Focal Changes Research Articles

P19 Diagnostic conundrums in paraneoplastic pemphigus

Abstract Paraneoplastic pemphigus (PNP) is a subset of pemphigus, a group of autoimmune blistering skin disorders. A 51-year-old man presented with paraneoplastic pemphigus associated with a hepatic neoplasm. He described an epigastric mass and associated mucositis affecting the orogenital mucosae, as well as the sclerae. Both computed tomography and magnetic resonance imaging demonstrated a 14-cm mass arising from the left lobe of the liver. A liver biopsy showed features of an atypical spindle-cell neoplasm, but a definite diagnosis was not possible. A diagnostic skin biopsy was taken from his outer lip mucosae. Histology showed surface ulceration with an acute inflammatory infiltrate, lichenoid lymphoplasmacytic infiltrate with focal basal vacuolar change, degenerate keratinocytes and adjacent suprabasal acantholysis and spongiosis. Perilesional direct immunofluorescence (DIF) was negative; however, indirect immunofluorescence (IIF) showed intercellular IgG antibodies on transitional epithelium with a high titre of 1 : 800 to rat bladder. These finding were consistent with the suspected clinical diagnosis of paraneoplastic pemphigus. The patient was commenced on oral prednisolone 1 mg kg−1 daily. Topical therapy included budesonide mixed with sweetener applied to the oral mucosae. Following this, a trial of 3 days of intravenous methylprednisolone along with 2% cocaine mouthwash, triple mouthwash (betamethasone, doxycycline and nystatin) and Dermovate® ointment was commenced, with improvement noted in pain, haemorrhage and ulceration. Intravenous immunoglobulin was administered preoperatively. The patient was subsequently transferred to a specialist centre for hepatobiliary surgery and listed for debulking of the liver mass. Postoperatively, he had plasmapheresis, with a noted reduction in mucosal ulceration and significant improvement in pain. Chemotherapy with doxorubicin and ifosfamide was initiated thereafter. PNP is a severe autoimmune blistering disorder characterized clinically by flaccid blisters and erosions. Although much is yet to be understood regarding the pathophysiology of PNP, studies show that the development of autoantibodies to the plakin family and desmogleins 1 and 3 play a particular role in its pathogenesis. In addition to autoantibodies, CD8+ T cells have also been shown to contribute to the development of PNP. In adults, the majority of cases are associated with an underlying haematological malignancy and, rarely, a solid-organ tumour. DIF findings include IgG and C3 deposition along the intercellular and basement membrane zones, while IIF detects autoantibodies to proteins found in transitional or stratified squamous epithelium. As in our case, reports have shown that the DIF can be negative, with one study showing a positive DIF in only 41% of cases. This case highlights the complex diagnostic and treatment challenges practitioners face when dealing with PNP and the patients it affects.

Cylindrical liquid crystal micro-lens array based on interdigital electrodes

ABSTRACT Based on the traditional structure of in plane switching liquid crystal display, a cylindrical liquid crystal micro-lens array driven by interdigital electrodes is proposed, and its performance is studied. Firstly, the director distribution and relative phase difference distribution of liquid crystal molecules were calculated, which shows that this structure can be used to fabricate cylindrical liquid crystal micro-lens. Then, by comparing lenses of difference sizes, it is found that narrow electrodes should be selected for lens production, and the centre of the electrode gap should be selected as the central axis of a single liquid crystal micro-lens. Finally, a certain electrode structure is selected to explore its focal length, focusing quality and zoom time. The results show that the focal length of the liquid crystal micro-lens decreases gradually with the increase of the driving voltage. When the driving voltage is between 3 Vrms and 5.5 Vrms, the liquid crystal micro-lens has good focusing quality, and its corresponding focal length changes from 1.63 mm to 20.28 mm. Based on this structure, when the liquid crystal lens is driven by the above two voltages alternately, the time required for liquid crystal molecules to reach stability is 2.35 s and 3.87 s respectively.

Cell-free DNA fragmentation profiling for therapeutic response monitoring in metastatic colorectal cancer.

e15664 Background: Currently available circulating cell-free DNA (cfDNA) assays require deep-targeted sequencing to detect cancer-specific mutations at low mutant allele frequency (MAF) levels in the blood. Recently, we developed a tumor-agnostic, mutation-independent approach that utilizes low-coverage whole genome sequencing called DELFI (DNA evaluation of fragments for early interception) Tumor Fraction (DELFI-TF), a model designed to predict plasma tumor fractions based on genome-wide fragmentation-related features. Here, we report the results of DELFI-TF applied to a prospective cohort of patients with metastatic colorectal cancer (mCRC). Methods: Overall, 692 longitudinal plasma samples collected from 153 initially treatment-naive mCRC patients participating in the phase III CAIRO5 study (NCT02162563) were sequenced at low coverage and used for training and cross-validation. In patients with tumor-tissue-proven RAS/BRAF mutations, the tumor fractions were quantified as the cfDNA MAF of the RAS/BRAF variant measured by droplet digital PCR (ddPCR). Using fragment-sequencing statistics, a Bayesian regression model was trained against the MAF of the tumor-specific driver RAS/BRAF variant in all longitudinal timepoints to generate DELFI-TF scores. Changes in longitudinal DELFI-TF scores during first-line therapy (DELFI-TF slopes) were examined to predict treatment response and survival outcomes. Results: The DELFI-TF scores were strongly correlated with RAS/BRAF cfDNA MAF measured by ddPCR ( Pearson, r= 0.85, p< 0.001). Baseline DELFI-TF correlated with dimensions of liver metastases reported in CT scans ( Pearson, r= 0.49, p< 0.001) as well as clinical response, with pre-treatment levels significantly lower in patients with a later-confirmed partial or complete response ( Wilcoxon, p< 0.05). Patients with low or negative DELFI-TF slopes presented with longer progression-free survival in the overall study population (13.4 months vs 10.4 months, HR = 2.03, 95% CI 1.25 to 3.32, Log-rank p< 0.01) and in patients who experienced durable clinical benefit (16.7 months vs 13.3 months, HR = 2.24, 95% CI 1.1 to 4.55, Log-rank p= 0.023). Patients with low or negative DELFI-TF slopes also experienced significantly longer overall survival (59.4 months vs 29.1 months, HR = 3.05, 95% CI 1.58-5.90, Log-rank p< 0.001). Tissue-informed focal and arm-level copy number changes were detected 4-12 weeks after liver metastases resection. Most patients detected as having a molecular relapse were diagnosed earlier than clinical recurrences identified by conventional imaging. Conclusions: DELFI-TF demonstrates the ability to use cfDNA fragmentomes to estimate cfDNA tumor burden with performance comparable to standard approaches for treatment response monitoring and clinical outcome prediction.

Клініко-генетичні характеристики дітей раннього віку з епілептичними енцефалопатіями та їхня роль у розвитку розладів аутистичного спектра

Purpose - to analyze the clinical and genetic characteristics of young children with developmental and epileptic encephalopathies and to determine their role in the formation of autism spectrum disorders (ASD). Materials and methods. The study included 58 children aged 0-3 years with the onset of epileptic seizures in the first year of life, clinical manifestations of developmental and epileptic encephalopathies with genetic etiology. The examination included assessment of neurological status, collection of anamnesis, assessment of semiology and determination of seizure type, assessment of development and screening for ASD at the age of 18 and 24 months, night sleep electroencephalography (video EEG), brain magnetic resonance imaging (MRI), screening for pathogenic variants by whole-exome sequencing or examination of relevant gene panels. Pathogenic variants of 33 different genes were found in the examined children. Pathogenic variants of genes responsible for the function of ion channels (41.3%), intracellular signaling systems (17.2%), organelles and intracellular membranes (12.1%) were most frequently found. 44.8% of children had symptoms of ASD at the age of 18 months, and 68.9% of children at the age of 24 months. The predominant types of epileptic seizures were myoclonic (37.9%) and focal clonic (34.4%). According to video EEG monitoring, interictal focal (39.6%) and multifocal (22.4%) epileptiform changes dominated in the examined children. According to MRI, structural changes of the brain were found in 86.2% of children. Conclusions. It is shown that children with a history of myoclonic seizures (RR=1.264) and infantile spasms (RR=1.44) have a high risk of developing ASD at 24 months. It has been established that there is a positive relationship between the presence in the child of mutations in the genes responsible for the functioning of ion channels (RR=1.32), as well as for the functioning of synapses, neurotransmitters and receptors (RR=1.5) and the development of ASD in 24 months. The research was carried out in accordance with the principles of the Declaration of Helsinki. The research protocol was approved by the Bioethics and Deontology Commission. Informed consent of the children’s parents was obtained for the research. No conflict of interests was declared by the authors.

Preclinical Cartilage Changes of the Knee Joint in Adolescent Competitive Volleyball Players: A Prospective T2 Mapping Study.

To investigate the potential effects of volleyball as a competitive sport in adolescence on the cartilage of knee joints using T2 mapping in MRI and identification of preclinical cartilage changes. Volleyball as an impact sport often leads to damage of the knee joint cartilage in adulthood. As T2 mapping is widely available and highly capable of detecting cartilage changes prior to conventional MRI sequences, such a detection may allow adolescent volleyball players to change their training regime before structural damage can occur to the cartilage and pose the risk of osteoarthritis. Comparative study of the patellar, femoral, and tibial cartilage of 60 knee joints using T2 mapping on 3 T MRI. In each case, both knees of 15 adolescent competitive volleyball athletes were compared with 15 controls. In the group of competitive athletes, more focal cartilage changes were detected in the medial facet of the patellofemoral cartilage and in the medial femoral condyle of the knee joint cartilage (p = .01 and p <.05, respectively). Furthermore, the latter showed a diffused increase in maximal T2 mapping values (p <.04 right and p = .05 left). The distribution of changes seems to further depend on the player's position. In adolescent volleyball players in competitive sports, T2 mapping demonstrates early cartilage changes in both the patellofemoral and medial femoral cartilages. The distribution of lesions depends on the player's position. Since the cascade from T2 relaxation time increase to conspicuous cartilage damage is well established, early counter-regulation (e. g., adapted training profile, targeted physiotherapy, and appropriate muscle building training) has the potential to prevent later damage. · Volleyball as a competitive sport in adolescence leads to preclinical knee cartilage changes.. · Cartilage changes are both focal and diffuse.. · Jumping-intensive player positions seem to show more patellofemoral and running-intensive more condylar cartilage changes.. · Early detection of these changes could prevent progression to cartilage damage through adapted training.. · Roth C, Hirsch F, Sorge I et al. Preclinical Cartilage Changes of the Knee Joint in Adolescent Competitive Volleyball Players: A Prospective T2 Mapping Study. Fortschr Röntgenstr 2023; 195: 913 - 923.

Clinical features of 23 neonates infected with Omicron variant of severe acute respiratory syndrome coronavirus 2

To summarize the clinical features of neonates infected with Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The medical data of 23 neonates with Omicron variant of SARS-CoV-2 infection admitted to the City North Campus of Urumqi First People's Hospital from October to December 2022 were retrospectively reviewed. All 23 infants had a history of exposure to confirmed caregivers with SARS-CoV-2 infection after birth, and none of them was vertically transmitted. Clinical classification: 5 cases of asymptomatic infection, 18 cases of mild infection, and no cases of moderate, severe, or critically ill. The first symptoms were fever in 13 cases, cough in 3 cases, nasal congestion in 1 case, and diarrhea in 1 case. Blood white blood cell counts decreased in 2 cases, and C-reactive protein increased in 1 case. Seven infants underwent chest X-ray examination due to cough or shortness of breath, and one of which showed focal exudative changes, while the rest showed no abnormal changes. All infants were discharged after symptomatic treatment and the median hospital stay was 6 days. The duration of nucleic acid positivity of SARS-CoV-2 was negatively correlated with N gene Ct values and ORF1ab gene Ct values (rs=-0.719 and -0.699, respectively; P<0.05). One month after discharge, all infants had no symptoms or signs of nucleic acid re-positivity. The clinical manifestations are usually mild or asymptomatic in neonates infected with SARS-CoV-2 Omicron variant. The lower the Ct values of the N and ORF1ab genes of SARS-CoV-2, the longer the duration of nucleic acid positivity. Neonates infected with SARS-CoV-2 Omicron variant can have a good prognosis after symptomatic treatment.

The Spectrum of Presentation, Diagnosis, and Clinical Outcome of Central Nervous System Tuberculosis: A Case Series in Bangabandhu Sheikh Mujib Medical University

Bangladesh has the highest prevalence of tuberculosis (TB). Of these, tubercular meningitis is the most common and most devastating. The usual course is that of insidious onset and subacute progression. Adults with TBM often present with the classic meningitis symptoms of fever, headache, and meningismus (stiff neck) along with focal neurological deficits, behavioral changes, and alterations in consciousness. TBM is prone to rapid deterioration once meningeal symptoms and focal neurological signs supervene, leading to stupor, coma, and death within 5 to 8 weeks [1,2].

Presymptomatic grey matter alterations in ALS kindreds: a computational neuroimaging study of asymptomatic C9orf72 and SOD1 mutation carriers

BackgroundThe characterisation of presymptomatic disease-burden patterns in asymptomatic mutation carriers has a dual academic and clinical relevance. The understanding of disease propagation mechanisms is of considerable conceptual interests, and defining the optimal time of pharmacological intervention is essential for improved clinical trial outcomes.MethodsIn a prospective, multimodal neuroimaging study, 22 asymptomatic C9orf72 GGGGCC hexanucleotide repeat carriers, 13 asymptomatic subjects with SOD1, and 54 “gene-negative” ALS kindreds were enrolled. Cortical and subcortical grey matter alterations were systematically appraised using volumetric, morphometric, vertex, and cortical thickness analyses. Using a Bayesian approach, the thalamus and amygdala were further parcellated into specific nuclei and the hippocampus was segmented into anatomically defined subfields.ResultsAsymptomatic GGGGCC hexanucleotide repeat carriers in C9orf72 exhibited early subcortical changes with the preferential involvement of the pulvinar and mediodorsal regions of the thalamus, as well as the lateral aspect of the hippocampus. Volumetric approaches, morphometric methods, and vertex analyses were anatomically consistent in capturing focal subcortical changes in asymptomatic C9orf72 hexanucleotide repeat expansion carriers. SOD1 mutation carriers did not exhibit significant subcortical grey matter alterations. In our study, none of the two asymptomatic cohorts exhibited cortical grey matter alterations on either cortical thickness or morphometric analyses.DiscussionThe presymptomatic radiological signature of C9orf72 is associated with selective thalamic and focal hippocampal degeneration which may be readily detectable before cortical grey matter changes ensue. Our findings confirm selective subcortical grey matter involvement early in the course of C9orf72-associated neurodegeneration.

Reliability of resting-state functional connectivity in the human spinal cord: Assessing the impact of distinct noise sources

The investigation of spontaneous fluctuations of the blood-oxygen-level-dependent (BOLD) signal has recently been extended from the brain to the spinal cord, where it has stimulated interest from a clinical perspective. A number of resting-state functional magnetic resonance imaging (fMRI) studies have demonstrated robust functional connectivity between the time series of BOLD fluctuations in bilateral dorsal horns and between those in bilateral ventral horns, in line with the functional neuroanatomy of the spinal cord. A necessary step prior to extension to clinical studies is assessing the reliability of such resting-state signals, which we aimed to do here in a group of 45 healthy young adults at the clinically prevalent field strength of 3T. When investigating connectivity in the entire cervical spinal cord, we observed fair to good reliability for dorsal-dorsal and ventral-ventral connectivity, whereas reliability was poor for within- and between-hemicord dorsal-ventral connectivity. Considering how prone spinal cord fMRI is to noise, we extensively investigated the impact of distinct noise sources and made two crucial observations: removal of physiological noise led to a reduction in functional connectivity strength and reliability – due to the removal of stable and participant-specific noise patterns – whereas removal of thermal noise considerably increased the detectability of functional connectivity without a clear influence on reliability. Finally, we also assessed connectivity within spinal cord segments and observed that while the pattern of connectivity was similar to that of whole cervical cord, reliability at the level of single segments was consistently poor. Taken together, our results demonstrate the presence of reliable resting-state functional connectivity in the human spinal cord even after thoroughly accounting for physiological and thermal noise, but at the same time urge caution if focal changes in connectivity (e.g. due to segmental lesions) are to be studied, especially in a longitudinal manner.

Computed tomographic parenchymal lung findings in premature infants with pulmonary vein stenosis.

Developmental pulmonary vein pulmonary vein stenosis in the setting of prematurity is a rare and poorly understood condition. Diagnosis can be challenging in the setting of chronic lung disease of prematurity. High-resolution non-contrast chest computed tomography (CT) is the conventional method of evaluating neonates for potential structural changes contributing to severe lung dysfunction and pulmonary hypertension but may miss pulmonary venous stenosis due to the absence of contrast and potential overlap in findings between developmental pulmonary vein pulmonary vein stenosis and lung disease of prematurity. To describe the parenchymal changes of pediatric patients with both prematurity and pulmonary vein stenosis, correlate them with venous disease and to describe the phenotypes associated with this disease. A 5-year retrospective review of chest CT angiography (CTA) imaging in patients with catheterization-confirmed pulmonary vein stenosis was performed to identify pediatric patients (< 18years) who had a history of prematurity (< 35weeks gestation). Demographic and clinical data associated with each patient were collected, and the patients' CTAs were re-reviewed to evaluate pulmonary veins and parenchyma. Patients with post-operative pulmonary vein stenosis and those with congenital heart disease were excluded. Data was analyzed and correlated for descriptive purposes. A total of 17 patients met the inclusion criteria (12 female, 5 male). All had pulmonary hypertension. There was no correlation between mild, moderate, and severe grades of bronchopulmonary dysplasia and the degree of pulmonary vein stenosis. There was a median of 2 (range 1-4) diseased pulmonary veins per patient. In total, 41% of the diseased pulmonary veins were atretic. The right upper and left upper lobe pulmonary veins were the most frequently diseased (n = 13/17, 35%, n = 10/17, 27%, respectively). Focal ground glass opacification, interlobular septal thickening, and hilar soft tissue enlargement were always associated with the atresia of an ipsilateral vein. Recognition of the focal parenchymal changes that imply pulmonary vein stenosis, rather than chronic lung disease of prematurity changes, may improve the detection of a potentially treatable source of pulmonary hypertension, particularly where nonangiographic studies result in a limited direct venous assessment.

Machine learning enables the design of a bidirectional focusing diffractive lens.

Machine learning can efficiently empower the inverse design of cascaded diffractive optical elements. In this work, we explore the inverse design of a bidirectional focusing diffractive lens in a cascaded configuration through the diffractive optical neural network (DONN) machine learning method. The bidirectional focusing diffractive lens consists of two on-axially cascaded multi-level diffractive lenses. Each lens consists of concentric rings with equal widths and varying heights. The height of each concentric ring is optimized as part of the design algorithm. The diffractive lens has a focal length f+ as light propagates in the forward (Z+) direction. As light propagates in the backward (Z-) direction, the focal length changes to f-. The designed lens is fabricated through a two-photon polymerization 3D printing technique. The proposed design is polarization insensitive and miniature and can be readily applied in future functional optical imaging systems.

Aspects of Stage-by-Stage Diagnosis of Pulmonary Mycobacteriosis in Real Clinical Practice

The objective: to analyze the effectiveness of etiological verification of pulmonary mycobacteriosis when using various biological materials at different diagnostic stages.Subjects and Methods. In Center for Diagnosis and Rehabilitation of Respiratory Diseases, CTRI, the results of stage-by-stage examinations of 142 patients (from 2018 to 2022) were analyzed. A retrospective, prospective, cohort, open study was conducted. Inclusion criteria: pulmonary mycobacteriosis etiologically verified by comprehensive microbiological examinations (molecular genetic and cultural tests) (with retrospective analysis after all stages of examination). Exclusion criteria: HIV infection. 115 women and 27 men were enrolled in the study, the age ranged from 21 to 86 years, the mean age was 57,9 years.All patients referred to CTRI for examination due to newly detected changes in the lungs (bronchiectasis, focal changes, and cavities). For etiological verification of the diagnosis, microbiological sputum testing was performed (Stage 1 of the examination); when negative results were obtained, bronchoscopy was prescribed and bronchobiopsies were used for microbiological and molecular genetic diagnostics – Stage 2. In case of negative results of Stage 2, the patient was recommended to undergo a diagnostic resection of the lung – Stage 3 of the examination. At all stages, specimens were sent for comprehensive microbiological testing: fluorescent microscopy to detect acid-fact mycobacteria, real-time polymerase chain reaction (PCR-RV) to detect NTBM DNA. Identification of NTBMB was carried out by molecular genetic methods (PCR for the presence of MTB DNA/NTBM (SYNTOL, Russia), and on DNA strips (GenoType Mycobacterium CM\AS Hain Livescience, Germany)). Specimens were cultured on a liquid medium in the ВАСТЕС MGIT960 (BD, USA).The diagnosis of mycobacteriosis was established in accordance with the diagnostic criteria proposed in the guidelines of the American Thoracic Society (ATS) and the Infectious Diseases Society of America (IDSA) (2020): detection of NTBM in 2 sputum samples or in 1 sample of bronchobiopsy specimens or in 1 surgical specimens [15].The studied data were entered to the Microsoft Office Excel sheet (Microsoft, USA) for statistical processing; the level of statistical significance of differences was taken as 0.05.Results. It was found that slow-growing NTBM were identified as etiologically significant in 93.0%, of which 78.1% was M. avium, fast-growing NTBM were represented only by M. abscessus, 7% of observations. During X-ray examination, the bronchiectatic form – 52.1% (74/142) was detected more often compared to the abdominal – 30.9% (44/142) and focal forms – 16.9% (24/142) (p&lt;0.001). When verifying mycobacteriosis in patients with a negative sputum test – Stage 2 of the examination – the effectiveness was 91.0% (80/88). Regardless of the radiological form of the disease and dissemination of the disease, bronchoscopy revealed pathology of the tracheobronchial tree in 85.2% of cases, mainly in the form of bronchitis with purulent secretions.

Raising Clinical Suspicion for Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like Episodes (MELAS): Recurrent Seizures, Stroke-like Episodes, and Cortical Atrophy in Young Patients (P3-1.007)

<h3>Objective:</h3> Phenotypic variability and lack of familiarity with criteria can make diagnosis of MELAS challenging. Clinicians should be cognizant and consider early MR spectroscopy with genetic screening. <h3>Background:</h3> MELAS is a rare, progressive mitochondrial disorder that can be missed if clinical suspicion is low. <h3>Design/Methods:</h3> A thorough chart review was conducted. <h3>Results:</h3> <h3>Case 1:</h3> A 33-year-old female presented with recurrent right-sided visual scotomas. MRI showed focal DWI changes to the occipital lobe. Continuous video-EEG showed subclinical occipital lobe seizures. The patient had a recurrent episode of right-sided vision changes, speech difficulty and poor comprehension. MRI showed cortical atrophy and DWI abnormalities without ADC mismatch in the left occipital and left posterior temporal lobes. Stroke and infectious workup was unrevealing. Another episode of numbness, hearing loss, and word-finding difficulty prompted MR spectroscopy, screening lactate level, and genetic analysis. The diagnosis of MELAS was established based on the patient’s recurrent seizures, cortical visual loss, acute lesions on MRI, high plasma lactate, and a confirmed, possibly pathogenic mutation in MT-TL1. She suffered from neurological deterioration and passed away 6 months later. <h3>Case 2:</h3> Patient is a 26-year-old male with a long history of migraines with visual disturbances. MRI showed edema in the left occipital lobe. Subsequently, he presented with an intractable headache associated with left-sided peripheral vision loss and left leg weakness. MRI was notable for hyperintense flair signal in the right occipital lobe and marked atrophy. EEG showed frequent seizures and workup for stroke and encephalitis was unrevealing. Lactate levels were elevated and genetic screening was notable for MT-TL1 mutation. <h3>Conclusions:</h3> Patients younger than 40 with stroke-like symptoms, brain atrophy disproportionate to age, and negative infectious and vascular workup should be evaluated for MELAS. MR Spectroscopy, lactate levels, and genetic testing are important non-invasive screening measures. <b>Disclosure:</b> Mr. Tallavajhala has nothing to disclose. Dr. Bochenek has stock in JNJ, Abbott, Moderna, Pfizer. Ms. Dwivedi has nothing to disclose. Ms. Caffio-Learner has nothing to disclose. Miss Suliman has nothing to disclose. Dr. Bashir has nothing to disclose. Dr. Kurukumbi has nothing to disclose.

The contribution of thalamic pathology to the clinical manifestations of frontotemporal dementia phenotypes (P5-12.004)

<h3>Objective:</h3> To systematically characterise thalamus pathology in frontotemporal dementia (FTD) phenotypes <h3>Background:</h3> FTD is classically associated with distinctive cortical atrophy patterns. However, the spectrum of cognitive and behavioural manifestations in FTD arise from multi-synaptic network dysfunction. The thalamus is a key hub of several corticobasal and corticocortical circuits. The main circuits relayed via the thalamic nuclei include the dorsolateral prefrontal circuit; the anterior cingulate circuit; and the orbitofrontal circuit. <h3>Design/Methods:</h3> Thalamus pathology was quantitatively evaluated at a nuclear, vertex and morphometric level in a prospective, multimodal imaging study using a standardised neuroimaging protocol. 10 patients with behavioural FTD (bvFTD), 15 patients with non-fluent variant primary progressive aphasia (nfvPPA) and 5 patients with semantic variant PPA (svPPA) were evaluated with reference to 100 healthy controls. All patients underwent detailed clinical and neuropsychological profiling and whole-genome sequencing. <h3>Results:</h3> Volumetric analyses revealed widespread bilateral thalamic nuclear volume loss in bvFTD; selective bilateral with left-sided predominant thalamic degeneration was captured in nfvPPA; and more focal, left-lateralised thalamic volume loss identified in svPPA. Vertex analyses showed diffuse thalamic surface changes in bvFTD and nfvPPA, but not svPPA. Morphometric analyses demonstrated extensive symmetric intra-thalamic changes in nfvPPA, and mostly right-sided changes in both bvFTD and svPPA. <h3>Conclusions:</h3> FTD is associated with considerable focal thalamic degeneration. Phenotype-specific thalamic traits mirror established cortical vulnerability patterns. Thalamic nuclei associated with behaviour and language functions are preferentially involved. FTD is not solely associated with cortical atrophy. The manifestations of FTD are likely to stem from cortico-subcortical circuitry dysfunction and not exclusively driven by focal cortical changes. <b>Disclosure:</b> Dr. McKenna has nothing to disclose. Dr. Hutchinson has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Hutchinson has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Teva. Dr. Hutchinson has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for Teva. Dr. Bede has nothing to disclose.

Prediction of Post-stroke Motor Recovery Benefits from Measures of Sub-acute Widespread Network Damages (P12-8.002)

<h3>Objective:</h3> Developing a more accurate post-stroke motor recovery prediction model leveraging brain network connectivity measurements. <h3>Background:</h3> Following an acute ischemic stroke, some patients recover almost completely, while others barely recover. It is known that lesion volume, initial motor impairment, and cortico-spinal tract asymmetry (benchmark features) significantly impact motor changes over time. However, accurate prediction models of patients’ recovery are still missing. Recent work suggested that disabilities arise not only from focal structural changes but also from widespread alterations in inter-regional connectivity. Here, we built on this hypothesis to develop a more accurate post-stroke motor recovery prediction model. <h3>Design/Methods:</h3> We evaluated a dataset of 37 patients (17 women) with upper extremity motor strokes. Their impairment was assessed at 2 weeks (baseline) and 3 months after the stroke using the Fugl-Meyer-Assessment. 18 graph measures of global structural connectivity were obtained using the patients’ T2 lesion mask to virtually reproduce the lesions in 60 healthy streamline tractography connectomes. We added these indirect measures to the benchmark features, and we used a ridge regression regularization in a leave-one-out cross-validation framework to predict motor recovery at 3 months post-injury. <h3>Results:</h3> Prediction accuracy significantly increased when using brain connectivity measures (R²=0.68, 95% CI: 0.64–0.74) as compared to benchmark features alone (R²=0.38, 95% CI: 0.31–0.51). <h3>Conclusions:</h3> We report that global measures of brain connectivity estimated by introducing virtual lesions in healthy structural connectomes significantly increase the accuracy of motor recovery prediction in stroke patients compared to focal and clinical measures used until now. This indirect estimation of the stroke impact on the whole brain connectome is more readily available than direct measures of structural connectivity obtained with magnetic resonance imaging (MRI) and would, therefore, have a more substantial clinical impact. <b>Disclosure:</b> An immediate family member of Dr. Pirondini has stock in Reach Neuro. The institution of Dr. Pirondini has received research support from NIH. The institution of an immediate family member of Dr. Pirondini has received research support from NIH. Dr. Pirondini has received intellectual property interests from a discovery or technology relating to health care. An immediate family member of Dr. Pirondini has received intellectual property interests from a discovery or technology relating to health care. Maria Giulia Preti has nothing to disclose. Dimitri Van De Ville has nothing to disclose. Prof. Guggisberg has nothing to disclose. Dr. Rivier has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Pyxis Partners.

Controllable terahertz beam focusing and rotating by graphene-assisted microring metasurfaces

This research proposes a terahertz (THz) metalens for focusing THz waves with an electrically controllable focal length. The dynamic of tuning of THz metalenses with graphene provides high controllability, fast responses, and compact structures for beam focusing. An array of graphene microrings has been presented with significant phase variations possibility. The three-dimensional finite-difference time-domain method has been employed for the analysis of the proposed structure. Applying a voltage to the graphene layer changes the graphene Fermi level, and the focal length can be controlled. As the chemical potential of graphene varies from 0.1 to 0.3 eV, the focal length changes 20.5λ (from 4 to 12.2 mm at the frequency of 0.75 THz). In addition, by biasing every array of graphene microrings with different gate voltages, we can electrically rotate the focal beam up to 32.02 deg. An equivalent circuit model (CM) is proposed for fast analysis and the verification of the FDTD results as well. The achieved results of the CM comply very well with those derived by the FDTD method. The proposed structure has the potential to be used in THz imaging.

Abstract 5714: Cell-free DNA fragmentation profiling for monitoring therapeutic response in metastatic colorectal cancer

Abstract BACKGROUND: Cell-free circulating tumor DNA (ctDNA) assays have been adopted to monitor therapeutic response in both early- and late-stage cancer. However, tests currently available require deep-targeted sequencing to detect cancer-specific mutations at low mutant allele frequency (MAF) levels in the circulation. Recently, we developed a tumor-agnostic approach called DELFI Tumor Fraction (DELFI-TF), a Bayesian probabilistic model designed to predict plasma tumor fractions based on genome-wide fragmentation-related features. METHODS: Overall, 692 longitudinal plasma samples collected from 153 patients with initially unresectable colorectal cancer (CRC) liver-only metastases participating in the phase III study CAIRO5 (NCT02162563) were split across a training (RAS/BRAF mutant) and a validation cohort (RAS/BRAF wildtype). For all cell-free DNA (cfDNA) samples of patients within the training cohort (n=312), the tumor burden was quantified as the MAF of the tumor-tissue-proven RAS/BRAF variant measured by digital droplet PCR (ddPCR). Using cfDNA fragment-sequencing statistics from low-coverage WGS data, a Bayesian regression model was trained against the MAF of the tumor-specific driver RAS/BRAF variant in all longitudinal timepoints in the training cohort. Changes in DELFI-TF scores during first-line FOLFOX/FOLFIRI and bevacizumab therapy were assessed to predict disease response. A tissue-informed approach was applied to detect minimal residual disease in the subgroup of patients treated with curative intent (complete resection of the primary tumor and liver metastases). RESULTS: In the training cohort, DELFI-TF scores strongly correlated with RAS/BRAF MAF measured by ddPCR (r=0.85, p&amp;lt;0.001). DELFI-TF captured plasma tumor fractions associated with copy number changes when ddPCR failed to detect RAS/BRAF mutations. Before treatment initiation, DELFI-TF correlated with the sum of the largest diameters on CT scans according to RECIST1.1 (r=0.49, p&amp;lt;0.001). Patients with negative and positive changes in DELFI-TF more often exhibited response and progressive disease based on consecutive RECIST assessments, respectively. Median progression-free survival was 9.9 and 12.8 months for patients with DELFI-TF low versus DELFI-TF high, respectively (p=0.007). Overall survival was 28.8 and 58.9 months for patients with DELFI-TF low versus DELFI-TF high, respectively (p=0.001). In patients treated with curative intent, tissue-informed focal and arm-level copy number changes were detected 4-12 weeks after metastasectomy. Most patients presenting molecular relapse were later diagnosed with clinical recurrence by conventional CT imaging. CONCLUSIONS: DELFI-TF demonstrates the ability to use cfDNA fragmentomes to estimate cfDNA tumor burden with a performance comparable to standard approaches for treatment response monitoring and clinical outcome prediction. Citation Format: Bahar Alipanahi, Iris van 't Erve, Keith Lumbard, Laurel K. Millberg, Zach Skidmore, Lorenzo Rinaldi, Jacob Carey, Jennifer Tom, Cornelis J. A. Punt, Nicholas C. Dracopoli, Gerrit A. Meijer, Robert B. Scharpf, Victor E. Velculescu, Remond Fijneman, Alessandro Leal. Cell-free DNA fragmentation profiling for monitoring therapeutic response in metastatic colorectal cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5714.

Broadband Achromatic Metalens in the Long-Wave Infrared Regime

Compared with conventional lenses, metalenses can offer smaller form factor, light weight and new functionality, and have become the focus of the recent investigations of metasurface. To date, quite a lot of studies have been reported for chromatic aberration correction of metalenses. Noting most work was carried out to satisfy the required group delay or dispersion by introducing sophisticated and integrated nanopillars, which are obtained using computationally intensive global search algorithms. Generally, the design is time-consuming. Here, we propose an alternative scheme, where metalens that corrects the chromatic aberration can be designed by optimizing the spectral degree of freedom C(ω), rather than relying on time-consuming algorithms. The proposed metalens is compatible with the complementary metal oxide semiconductor (CMOS) fabrication process. The numerically demonstrated metalens with a diameter of 200 μm and a numerical aperture (NA) of 0.24 has a small focal length fractional change (FLFC) of 4.1% over the wavelength of 9∼12 μm with an average efficiency of 51.7% in transmission mode. Moreover, the effect of fabrication deviations on the performance of the metalens is analyzed, showing critical dimension (CD) bias, sidewall angle and pillar height all have different levels of influence on the performance of the metalens.

Group Polarization in Board Decisions about Strategic Change: Evidence from Chinese Publicly Listed Companies (2008–2018)

ABSTRACTStrategic management scholars have shown increasing interest in explaining strategic change from the perspective of cognitive bias. However, most studies focus on individual cognitive bias but pay little attention to group cognitive bias. This study introduces a typical group cognitive bias (group polarization) to explain strategic change decisions made by the board of directors. Following the theory of group polarization, we argue that, when the average prior strategic change experienced in performance decline by board directors is relatively high (or low), the focal strategic change in performance decline will become even higher (or lower). We further contend that the proportion of female directors and board versus CEO power as the contingencies can mitigate this group polarization effect. Our hypotheses were strongly supported by a longitudinal sample of Chinese publicly listed companies during 2008–2018. The study's framework and findings contribute to the contextualization of social psychology research on group polarization in the study of board's strategic decision-making.

Subclinical high-resolution chest CT scan features in psoriasis

BackgroundAlthough psoriasis is considered a systemic disease, no clear association has been established between psoriasis and lung diseases. This study aims to detect and describe subclinical pulmonary involvement in psoriasis patients with various degrees of cutaneous manifestations. MethodsAdult psoriasis patients with no known active pulmonary disease or respiratory symptoms were screened for subclinical pulmonary manifestations and possible parenchymal changes using high-resolution computed tomography (HRCT) scan of the chest. Patients were classified according to the severity of skin manifestations. The clinical characteristics and radiographic findings of these patients were evaluated. ResultsFifty-nine patients with psoriasis were included, among which 47 (79.7%) had abnormal HRCT scan features. Micronodules were the most common detected lung lesions (66.1%), followed by nonspecific interstitial changes (32.2%), including pleuro-parenchymal band/atelectasis, scarring, and focal ground-glass opacities. Other HRCT findings included emphysematous changes and calcified granulomas. Abnormal HRCT findings correlated with older age and duration of psoriasis but not with the severity of skin manifestations. ConclusionsMicronodules and minor focal nonspecific interstitial changes were the most detected lung alterations in patients with psoriasis. These findings of the pilot study highlight a possible pulmonary involvement in patients with psoriasis. Larger multicenter studies are needed to clarify these findings further. LimitationsA major limitation of the study, is the lack of a control group with similar radiologic findings of different conditions done in the same geographical region.