressed. Our findings demonstrate a remarkable capability to significantly augment the third-order nonlinear susceptibility across a defined frequency range, while concurrently gauging the impact of nonlocality on this enhancement.

Inbred SJL mice recapitulate human resistance to Cryptococcus infection due to differential immune activation.

IMPORTANCE: Cryptococcosis studies often utilize the common C57BL/6J mouse model. Unfortunately, infection in these mice fails to replicate the basic course of human disease, particularly hampering immunological studies. This work demonstrates that SJL/J mice can recapitulate human infection better than other mouse strains. The immunological response to Cryptococcus infection in SJL/J mice was markedly different from C57BL/6J and much more productive in combating this infection. Characterization of infected mice demonstrated strain-specific genetic linkage and differential regulation of multiple important immune-relevant genes in response to Cryptococcus infection. While our results validate many of the previously identified immunological features of cryptococcosis, we also demonstrate limitations from previous mouse models as they may be less translatable to human disease. We concluded that SJL/J mice more faithfully recapitulate human cryptococcosis serving as an exciting new animal model for immunological and genetic studies.

Differentiation between normal and abnormal kidneys using 99mTc-DMSA SPECT with deep learning in paediatric patients.

AIM: To investigate the feasibility of using deep learning (DL) to differentiate normal from abnormal (or scarred) kidneys using technetium-99m dimercaptosuccinic acid (99mTc-DMSA) single-photon-emission computed tomography (SPECT) in paediatric patients. MATERIAL AND METHODS: Three hundred and one 99mTc-DMSA renal SPECT examinations were reviewed retrospectively. The 301 patients were split randomly into 261, 20, and 20 for training, validation, and testing data, respectively. The DL model was trained using three-dimensional (3D) SPECT images, two-dimensional (2D) maximum intensity projections (MIPs), and 2.5-dimensional (2.5D) MIPs (i.e., transverse, sagittal, and coronal views). Each DL model was trained to determine renal SPECT images into either normal or abnormal. Consensus reading results by two nuclear medicine physicians served as the reference standard. RESULTS: The DL model trained by 2.5D MIPs outperformed that trained by either 3D SPECT images or 2D MIPs. The accuracy, sensitivity, and specificity of the 2.5D model for the differentiation between normal and abnormal kidneys were 92.5%, 90% and 95%, respectively. CONCLUSION: The experimental results suggest that DL has the potential to differentiate normal from abnormal kidneys in children using 99mTc-DMSA SPECT imaging.

The Effect of Renin-Angiotensin-Aldosterone System Inhibitors on Outcomes of Patients Treated with Immune Checkpoint Inhibitors: a Retrospective Cohort Study.

AIMS: Renin-angiotensin-aldosterone system inhibitors (RAASi) are associated with improved survival outcomes in patients receiving immune checkpoint inhibitors (ICIs), but the data on the response to treatment and tumour-based endpoints across different tumour types are unknown. MATERIALS AND METHODS: We carried out a retrospective study at two tertiary referral centres in Taiwan. All adult patients treated with ICIs between January 2015 and December 2021 were included. The primary outcome was overall survival and the secondary outcomes were progression-free survival (PFS) and clinical benefit rates. RESULTS: In total, 734 patients were enrolled in our study, of which 171 were RAASi users and 563 were non-users. Compared with non-users, RAASi users had a longer median overall survival [26.8 (interquartile range 11.3-not reached) versus 15.2 (interquartile range 5.1-58.4) months, P < 0.001] and PFS [12.2 (interquartile range 3.9-34.5) versus 5.0 (interquartile range 2.2-15.2) months, P < 0.001]. In univariate Cox proportional hazard analyses, the use of RAASi was associated with a 40% reduction in the risk of mortality [hazard ratio 0.58 (95% confidence interval 0.44-0.76), P < 0.001] and disease progression [hazard ratio 0.62 (95% confidence interval 0.50-0.77), P < 0.001]. The association remained significant after adjusting for underlying comorbidities and cancer therapy in multivariate Cox analyses. A similar trend was observed for PFS. Furthermore, RAASi users experienced a greater clinical benefit rate than non-users (69% versus 57%, P = 0.006). Importantly, the use of RAASi before ICI initiation was not associated with improved overall survival and PFS. RAASi were not associated with an increased risk of adverse events. CONCLUSION: The use of RAASi is associated with improved survival outcomes, treatment response and tumour-based endpoints in patients undergoing immunotherapy.

A Novel Model and Infrastructure for Clinical Outcomes Data Collection and Their Systematic Evaluation for UK Patients Receiving Proton Beam Therapy.

AIMS: To establish an infrastructure for sustainable, comprehensive data collection and systematic outcomes evaluation for UK patients receiving proton beam therapy (PBT). MATERIALS AND METHODS: A Proton Outcomes Working Group was formed in 2014 to develop a national minimum dataset for PBT patients and to define a clinically integrated informatics solution for data collection. The Christie Proton Beam Therapy Centre formed its Proton Clinical Outcomes Unit in 2018 to collect, curate and analyse outcomes data prospectively for UK-treated patients and retrospectively for UK patients referred abroad for PBT since 2008 via the Proton Overseas Programme (POP). RESULTS: A single electronic form (eForm) was developed to capture the agreed data, using a data tree approach including conditional logic: data items are requested once, further questions depend on previous answers and are sensitive to tumour site and patient pathway time point. Relevant data automatically populate other forms, saving time, prompting completeness of clinical assessments and ensuring data consistency. Completed eForm data populate the electronic patient record and generate individualised outputs, including consultation letters, treatment summary and surveillance plans, based on organs at risk irradiated, age and sex. All data regarding POP-treated patients are verified and migrated into the system, ensuring that patient data, whether overseas or UK treated, are consistently recorded. The eForm utilises a 'user friendly' web portal interface, the Clinical Web Portal, including clickable tables and infographics. Data items are coded to a universally recognised standard comparable with other data systems. Patient-reported outcomes are also integrated, highlighting significant toxicities and prompting a response. Outcomes data can be correlated with dosimetric DICOM data to support radiation dose modelling. CONCLUSION: Outcomes data from both POP-treated and The Christie-treated patients support long-term care, allow evaluation of PBT efficacy and safety, assist future selection of PBT patients and support hypothesis generation for future clinical trials.

Degradable RGD-Functionalized 3D-Printed Scaffold Promotes Osteogenesis.

To establish an ideal microenvironment for regenerating maxillofacial defects, recent research interests have concentrated on developing scaffolds with intricate configurations and manipulating the stiffness of extracellular matrix toward osteogenesis. Herein, we propose to infuse a degradable RGD-functionalized alginate matrix (RAM) with osteoid-like stiffness, as an artificial extracellular matrix, to a rigid 3D-printed hydroxyapatite scaffold for maxillofacial regeneration. The 3D-printed hydroxyapatite scaffold was produced by microextrusion technology and showed good dimensional stability with consistent microporous detail. RAM was crosslinked by calcium sulfate to manipulate the stiffness, and its degradation was accelerated by partial oxidation using sodium periodate. The results revealed that viability of bone marrow stem cells was significantly improved on the RAM and was promoted on the oxidized RAM. In addition, the migration and osteogenic differentiation of bone marrow stem cells were promoted on the RAM with osteoid-like stiffness, specifically on the oxidized RAM. The in vivo evidence revealed that nonoxidized RAM with osteoid-like stiffness upregulated osteogenic genes but prevented ingrowth of newly formed bone, leading to limited regeneration. Oxidized RAM with osteoid-like stiffness facilitated collagen synthesis, angiogenesis, and osteogenesis and induced robust bone formation, thereby significantly promoting maxillofacial regeneration. Overall, this study supported that in the stabilized microenvironment, oxidized RAM with osteoid-like stiffness offered requisite mechanical cues for osteogenesis and an appropriate degradation profile to facilitate bone formation. Combining the 3D-printed hydroxyapatite scaffold and oxidized RAM with osteoid-like stiffness may be an advantageous approach for maxillofacial regeneration.

In Vivo Efficacy of Olorofim against Systemic Scedosporiosis and Lomentosporiosis.

Clinically relevant members of the Scedosporium/Pseudallescheria species complex and Lomentospora prolificans are generally resistant against currently available systemic antifungal agents in vitro, and infection due to these species is difficult to treat. We studied the in vivo efficacy of a new fungicidal agent, olorofim (formerly F901318), against scedosporiosis and lomentosporiosis in neutropenic animals. Cyclophosphamide-immunosuppressed CD-1 mice infected by Scedosporium apiospermum, Pseudallescheria boydii (Scedosporium boydii), and Lomentospora prolificans were treated by intraperitoneal administration of olorofim (15 mg/kg of body weight every 8 h for 9 days). The efficacy of olorofim treatment was assessed by the survival rate at 10 days postinfection, levels of serum (1-3)-ß-d-glucan (BG), histopathology, and fungal burdens of kidneys 3 days postinfection. Olorofim therapy significantly improved survival compared to that of the untreated controls; 80%, 100%, and 100% of treated mice survived infection by Scedosporium apiospermum, Pseudallescheria boydii, and Lomentospora prolificans, respectively, while less than 20% of the control mice (phosphate-buffered saline [PBS] treated) survived at 10 days postinfection. In the olorofim-treated neutropenic CD-1 mice infected with any of the three species, serum BG levels were significantly suppressed and fungal DNA detected in the target organs was significantly lower than in controls. Furthermore, histopathology of kidneys revealed no or only a few lesions with hyphal elements in the olorofim-treated mice, while numerous fungal hyphae were present in control mice. These results indicate olorofim to be a promising therapeutic agent for systemic scedosporiosis/lomentosporiosis, devastating emerging fungal infections that are difficult to treat with currently available antifungals.

Assessment of the efficacy of intra-articular platelet rich plasma treatment in an ACLT experimental model by dynamic contrast enhancement MRI of knee subchondral bone marrow and MRI T2∗ measurement of articular cartilage.

OBJECTIVE: The vascularization of subchondral bone plays a significant role in the progression of knee osteoarthritis (OA). Treatment with platelet-rich plasma (PRP) has positive effects on cartilage lesions. However, PRP's efficacy for subchondral bone marrow lesions and the relationship of these lesions to cartilage are still undiscovered. Therefore, our aims were first to longitudinally investigate the change in subchondral flow by dynamic contrast enhanced MRI and degeneration of cartilage by MRI T2∗ in an anterior cruciate transection rodent (ACLT) model, and second to examine changes in parameters after intra-articular PRP injection. DESIGN: A 32-week investigation in 18 rats allocated to sham-control, ACLT with normal saline injection (ACLT + NS), and ACLT with PRP injection groups ended with histological evaluation. Another rat was used as a donor of allogenic PRP. RESULTS: Compared to the sham-control group, the ACLT + NS group had higher subchondral blood volume A (0.051, 95% confidence interval: 0.009, 0.092) and lower venous washout kel (-0.030: -0.055, -0.005) from week 4; lower permeability kep from week 18 (-0.954: -1.339, -0.569); higher cartilage T2∗ values (1.803: 1.504, 2.102) reflecting collagen loss beginning at week 10. For the PRP treatment group, subchondral bone marrow A and cartilage T2∗ decreased from week 10. Histological results confirmed and were correlated with the MRI findings. CONCLUSION: Subchondral hyper-perfusion plays a vital role in the pathogenesis of OA and was associated with cartilage degeneration. The efficacy of PRP can be observed from reduced perfusion and MRI T2∗ values.

Reducing scan time of paediatric 99mTc-DMSA SPECT via deep learning.

AIM: To investigate the feasibility of reducing the scan time of paediatric technetium 99m (99mTc) dimercaptosuccinic acid (DMSA) single-photon-emission computed tomographic (SPECT) using a deep learning (DL) method. MATERIAL AND METHODS: A total of 112 paediatric 99mTc-DMSA renal SPECT scans were analysed retrospectively. Of the 112 examinations, 88 (84 for training and four for validation) were used to train a DL-based model that could generate full-acquisition-time reconstructed SPECT images from half-time acquisition. The remaining 24 examinations were used to evaluate the performance of the trained model. RESULTS: DL-based SPECT images obtained from half-time acquisition have image quality similar to the standard clinical SPECT images obtained from full-acquisition-time acquisition. Moreover, the accuracy, sensitivity and specificity of the DL-based SPECT images for detection of affected kidneys were 91.7%, 83.3%, and 100%, respectively. CONCLUSION: These preliminary results suggest that DL has the potential to reduce the scan time of paediatric 99mTc-DMSA SPECT imaging while maintaining diagnostic accuracy.

Knowledge, attitudes and practices of neonatal professionals regarding pain management.

Pain management is an important issue which impacts the prognosis of neonates in neonatal intensive care units. Evidence has shown that professionals' knowledge and attitudes regarding pain management can impact the quality of their practice. The purpose of this study was to evaluate the knowledge, attitudes, and practices of neonatal professionals regarding neonatal pain management. A cross-sectional study was performed involving neonatal physicians and nurses, using a research questionnaire to investigate the knowledge and attitudes of professionals as well as to assess their practice of pain management. Research found an apparent discrepancy between the knowledge levels of neonatologists and nurses regarding pain assessment and management, with nurses displaying weaker professional knowledge and more negative attitudes toward pain management than did neonatologists. Additionally, research revealed a lack of knowledge and negative attitudes among participants regarding the provision of sufficient opioid analgesics to sick infants during invasive procedures and even for dying neonates. There is an urgent need for continuing education regarding neonatal pain management with the goal of empowering neonatal professionals; further research is needed into the question of how to translate education into more reliable practice.Conclusion: This research provides useful information regarding the knowledge, attitudes, and clinical practice of neonatal pain management among neonatologists and nurses and points out some differences in the knowledge levels of these two groups. What is Known: •Neonates can perceive and respond to pain stimuli by showing their biological signals similarly to children and adults. •Untreated or insufficient pain management for high-risk neonates has short-term. negative effects and may also induce long-term negative effects. What is New: •The level of knowledge, the attitudes, and the practices regarding neonatal pain in intensive care are different among neonatal professionals. •There is an urgent need to provide interdisciplinary continuing education to improve the knowledge of neonatal professionals and encourage them to more highly prioritize neonatal pain management.

Pencil Beam Scanning Proton Therapy Case Selection for Paediatric Abdominal Neuroblastoma: Effects of Tumour Location and Bowel Gas.

AIMS: Pencil beam scanning (PBS) proton therapy is an increasingly used radiation modality for childhood malignancies due to its ability to minimise dose to surrounding organs. However, the dosimetry is extremely sensitive to anatomical and density changes. The aims of this study were to investigate if there is a dosimetric benefit or detriment with PBS for paediatric abdominal neuroblastoma, assess gastrointestinal air variability and its dosimetric consequences, plus identify if there are factors that could assist case selection for PBS referral. MATERIALS AND METHODS: Twenty neuroblastoma cases were double-planned with PBS and intensity-modulated arc therapy (IMAT). Cases were divided into unilateral, midline unilateral and midline bilateral locations in relation to the kidneys. Plans were recalculated after the gastrointestinal volume was simulated as air (Hounsfield Units -700) and water (Hounsfield Units 0), then compared with nominal plans (recalculated - nominal, ΔD). Forty-three weekly cone beam computed tomography scans were analysed to quantify gastrointestinal air variability during treatment. RESULTS: PBS reduced the mean dose to normal tissues at all tumour locations, particularly unilateral tumours. However, 15% had better dosimetry with IMAT, all of which were midline tumours. Increased gastrointestinal air caused significant compromises to PBS versus IMAT plans for midline tumours [median/maximum ΔD95% clinical target volume (CTV) -2.4%/-15.7% PBS versus 1.4%/0% IMAT, P = 0.003], whereas minimal impact was observed for unilateral tumours (ΔD95% CTV -0.5%/-1.9% PBS versus 0.5%/-0.5% IMAT, P = 0.008). D95% CTV was significantly decreased in PBS plans if planning target volume (PTV) ≥400 cm3 (median -4.1%, P = 0.001) or PTV extension ≥60% anterior to vertebral body (-2.1%, P = 0.002). A larger variation in gastrointestinal air was observed in patients treated under general anaesthesia (median 38.4%) versus awake (11.5%); P = 0.004. CONCLUSION: In this planning study, tumours at the unilateral location consistently showed improved dose reductions to normal tissue with minimal dose degradation from increased gastrointestinal air with PBS plans. Tumour location, PTV volume and anterior extension of PTV are useful characteristics in facilitating patient selection for PBS.

Comparing Proton to Photon Radiotherapy Plans: UK Consensus Guidance for Reporting Under Uncertainty for Clinical Trials.

In the UK, the recent introduction of high-energy proton beam therapy into national clinical practice provides an opportunity for new clinical trials, particularly those comparing proton and photon treatments. However, comparing these different modalities can present many challenges. Although protons may confer an advantage in terms of reduced normal tissue dose, they can also be more sensitive to uncertainty. Uncertainty analysis is fundamental in ensuring that proton plans are both safe and effective in the event of unavoidable discrepancies, such as variations in patient setup and proton beam range. Methods of evaluating and mitigating the effect of these uncertainties can differ from those approaches established for photon therapy treatments, such as the use of expansion margins to assure safety. These differences should be considered when comparing protons and photons. An overview of the effect of uncertainties on proton plans is presented together with an introduction to some of the concepts and terms that should become familiar to those involved in proton therapy trials. This report aims to provide guidance for those engaged in UK clinical trials comparing protons and photons. This guidance is intended to take a pragmatic approach considering the tools that are available to practising centres and represents a consensus across multidisciplinary groups involved in proton therapy in the UK.

[Changes of BK(Ca) on vascular striaepericytes of D-galactose-induced aging model in guinea pigs].

Objective: The aging model of guinea pigs induced by D-galactose was set up to investigate the changes of BK(Ca) expression and function on cochlear pericytes and their relationship with age-related hearing loss. Methods: Thirty healthy 8-week-old guinea pigs were randomly divided into three groups, with 10 in each group: D-galactose aging model group, subcutaneous injection of D-galactose (500 mg/kg) daily for 6 weeks; saline control group, the same amount of saline was injected into the neck of the aging model group for 6 weeks; the blank control group, no treatment was performed. The threshold of auditory brainstem response (ABR) was detected. The content of BK(Ca) in the perivascular cells of the guinea pig cochlear cells was detected by immunofluorescence technique. The changes of peripheral current density and BK(Ca) current were detected by patch clamp technique. The data were analyzed by GraphPad Prism software. Results: Compared with the saline group and the control group, the ABR threshold and the amplitude of the wave I were significantly decreased in the aging model group, and the difference was statistically significant (P<0.01). Compared with the control group, the expression of BK(Ca) in the vascular pericytes of guinea pigs in the aging model group was significantly reduced (1.00±0.08 vs 0.27±0.03,the difference was statistically significant P<0.01), and the cell current density and BK(Ca) net current value were also significantly reduced with statistically significant (P<0.01). Conclusions: D-galactose can successfully induce guinea pig aging model, in which BK(Ca) expression decreases and net current value decreases in pericytes of cochlear striavascularis, and changes in BK(Ca) expression and function may be related to age-related hearing loss.

The impact of proton LET/RBE modeling and robustness analysis on base-of-skull and pediatric craniopharyngioma proton plans relative to VMAT.

Purpose: Pediatric craniopharyngioma, adult base-of-skull sarcoma and chordoma cases are all regarded as priority candidates for proton therapy. In this study, a dosimetric comparison between volumetric modulated arc therapy (VMAT) and intensity modulated proton therapy (IMPT) was first performed. We then investigated the impact of physical and biological uncertainties. We assessed whether IMPT plans remained dosimetrically superior when such uncertainty estimates were considered, especially with regards to sparing organs at risk (OARs).Methodology: We studied 10 cases: four chondrosarcoma, two chordoma and four pediatric craniopharyngioma. VMAT and IMPT plans were created according to modality-specific protocols. For IMPT, we considered (i) variable RBE modeling using the McNamara model for different values of (α/ß)x, and (ii) robustness analysis with ±3 mm set-up and 3.5% range uncertainties.Results: When comparing the VMAT and IMPT plans, the dosimetric advantages of IMPT were clear: IMPT led to reduced integral dose and, typically, improved CTV coverage given our OAR constraints. When physical robustness analysis was performed for IMPT, some uncertainty scenarios worsened the CTV coverage but not usually beyond that achieved by VMAT. Certain scenarios caused OAR constraints to be exceeded, particularly for the brainstem and optical chiasm. However, variable RBE modeling predicted even more substantial hotspots, especially for low values of (α/ß)x. Variable RBE modeling often prompted dose constraints to be exceeded for critical structures.Conclusion: For base-of-skull and pediatric craniopharyngioma cases, both physical and biological robustness analyses should be considered for IMPT: these analyses can substantially affect the sparing of OARs and comparisons against VMAT. All proton RBE modeling is subject to high levels of uncertainty, but the clinical community should remain cognizant possible RBE effects. Careful clinical and imaging follow-up, plus further research on end-of-range RBE mitigation strategies such as LET optimization, should be prioritized for these cohorts of proton patients.

Efficacy of Olorofim (F901318) against Aspergillus fumigatus, A. nidulans, and A. tanneri in Murine Models of Profound Neutropenia and Chronic Granulomatous Disease.

The emergence of azole resistance in Aspergillus fumigatus as well as an increasing frequency of multiresistant cryptic Aspergillus spp. necessitates exploration of new classes of antifungals. Olorofim (formerly F901318) is a new fungicidal agent that prevents the growth of ascomycetous mold species via inhibition of de novo pyrimidine biosynthesis, a mechanism of action distinct from that of currently available antifungal drugs. We studied the in vivo efficacy of olorofim intraperitoneal therapy (15 mg/kg of body weight every 8 h for 9 days) against infection with A. fumigatus, A. nidulans, and A. tanneri in both neutropenic CD-1 mice and mice with chronic granulomatous disease (CGD) (gp91-/-phox mice). In the neutropenic mouse model, 80% to 88% of treated mice survived for 10 days, and in the CGD group, 63% to 88% of treated mice survived for 10 days, depending on the infecting species, while less than 10% of the mice in the control groups survived for 10 days. In the olorofim-treated groups, galactomannan levels were significantly suppressed, with lower organ fungal DNA burdens being seen for all three Aspergillus spp. Histopathological slides revealed a limited number of inflammatory foci with or without detectable fungal elements in the kidneys of neutropenic CD-1 mice and in the lungs of CGD mice. Furthermore, the efficacy of olorofim was unrelated to the triazole MICs of the infecting Aspergillus spp. These results show olorofim to be a promising therapeutic agent for invasive aspergillosis.

Periorbital erythema and swelling as a presenting sign of lupus erythematosus in tertiary referral centers and literature review.

Background Cutaneous lupus erythematosus (CLE) includes a broad range of dermatologic manifestations. Periorbital involvement, however, is a relatively rare clinical presentation of CLE. Objectives This clinical study aimed to investigate the characteristics of this unique presentation of CLE in tertiary medical centers. Methods We enrolled patients with periorbital erythema and swelling as the presenting sign of lupus erythematosus, from January 2003 to November 2017, using the data of 553 pathologically proven CLE cases from the registration database of the Chang Gung Memorial Hospitals in Taiwan. Results We enrolled a total of 25 patients. The mean age was 46.7 years and 68% of the patients were female. Most of the patients (84.0%) presented with unilateral involvement, with the left orbit involved in 15 patients (60%); the upper eyelid was the most frequently involved (72%). Mean duration between the onset of clinical manifestations and the diagnosis of CLE was approximately 59 weeks. Nineteen patients had been previously misdiagnosed. All patients had features compatible with CLE on histopathological examination. In contrast, laboratory analysis of the autoimmune profile often revealed negative results, including those for antinuclear antibodies (25%). Notably, anti-SSA/SSB (45.5%) showed the highest positive rate. During follow-up, six patients developed systemic lupus erythematosus (SLE) and two patients developed Sjögren syndrome. Conclusions The diagnosis of CLE presenting as periorbital erythema and swelling is often delayed because of clinical mimicry and the high proportion of negative results on autoantibody tests. Increased clinical suspicion and prompt histopathological examination are crucial for early diagnosis. Moreover, one-fourth of the patients ultimately developed SLE, which highlights the importance of clinical awareness.