Short bowel syndrome and the impact on patients and their families: a qualitative study.

BACKGROUND: Short bowel syndrome (SBS) is a malabsorptive condition that can result in intestinal failure (SBS-IF). Many patients with SBS-IF require home parenteral nutrition (PN) for survival. However, PN has profound effects on patients and their family members. The present study aimed to understand the lived experience of SBS-IF for patients and their families. METHODS: In-depth semi-structured qualitative interviews were conducted with 15 patients with SBS-IF and five adult family members living with someone with SBS-IF. A patient-centric approach was taken, with a patient steering group providing input and guidance to develop the interview guide. Key concepts were identified using thematic analysis of interview transcripts. RESULTS: Patients' lives were dominated by having SBS-IF. They described physical impacts that included patient-reported signs and symptoms and physical restrictions comprising of restrictions on daily life, actives of daily living and physical functioning. In addition, they encountered emotional impacts with a plethora of negative feelings and social impacts, such as difficulties socialising and maintaining relationships. Patients coped by adapting their life around SBS-IF, having support and adopting an attitude of gratitude and acceptance. Family members were also affected and, along with patients, appreciated the respite of a night off from infusions. CONCLUSIONS: Patients and families face many difficulties with SBS-IF. Healthcare professionals can support patients by facilitating them explore what others have found beneficial; adapting their life around PN, viewing PN with acceptance and trying to cultivate gratitude. Further research into the support required for families may be beneficial.

Patterns of response and progression in bone and soft tissue during and after treatment with radium-223 for metastatic castrate-resistant prostate cancer.

BACKGROUND: Radium-223 improves survival and time to first symptomatic skeletal event in symptomatic bone predominant metastatic castrate-resistant prostate cancer (mCRPC). The imaging response to radium-223 has not been well characterized. METHODS: To describe patterns of response and progression with radium-223, we performed a retrospective review of all mCPRC patients who received radium-223 at Duke from 1 June 2013 to 1 June 2015. Radionuclide bone scans obtained at baseline, during, and after treatment were reviewed by two radiologists. The automated bone scan index (aBSI) was generated at each time point using EXINI boneBSI version 2.4. Computed tomography (CT) and magnetic resonance imaging (MRI) clinical radiology reports were reviewed to evaluate for soft tissue, visceral, epidural, and bone progression. Clinical data were abstracted from the electronic health record. RESULTS: We identified 61 men who received at least one dose of radium-223 at Duke during the study period (median, 5 doses; range, 1-6). Among men with imaging during treatment, 2 of 14 (14.3%) had resolution of greater than or equal to 1 lesion on bone scan, 4 of 14 (28.6%) had zero new bone lesions, 10 of 14 (71.4%) had greater than or equal to 1 new bone lesion, 14 of 26 (53.9%) progressed on CT. After radium-223, 6 of 39 (15.4%) had resolution of 1 to 4 bone lesions, 15 of 39 (38.5%) demonstrated zero new bone lesions, 24 of 39 (61.5%) progressed on bone scan, 15 of 37 (40.5%) progressed on CT, and 10 of 34 (29.4%) progressed on both bone scan and CT. No men with zero new bone lesions after radium-223 ultimately progressed in bone alone and only 3 of 15 eventually demonstrated any progression in the bone. aBSI decreased significantly from baseline to after radium-223 among men with zero new bone lesions (median change in aBSI -0.23 [IQR, -1.5, 0.02]) and increased significantly for men with greater than or equal to 1 new postradium bone lesions (median change in aBSI 1.41 [IQR, -0.05, 3.63] [P = 0.018]). CONCLUSIONS: Bone and soft tissue progression during and following radium-223 is common in heavily pretreated men with mCRPC. However, stable disease and responses were observed in a subset of patients and may be associated with durable treatment response in the bone. Prospective studies are needed to further investigate the change in aBSI as a biomarker of bone scan response/stabilization and progression following treatment with radium-223.

Non-invasive sensitive brain tumor detection using dual-modality bioimaging nanoprobe.

Despite decades of efforts, non-invasive sensitive detection of small malignant brain tumors still remains challenging. Here we report a dual-modality 124I-labeled gold nanostar (124I-GNS) probe for sensitive brain tumor imaging with positron emission tomography (PET) and subcellular tracking with two-photon photoluminescence (TPL) and electron microscopy (EM). Experiment results showed that the developed nanoprobe has potential to reach sub-millimeter intracranial brain tumor detection using PET scan, which is superior to any currently available non-invasive imaging modality. Microscopic examination using TPL and EM further confirmed that GNS nanoparticles permeated the brain tumor leaky vasculature and accumulated inside brain tumor cells following systemic administration. Selective brain tumor targeting by enhanced permeability and retention effect and ultrasensitive imaging render 124I-GNS nanoprobe promise for future brain tumor-related preclinical and translational applications.

A novel quantitative polymerase chain reaction to monitor urinary tract mycoplasma infection in a dog.

The aim of the study was to develop a quantitative real-time PCR assay for diagnosis and monitoring of mycoplasma urinary tract infections (UTI) in a dog. An English Cocker Spaniel dog with the history of urinary tract infection was physically examined and laboratory findings identified chronic renal insufficiency and urinary tract infection. Attempts to culture organisms from pyuric urine failed, and empirical antibiotic therapy did not resolve the pyuria. A mycoplasma species most closely resembling Ureaplasma canigenitalium was identified in urine samples by conventional PCR and sequencing. A quantitative PCR method was developed to monitor and finally verify successful treatment. This novel approach to monitoring mycoplasma urinary tract infections is conceptually simple, and provides rapid results. It may have wider application in monitoring treatment efficacy for infections with other Mycoplasma spp. as well as additional organisms that are difficult to culture. SIGNIFICANCE AND IMPACT OF THE STUDY: In this study, we highlight two different findings, detection of Ureaplasma canigenitalium in a dog with chronic urinary tract infection and development of a quantitative real-time PCR test to track treatment results in an infected dog. This report is the first report of detection of U. canigenitalium in one dog in Australia. This novel qPCR method for monitoring mycoplasma urinary tract infections is conceptually simple and provides results fast. It will have wider applications in monitoring treatment efficacy for infections with mycoplasmas and mycoplasma-like organisms that are difficult to culture, and provides a sensitive guide to treatment progress.

Extended depth-of-field microscopy with a high-speed deformable mirror.

We present a wide-field fluorescence microscopy add-on that provides a fast, light-efficient extended depth-of-field (EDOF) using a deformable mirror with an update rate of 20 kHz. Out-of-focus contributions in the raw EDOF images are suppressed with a deconvolution algorithm derived directly from the microscope 3D optical transfer function. Demonstrations of the benefits of EDOF microscopy are shown with GCaMP-labeled mouse brain tissue.

Band Gap Engineering with Ultralarge Biaxial Strains in Suspended Monolayer MoS2.

We demonstrate the continuous and reversible tuning of the optical band gap of suspended monolayer MoS2 membranes by as much as 500 meV by applying very large biaxial strains. By using chemical vapor deposition (CVD) to grow crystals that are highly impermeable to gas, we are able to apply a pressure difference across suspended membranes to induce biaxial strains. We observe the effect of strain on the energy and intensity of the peaks in the photoluminescence (PL) spectrum and find a linear tuning rate of the optical band gap of 99 meV/%. This method is then used to study the PL spectra of bilayer and trilayer devices under strain and to find the shift rates and Grüneisen parameters of two Raman modes in monolayer MoS2. Finally, we use this result to show that we can apply biaxial strains as large as 5.6% across micron-sized areas and report evidence for the strain tuning of higher level optical transitions.

Incidental Thyroid Nodules at Non-FDG PET Nuclear Medicine Imaging: Evaluation of Prevalence and Malignancy Rate.

OBJECTIVE: The purpose of this study was to estimate the prevalence of thyroid nodules detected incidentally on non-FDG PET nuclear medicine imaging studies, the malignancy rate, and predictors of malignancy. MATERIALS AND METHODS: A retrospective review of more than 10 years of patient records at an academic medical center identified the cases of 31 patients with incidental focal radiotracer-avid thyroid findings on non-FDG PET nuclear medicine studies who underwent biopsy or surgical excision. Statistical analysis of patient and imaging features was performed to identify features predictive of malignancy. Society of Radiologists in Ultrasound and American Thyroid Association biopsy criteria were applied to patients who had ultrasound images for review. RESULTS: Thirty-one patients had incidental thyroid findings on (99m)Tc-sestamibi parathyroid scans (80.6%), (111)In-pentetreotide scans (16.1%), and (99m)Tc-tetrofosmin cardiac scans (3.2%). These three types of scans accounted for 21,402 total examinations in the study period. Thus, the prevalence of incidental thyroid findings on non-PET nuclear medicine studies that were evaluated by pathologic examination was 0.14%. The malignancy rate was 16.1% (5/31). No clinical or imaging features were identified as predictive of malignancy. Society of Radiologists in Ultrasound and American Thyroid Association criteria were applied to 23 thyroid nodules with available ultrasound images. According to both sets of criteria, biopsy was recommended for 19 of 23 (82.6%) nodules, and one of three (33.3%) cases of thyroid cancer was missed. CONCLUSION: Most thyroid nodules incidentally detected on non-FDG PET nuclear medicine studies are detected on (99m)Tc-sestamibi parathyroid scans and (111)In-pentetreotide scans. Because these nodules are extremely rare and the malignancy rate is high, further evaluation of incidental focal radiotracer-avid thyroid findings with ultrasound is an appropriate recommendation.

Outcomes and predictors of response from an optimised, multidisciplinary intervention for chronic fatigue states.

BACKGROUND: Medically unexplained chronic fatigue states are prevalent and challenging to manage. Cognitive behavioural therapy (CBT) and graded exercise therapy (GET) are effective in clinical trials. The evaluation of delivery in a standard healthcare setting is rare. An integrated treatment programme with individualised allocation of resources to patients' needs was developed and implemented through an academic outpatient clinic. It was hypothesised that the programme would result in similar responses to those observed in the clinical trials. AIM: To evaluate the outcomes of an integrated, 12-week CBT and GET programme delivered by exercise physiologists and clinical psychologists. METHODS: Consecutive eligible patients (n = 264) who met the diagnostic criteria for chronic fatigue syndrome or post-cancer fatigue were evaluated with self-report measures of fatigue, functional capacity and mood disturbance at baseline, end-of-treatment (12 weeks) and follow-up (24 weeks). A semi-structured interview recording the same parameters was conducted pre- and post-treatment by an independent clinician. Primary outcome was analysed by repeated measures analysis of variance and predictors of response were analysed by logistic regression. RESULTS: The intervention produced sustained improvements in symptom severity and functional capacity. A substantial minority of patients (35%) gained significant improvement, with male gender and higher pain scores at baseline predicting non-response. A small minority of patients (3%) worsened. CONCLUSION: The manualised protocol of integrated CBT and GET was successfully implemented, confirming the generally positive findings of clinical trials. Assessment and treatment protocols are available for dissemination to allow standardised management. The beneficial effects described here provide the basis for ongoing studies to optimise the intervention further and better identify those most likely to respond.

Certolizumab pegol in rheumatoid arthritis patients with low to moderate activity: the CERTAIN double-blind, randomised, placebo-controlled trial.

OBJECTIVES: This 52-week, randomised, double-blind phase IIIb study assessed efficacy and safety of certolizumab pegol (CZP) as add-on therapy to non-biologic disease-modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis (RA) patients with low to moderate disease activity, and stopping therapy in patients in sustained remission. METHODS: Patients were randomised 1:1 to CZP (400 mg at weeks 0, 2 and 4, then 200 mg every 2 weeks) or placebo (every 2 weeks) plus current non-biologic DMARDs. At week 24, patients who achieved the primary endpoint of Clinical Disease Activity Index (CDAI) remission at both weeks 20 and 24 stopped study treatment and continued in the study until week 52. RESULTS: Of 194 patients (CZP=96; placebo=98), >90% had moderate disease activity at baseline. Significantly more CZP patients met the primary endpoint than placebo patients (week 20 and 24 CDAI remission rates: 18.8% vs 6.1%; p≤0.05). At week 24, 63.0% vs 29.7% of CZP versus placebo patients (p<0.001) achieved LDA. Disease activity score (ESR) based on 28-joint count and Simplified Disease Activity Index remission rates were also significantly higher with CZP versus placebo (19.8% vs 3.1%; p≤0.01 and 14.6% vs 4.1%; p≤0.05). CZP patients reported improvements in physical function versus placebo (mean Health Assessment Questionnaire-Disability-Index change from baseline: CZP, -0.25 vs placebo, -0.03; p≤0.01). During the period following withdrawal of CZP or placebo, only 3/17 prior CZP patients and 2/6 prior placebo patients maintained CDAI remission until week 52, but CZP reinstitution allowed renewed improvement. Adverse and serious adverse event rates were comparable between CZP and placebo groups. CONCLUSIONS: Addition of CZP to non-biologic DMARDs is an effective treatment in RA patients with predominantly moderate disease activity, allowing low-disease activity or remission to be reached in a majority of the patients. However, the data suggest that CZP cannot be withdrawn in patients achieving remission. TRIAL REGISTRATION NUMBER: NCT00674362.

Dictionary-based image reconstruction for superresolution in integrated circuit imaging.

Resolution improvement through signal processing techniques for integrated circuit imaging is becoming more crucial as the rapid decrease in integrated circuit dimensions continues. Although there is a significant effort to push the limits of optical resolution for backside fault analysis through the use of solid immersion lenses, higher order laser beams, and beam apodization, signal processing techniques are required for additional improvement. In this work, we propose a sparse image reconstruction framework which couples overcomplete dictionary-based representation with a physics-based forward model to improve resolution and localization accuracy in high numerical aperture confocal microscopy systems for backside optical integrated circuit analysis. The effectiveness of the framework is demonstrated on experimental data.

Lifetime Attributable Risk of Cancer From Radiation Exposure During Parathyroid Imaging: Comparison of 4D CT and Parathyroid Scintigraphy.

OBJECTIVE: The purpose of this study is to measure the organ doses and effective dose (ED) for parathyroid 4D CT and scintigraphy and to estimate the lifetime attributable risk of cancer incidence associated with imaging. MATERIALS AND METHODS: Organ radiation doses for 4D CT and scintigraphy were measured on the basis of imaging with our institution's protocols. An anthropomorphic phantom with metal oxide semiconductor field effect transistor detectors was scanned to measure CT organ dose. Organ doses from the radionuclide were based on International Commission for Radiological Protection report 80. ED was calculated for 4D CT and scintigraphy and was used to estimate the lifetime attributable risk of cancer incidence for patients differing in age and sex with the approach established by the Biologic Effects of Ionizing Radiation VII report. A 55-year-old woman was selected as the standard patient according to the demographics of patients with primary hyperparathyroidism. RESULTS: Organs receiving the highest radiation dose from 4D CT were the thyroid (150.6 mGy) and salivary glands (137.8 mGy). For scintigraphy, the highest organ doses were to the colon (41.5 mGy), gallbladder (39.8 mGy), and kidneys (32.3 mGy). The ED was 28 mSv for 4D CT, compared with 12 mSv for scintigraphy. In the exposed standard patient, the lifetime attributable risk for cancer incidence was 193 cancers/100,000 patients for 4D CT and 68 cancers/100,000 patients for scintigraphy. Given a baseline lifetime incidence of cancer of 46,300 cancers/100,000 patients, imaging results in an increase in lifetime incidence of cancer over baseline of 0.52% for 4D CT and 0.19% for scintigraphy. CONCLUSION: The ED of 4D CT is more than double that of scintigraphy, but both studies cause negligible increases in lifetime risk of cancer. Clinicians should not allow concern for radiation-induced cancer to influence decisions regarding workup in older patients.

Inverse correlation of serum inflammatory markers with metabolic parameters in healthy, Black and White prepubertal youth.

OBJECTIVE: To examine for the first time the associations between pro-inflammatory cytokines and obesity-related metabolic biomarkers in, exclusively prepubertal, otherwise healthy obese and non-obese Black and White children, 7-9 years of age. DESIGN AND METHODS: Body mass index (BMI), homeostasis model assessment-estimated insulin resistance, visceral adipose tissue and subcutaneous adipose tissue (SAT (magnetic resonance imaging)); total body fat (dual-energy X-ray absorptiometry), ectopic, intrahepatic lipid (IHL) and intramyocellular lipid (IMCL) fat (proton magnetic resonance spectroscopy) and serum levels of interleukin (IL)-1, IL-6, IL-8, tumor necrosis factor alpha (TNF-α) and monocyte chemoattractant protein-1 were measured in 40 obese and non-obese children. Relationships between inflammatory cytokines and obesity were assessed by analysis of variance and Spearman's rank correlation. RESULTS: Significant inverse correlations were found between BMI z-score, SAT, total BF, and IHL and levels of TNF-α (Spearman's ρ=-0.36, -0.39, -0.43 and -0.39, respectively; P<0.05). Levels of IL-8 were significantly and inversely correlated with IMCL (-0.39; P=0.03) and remained significant after adjusting for race. IMCL was inversely associated with TNF-α only after adjusting for race (-0.37; P=0.04). CONCLUSIONS: Relationships between pro-inflammatory and metabolic markers commonly observed in adults are reversed in healthy, Black and White children before puberty. Prospective studies are warranted to determine how these inverse relationships modify chronic disease risk later in life.

Effect of vector asymmetry of radially polarized beams in solid immersion microscopy.

We theoretically and experimentally investigate the effect of imperfect vector symmetry on radially polarized beams focused by an aplanatic solid immersion lens at a numerical aperture of 3.3. We experimentally achieve circularly symmetric focused spot with a full-width-half-maximum of ~λ0/5.7 at λ0 = 1,310 nm, free-space wavelength. The tight spatial confinement and overall circular symmetry of the focused radially polarized beam are found to be sensitive to perturbations of its cylindrical polarization symmetry. The addition of a liquid crystal based variable retarder to the optical path can effectively ensure the vector symmetry and achieve circularly symmetric focused spots at such high numerical aperture conditions.

Evanescent waves in high numerical aperture aplanatic solid immersion microscopy: effects of forbidden light on subsurface imaging.

The collection of light at very high numerical aperture allows detection of evanescent waves above the critical angle of total internal reflection in solid immersion lens microscopy. We investigate the effect of such evanescent modes, so-called forbidden light, on the far-field imaging properties of an aplanatic solid immersion microscope by developing a dyadic Green's function formalism in the context of subsurface semiconductor integrated circuit imaging. We demonstrate that the collection of forbidden light allows for sub-diffraction spatial resolution and substantial enhancement of photon collection efficiency albeit inducing wave-front discontinuities and aberrations.

Charge tuning of nonresonant magnetoexciton phonon interactions in graphene.

Far from resonance, the coupling of the G-band phonon to magnetoexcitons in single layer graphene displays kinks and splittings versus filling factor that are well described by Pauli blocking and unblocking of inter- and intra-Landau level transitions. We explore the nonresonant electron-phonon coupling by high-magnetic field Raman scattering while electrostatic tuning of the carrier density controls the filling factor. We show qualitative and quantitative agreement between spectra and a linearized model of electron-phonon interactions in magnetic fields. The splitting is caused by dichroism of left- and right-handed circular polarized light due to lifting of the G-band phonon degeneracy, and the piecewise linear slopes are caused by the linear occupancy of sequential Landau levels versus ν.

Crude-oil biodegradation via methanogenesis in subsurface petroleum reservoirs.

Biodegradation of crude oil in subsurface petroleum reservoirs has adversely affected the majority of the world's oil, making recovery and refining of that oil more costly. The prevalent occurrence of biodegradation in shallow subsurface petroleum reservoirs has been attributed to aerobic bacterial hydrocarbon degradation stimulated by surface recharge of oxygen-bearing meteoric waters. This hypothesis is empirically supported by the likelihood of encountering biodegraded oils at higher levels of degradation in reservoirs near the surface. More recent findings, however, suggest that anaerobic degradation processes dominate subsurface sedimentary environments, despite slow reaction kinetics and uncertainty as to the actual degradation pathways occurring in oil reservoirs. Here we use laboratory experiments in microcosms monitoring the hydrocarbon composition of degraded oils and generated gases, together with the carbon isotopic compositions of gas and oil samples taken at wellheads and a Rayleigh isotope fractionation box model, to elucidate the probable mechanisms of hydrocarbon degradation in reservoirs. We find that crude-oil hydrocarbon degradation under methanogenic conditions in the laboratory mimics the characteristic sequential removal of compound classes seen in reservoir-degraded petroleum. The initial preferential removal of n-alkanes generates close to stoichiometric amounts of methane, principally by hydrogenotrophic methanogenesis. Our data imply a common methanogenic biodegradation mechanism in subsurface degraded oil reservoirs, resulting in consistent patterns of hydrocarbon alteration, and the common association of dry gas with severely degraded oils observed worldwide. Energy recovery from oilfields in the form of methane, based on accelerating natural methanogenic biodegradation, may offer a route to economic production of difficult-to-recover energy from oilfields.

Functional outcomes and quality of life after chemoradiotherapy: baseline and 3 and 6 months post-treatment.

Concomitant chemoradiotherapy provides organ preservation for those patients with head and neck cancer. We report the results of a prospective study that examined functional outcomes and quality of life (QOL) after chemoradiotherapy over the first 6 months post-treatment (tx). Twenty-nine patients with head and neck cancer were treated with chemoradiotherapy. All were seen baseline and 3 and 6 months post-tx. Assessments included the performance status scale (PSS), Karnofsky performance status scale, tongue strength, jaw opening, and saliva weight. QOL was patient-rated using the eating assessment tool (EAT-10), MD Anderson dysphagia inventory, speech handicap index (SHI), and the EORTC H&N35 scale. Repeated-measures ANOVAs were used, with significance at p < 0.05. PSS scores were significantly different across time points. Tongue strength, jaw range of motion (ROM), and saliva weight were significantly lower at 3 and 6 months than at baseline. QOL was significantly worse after tx, although it improved by 6 months as rated with the EAT-10 and the SHI scores were significantly worse at 3 and 6 months. EORTC domains of swallowing, senses, speech, dry mouth, and sticky saliva were significantly worse at 3 and 6 months. Concomitant chemoradiotherapy for treatment of head and neck tumors can result in impaired performance outcomes and QOL over the first 6 months post-tx. However, performance status, tongue strength, jaw ROM, and eating QOL were only mildly impaired by 6 months post-tx. Saliva production and speech QOL remained significantly impaired at 6 months post-treatment. Current studies are examining outcomes at 12 and 24 months post-treatment to better predict outcomes over time in this population.

How graphene slides: measurement and theory of strain-dependent frictional forces between graphene and SiO2.

Strain, bending rigidity, and adhesion are interwoven in determining how graphene responds when pulled across a substrate. Using Raman spectroscopy of circular, graphene-sealed microchambers under variable external pressure, we demonstrate that graphene is not firmly anchored to the substrate when pulled. Instead, as the suspended graphene is pushed into the chamber under pressure, the supported graphene outside the microchamber is stretched and slides, pulling in an annulus. Analyzing Raman G band line scans with a continuum model extended to include sliding, we extract the pressure dependent sliding friction between the SiO2 substrate and mono-, bi-, and trilayer graphene. The sliding friction for trilayer graphene is directly proportional to the applied load, but the friction for monolayer and bilayer graphene is inversely proportional to the strain in the graphene, which is in violation of Amontons' law. We attribute this behavior to the high surface conformation enabled by the low bending rigidity and strong adhesion of few layer graphene.

First detection of Omicron variant BA.4.1 lineage in dogs, Chile.

SARS-CoV-2's rapid global spread caused the declaration of COVID-19 as a pandemic in March 2020. Alongside humans, domestic dogs and cats are also susceptible to infection. However, limited reports on pet infections in Chile prompted a comprehensive study to address this knowledge gap. Between March 2021 and March 2023, the study assessed 65 pets (26 dogs and 39 cats) from 33 COVID-19+ households alongside 700 nasal swabs from animals in households with unknown COVID-19 status. Using RT-PCR, nasal, fecal, and environmental samples were analyzed for the virus. In COVID-19+ households, 6.06% tested positive for SARS-CoV-2, belonging to 3 dogs, indicating human-to-pet transmission. Pets from households with unknown COVID-19 status tested negative for the virus. We obtained 2 SARS-CoV-2 genomes from animals, that belonged to Omicron BA.4.1 variant, marking the first report of pets infected with this lineage globally. Phylogenetic analysis showed these sequences clustered with human sequences collected in Chile during the same period when the BA.4.1 variant was prevalent in the country. The prevalence of SARS-CoV-2 in Chilean pets was relatively low, likely due to the country's high human vaccination rate. Our study highlights the importance of upholding and strengthening human vaccination strategies to mitigate the risk of interspecies transmission. It underscores the critical role of the One Health approach in addressing emerging zoonotic diseases, calling for further research on infection dynamics and risk factors for a comprehensive understanding.