Early Clues Research Articles

Chest computed tomography manifestations in neonates with chronic granulomatous disease

To study chest computed tomography (CT) manifestations in neonates with chronic granulomatous disease (CGD) to provide clues for early diagnosis of this disease. A retrospective analysis was conducted on the clinical data and chest CT scan results of neonates diagnosed with CGD from January 2015 to December 2022 at Anhui Provincial Children's Hospital. Nine neonates with CGD were included, with eight presenting respiratory symptoms as the initial sign. Chest CT findings included: consolidation in all 9 cases; nodules in all 9 cases, characterized by multiple, variably sized scattered nodules in both lungs; masses in 4 cases; cavities in 3 cases; abscesses in 6 cases; bronchial stenosis in 2 cases; pleural effusion, interstitial changes, and mediastinal lymphadenopathy each in 1 case. CT enhancement scans showed nodules and masses with uneven or ring-shaped enhancement; no signs of pulmonary emphysema, lung calcification, halo signs, crescent signs, bronchiectasis, or scar lesions were observed. There was no evidence of rib or vertebral bone destruction. Fungal infections were present in 8 of the 9 cases, including 6 with Aspergillus infections; three of these involved mixed infections with Aspergillus, with masses most commonly associated with mixed Aspergillus infections (3/4). The primary manifestations of neonatal CGD on chest CT are consolidation, nodules, and/or masses, with Aspergillus as a common pathogen. These features can serve as early diagnostic clues for neonatal CGD.

Unmasking early colorectal cancer clues: in silico and in vitro investigation of downregulated IGF2, SOCS1, MLH1, and CACNA1G in SSA polyps

Background and aimColorectal cancer (CRC) originates from pre-existing polyps in the colon. The development of different subtypes of CRC is influenced by various genetic and epigenetic characteristics. CpG island methylator phenotype (CIMP) is found in about 15–20% of sporadic CRCs and is associated with hypermethylation of certain gene promoters. This study aims to find prognostic genes and compare their expression and methylation status as potential biomarkers in patients with serrated sessile adenomas/polyps (SSAP) and CRC, in order to evaluate which, one is a better predictor of disease.MethodThis study employed a multi-phase approach to investigate genes associated with CRC and SSAP. Initially, two gene expression datasets were analyzed using R and Limma package to identify differentially expressed genes (DEGs). Venn diagram analysis further refined the selection, revealing four genes from the Weissenberg panel with significant changes. These genes, underwent thorough in silico evaluations. Once confirmed, they proceeded to wet lab experimentation, focusing on expression and methylation status. This comprehensive methodology ensured a robust examination of the genes involved in CRC and SSAP.ResultThis study identified cancer-specific genes, with 8,351 and 1,769 genes specifically down-regulated in SSAP and CRC tissues, respectively. The down-regulated genes were associated with cell adhesion, negative regulation of cell proliferation, and drug response. Four highly downregulated genes in the Weissenberg panel, including CACNA1G, IGF2, MLH1, and SOCS1. In vitro analysis showed that they are hypermethylated in both SSAP and CRC samples while their expressions decreased only in CRC samples.ConclusionThis suggests that the decrease in gene expression could help determine whether a polyp will become cancerous. Using both methylation status and gene expression status of genes in the Weissenberg panel in prognostic tests may lead to better prognoses for patients.

Febrile Rash: An Early Diagnostic Clue to Infectious Illness in Travelers Returning from Thailand

Febrile Rash: An Early Diagnostic Clue to Infectious Illness in Travelers Returning from Thailand

Early clues in the battle against advanced gastric cancer: How plasma ctDNA signals the effectiveness of PD-1 inhibitors with chemotherapy.

3042 Background: Combination therapy with Programmed Death 1 (PD-1) inhibitors and chemotherapy has shown efficacy in improving survival in advanced gastric cancer, but not all patients derive benefit. We aimed to explore whether early dynamic changes in circulating tumor DNA (ctDNA) can serve as predictors of treatment response and long-term survival in patients receiving first-line PD-1 inhibitors combined with chemotherapy. Methods: This is a prospective, single-center trial in which all patients are adults with advanced or metastatic GC/GEJC confirmed by pathology or imaging. 30 eligible patients will receive PD-1 mab (sintilimab/nivolumab (NIVO) Q3W) and chemotherapy (SOX/XELOX Q3W) regardless of programmed death ligand-1 status. Blood samples were collected before treatment and after two treatment cycles for ctDNA analysis. Plasma ctDNA was isolated for evaluating variant allele frequencies (VAF) of somatic mutations in 47 cancer-related genes using next-generation sequencing (NGS), ctDNA response was defined as clearance of maximum VAF (maxVAF) compared to baseline. CT scans were performed after every two cycles and will be categorized as responding (complete response plus partial response) or non-responding (progress disease plus stable disease) according to RECIST v1.1. Overall survival was calculated from the date of first PD-1 mab infusion to the time of death or censored at most recent follow-up; progression‐free survival was calculated from the date of first PD-1 mab infusion to the time of death or first documented progression, whichever came first, or censored at most recent follow-up. Results: In thirty advanced gastric cancer patients, the dynamic changes in maxVAF demonstrated a significant association with patients attaining either complete response (CR) or partial response (PR) to treatment (P=0.0021), but showed no correlation with stable disease (SD) or progress disease (PD). A substantial agreement was observed between ctDNA response and the best tumor shrinkage rate (Cohen's kappa=0.69). The objective response rate (ORR) among ctDNA responders was 85%, markedly higher compared to the 22% observed in non-responders (P=0.0073). Additionally, patients with ctDNA response had a significantly longer progression‐free survival (PFS) compared to patients without ctDNA response (median PFS 15.6 months vs 6.0 months; HR, 0.18; 95% CI, 0.06 to 0.61; p=0.003), overall survival (OS) was also significantly longer among ctDNA responders (median OS not reach[NR] vs 9.0 months; HR, 0.10; 95% CI, 0.01 to 0.88; p=0.011). Conclusions: ctDNA response serves as a potential biomarker for assessing treatment efficacy and long-term outcomes in advanced gastric cancer patients treated with first-line PD-1 inhibitors and chemotherapy. Clinical trial information: ChiCTR2200065366.

Early diagnostic clues of mucolipidosis type II: Significance of radiological findings.

Mucolipidosis type-II (ML-II) is an ultra-rare disorder caused by deficiency of N-acetylglucosaminyl-1-phosphotransferase enzyme due to biallelic pathogenic variants in GNPTAB gene. There are a few known about the natural history of ML-II. In this study, we presented the natural course of 24 patients diagnosed with ML-II. Mean age at diagnosis was 9.3 ± 5.7 months. All patients had coarse face, developmental delay, and hypotonia. The mean survival time was 3.01 ± 1.4 years. The oldest patient was 6.5 years old. Twelve patients died due to lung infection and respiratory failure. We observed early and significant radiological findings of ML-II were different from typical dysostosis multiplex such as femoral cloaking, rickets-like changes, and talocalcaneal stippling. These are significant findings observed in the fetal or newborn period which is considered to be highly characteristic of ML-II and disappears in the first year. Cloaking, rickets-like changes, and stippling were not observed in patients older than three months of age and this suggests that these findings disappear within the first year. These radiological features can be used as important clues for diagnosis. We detected eight different pathogenic variants in GNPTAB gene, three of them were novel.

Vernix caseosa reveals mechanistic clues linking maternal obesity to atopic dermatitis pathogenesis

Maternal overweight and obesity have been associated with an increased risk of atopic dermatitis (AD) in the offspring, but the underlying mechanisms are unclear. Vernix caseosa (VC) is a proteolipid material covering the fetus produced during skin development. However, whether maternal prepregnancy weight excess influences fetal skin development is unknown. Characterizing the VC of newborns from mothers with prepregnancy overweight and obesity might reveal AD-prone alterations during fetal skin development. We sought to explore AD biomarkers and staphylococcal loads in VC from the offspring of mothers who were overweight/obese (O/O) before pregnancy versus in those from offspring of normal weight mothers. The VC of newborns of 14 O/O and 12 normal weight mothers were collected immediately after birth. Biomarkers were determined by ELISA and staphylococcal species by quantitative PCR. The VC from the O/O group showed decreased expression of skin barrier proteins (filaggrin and loricrin) and increased levels of proinflammatory biomarkers (IgA, thymic stromal lymphopoietin [TSLP], S100A8, IL-25, and IL-33). No differences in concentrations of antimicrobial peptides and enzymes were detected. The VC from the O/O group had a lower Staphylococcus epidermidis and Staphylococcus hominis commensal bacterial load, whereas Staphylococcus aureus bacterial load was not significantly different between the 2 groups. Maternal body mass index was negatively correlated with VC filaggrin expression and S epidermidis load and was positively associated with TSLP concentration. One-year follow-up established that the offspring of O/O mothers had a higher incidence of AD that was specifically linked with decreased VC filaggrin expression and lower S epidermidis load. VC from neonates of mothers with prepregnancy overweight and obesity exhibit skin barrier molecular alterations and staphylococcal dysbiosis that suggest earlymechanistic clues to this population's increased risk of AD.

Early clues and molecular mechanism involved in neurodegenerative diseases induced in immature mice by combined exposure to polypropylene microplastics and DEHP

Studies have shown that exposure to either microplastics (MPs) or di-(2-ethylhexyl) phthalic acid (DEHP) alone can cause neurotoxicity in animals, but it remains uncertain whether and to what extent co-exposure to these two substances, which often occur together in reality, can also induce neurotoxicity. This study aimed to investigate the neurotoxicity and molecular mechanisms of combined exposure to DEHP and polypropylene microplastics (synthetic PP-MPs were used), the microplastics most commonly encountered by young children, in immature mice. The results showed that exposure to PP-MPs and/or DEHP did cause neurotoxic effects in immature mice, including induction of neurocognitive and memory deficits, damage to the CA3 region of the hippocampus, increased oxidative stress, and decreased AChE activity in the brain. The severity of the neurotoxicity increased with increasing concentrations of PP-MPs, combined exposure to PP-MPs and DEHP exhibited additive or synergistic effects. Transcriptomic analyses revealed that the PP-MPs and/or DEHP exposure altered the expression profiles of gene clusters involved in the stress response, and in protein processing in endoplasmic reticulum. Quantitative analyses further indicated that PP-MPs and/or DEHP exposure inhibited the activity of the heat shock response mediated by heat shock transcription factor 1, while chronically activated the unfolded protein response, consequently inducing neurotoxicity through neuronal apoptosis and neuroinflammation in the immature mice. As a pioneer study to highlight the neurotoxicity induced by combined exposure to PP-MPs and DEHP in immature mice, this research provides new insights into mitigating the health risks of PP-MPs and DEHP exposure in young children.

Transcriptome analysis of ovules offers early developmental clues after fertilization in Cicer arietinum L.

The online version contains supplementary material available at 10.1007/s13205-023-03599-8.

New pattern of individualized management of chronic diseases: focusing on inflammatory bowel diseases and looking to the future.

Non-infectious chronic diseases, especially inflammatory bowel diseases (IBDs), hypertension, and diabetes mellitus, are characterized by a prolonged and multisystemic course, and their incidence increases annually, usually causing serious economic burden and psychological stress for patients. Therefore, these diseases deserve scientific and consistent disease management. In addition, the lack of a comprehensive "early disease clues tracking-personalized treatment system-follow-up" model in hospitals also exacerbates this dilemma. Based on these facts, we propose an individualized prediction management system for IBDs based on chronic diseases, focusing on the established IBDs-related prediction models and summarizing their advantages and disadvantages. We call on researchers to pay attention to the integration of models with clinical practice and the continuous correction of models to achieve truly individualized medical treatment for chronic diseases, thus providing substantial value for the rapid diagnosis and adequate treatment of chronic diseases such as IBDs, which follow the "relapse-remission" disease model, and realizing long-term drug use and precise disease management for patients. The goal is to achieve a new level of chronic disease management by scientifically improving long-term medication, precise disease management, and individualized medical treatment, effectively prolonging the remission period and reducing morbidity and disability rates.

Vocal Cord Paralysis and Feeding Difficulties as Early Diagnostic Clues of Congenital Myasthenic Syndrome with Neonatal Onset: A Case Report and Review of Literature.

Herein, we present a newborn female with congenital vocal cord paralysis who required a tracheostomy in the neonatal period. She also presented with feeding difficulties. She was later diagnosed with a clinical picture of congenital myasthenia, associated with three variants of the MUSK gene: the 27-month follow-up was described. In particular, the c.565C>T variant is novel and has never been described in the literature; it causes the insertion of a premature stop codon (p.Arg189Ter) likely leading to a consequent formation of a truncated nonfunctioning protein. We also systematically collected and summarized information on patients' characteristics of previous cases of congenital myasthenia with neonatal onset reported in the literature to date, and we compared them to our case. The literature reported 155 neonatal cases before our case, from 1980 to March 2022. Of 156 neonates with CMS, nine (5.8%) had vocal cord paralysis, whereas 111 (71.2%) had feeding difficulties. Ocular features were evident in 99 infants (63.5%), whereas facial-bulbar symptoms were found in 115 infants (73.7%). In one hundred sixteen infants (74.4%), limbs were involved. Respiratory problems were displayed by 97 infants (62.2%). The combination of congenital stridor, particularly in the presence of an apparently idiopathic bilateral vocal cord paralysis, and poor coordination between sucking and swallowing may indicate an underlying congenital myasthenic syndrome (CMS). Therefore, we suggest testing infants with vocal cord paralysis and feeding difficulties for MUSK and related genes to avoid a late diagnosis of CMS and improve outcomes.

Cardiac amyloidosis: state-of-the-art review.

Cardiac amyloidosis (CA) is caused by deposition of amyloid fibrils in the myocardium and has two main subtypes, transthyretin cardiac amyloidosis (ATTR) and immunoglobulin light chain cardiac amyloidosis (AL). ATTR is further differentiated into wild-type (wtATTR) and hereditary (hATTR), depending on the absence or presence of mutation in the transthyretin gene. The increased recognition of disease with the improvement in diagnostic armamentarium and serendipitous advancements in the therapeutic landscape have changed the status of CA from being a rare and untreatable disease to being a not-so-rare and treatable disease. Both ATTR and AL have certain clinical aspects that can provide early clues for the disease. While electrocardiography followed by echocardiography and subsequently cardiac magnetic resonance can raise suspicion for CA, the definitive diagnosis of ATTR is non-invasively established by bone scintigraphy while that of AL always needs histological confirmation. Severity of CA can be gauged by serum biomarker-based staging of both ATTR and AL. ATTR therapies work by silencing or stabilizing TTR or by degrading amyloid fibrils, while AL is managed with anti-plasma cell therapies and autologous stem cell transplant.

Systemic sclerosis sine scleroderma presenting as renal crisis, a case report and review of the literature

Systemic sclerosis sine scleroderma is a rare subset of systemic sclerosis with isolated organ involvement. Scleroderma renal crisis is a severe manifestation of systemic sclerosis characterized by malignant hypertension, oligo/anuric renal failure, and thrombotic microangiopathy. We present a case of a 55-year-old male with uncontrolled hypertension who presented with hematospermia and was found to have acute renal failure, microangiopathic hemolytic anemia, concerning thrombotic microangiopathy. Empiric management for thrombotic thrombocytopenic purpura (TTP) with plasma exchange and corticosteroids yielded a paradoxical response, ultimately leading to the diagnosis of systemic sclerosis sine scleroderma presenting as scleroderma renal crisis (SRC) after serological confirmation. Given the morbidity and mortality associated with scleroderma renal crisis, it should be increasingly considered as a differential for thrombotic microangiopathy even without outward manifestations of systemic sclerosis. Additionally, the empiric management of TTP can include the use of corticosteroids which can exacerbate SRC, an early clinical clue in the diagnosis of this disease.

Fatal Disseminated Coccidioidomycosis in Cirrhosis: A Case Series

PurposeCoccidioidomycosis is endemic to the Southwest United States and Mexico. In this case series we describe 3 cases, occurring in the Southwest United States, of patients with disseminated coccidioidomycosis infection in cirrhosis, all with a miliary pattern present on chest imaging. MethodsThis case series was performed conducting a review of patients’ electronic health records and thorough review of the literature for coccidioidomycosis infection in patients with liver disease. ResultsThree patients with different etiology of liver disease with Model for End-stage Liver Disease – Sodium (MELD-Na) scores >20 had chest imaging findings indicative of a miliary pattern on presentation. Each patient subsequently had extensive infectious disease workup that showed evidence of disseminated coccidioidomycosis. All 3 patients clinically worsened and eventually died. ConclusionsThis case series highlights the severity of disseminated coccidioidomycosis in patients with cirrhosis in an endemic area, as well as potential early clues such as miliary patterns on chest imaging. A review of the literature found a significant connection among potential mechanisms describing why patients with cirrhosis have such adverse outcomes in the setting of disseminated coccidioidomycosis, including cirrhosis-associated immune dysfunction and genetic defects in immune functioning.

Rapid Response Team Activation Triggers in Adults and Children: An Integrative Review.

This integrative review aims to identify the triggers for rapid response team (RRT) activation and their outcomes in pediatric patients and to compare them with those of adult patients. In addition, this integrative review synthesizes the outcomes of cardiopulmonary resuscitation (CPR), intensive care unit (ICU) admission, length of hospital stay, and mortality following RRT activation. An integrative review using the Whittemore and Knafl methodology was undertaken with a search of three large databases (PubMed, Ovid MEDLINE, and CINAHL) and found 25 relevant studies published in the years 2017 through 2022. Tachypnea, decreased oxygen saturation, tachycardia, changes in blood pressure, and level of consciousness were the most common triggers in both populations. However, specific activation triggers differed between children and adults. The most common triggers for RRT are detectable through vital signs monitoring; therefore, vigilant tracking of patients' vital signs is critical and can provide early clues to clinical deterioration.

Dr. Ani John (1950-2007): An exemplary dental educator and administrator and the first female President of the Indian Academy of Oral Medicine and Radiology.

Dr. Ani John (1950-2007): An exemplary dental educator and administrator and the first female President of the Indian Academy of Oral Medicine and Radiology.

Administration of GnRH at day 20 of AI and embryonic losses in synchronized crossbred buffalo.

Following the application of different artificial insemination and synchronization protocols, the synchronized buffaloes had a higher incidence of early embryonic or fetal death, thus impairing reproductive performance. Therefore, there is a need to devise a synchronizing program that can improve conception, allow early pregnancy diagnosis, reduce early embryonic losses, and provide an early clue for pregnancy diagnosis and establishment. The present study aimed (1) to determine the effect of administration of different GnRH doses at day 20 of artificial insemination (AI) on the reproductive performance of buffaloes and (2) to observe the influence of synchronization protocol, parity, age, milk production, and body condition score (BCS) on early embryonic loss and progesterone (P4) levels in crossbred buffaloes. Crossbred buffaloes (n = 101) were synchronized using the GPGMH protocol. At day 20 of AI, the synchronized buffaloes were randomly divided into four groups and administrated GnRH doses (0, 100, 150, and 200 μg). The buffaloes were monitored for ovarian dynamics, P4 level, non-return rate, embryonic/fetal losses, and pregnancy rates. The previously synchronized buffaloes were also classified for synchronization protocol (with or without GnRH), parity (nulli- or multiparous), milk production (high or low), BCS (low, medium, or good) or age (>3 or < 3 years) groups for observing the embryonic loss and P4 level variations. The results indicated no difference (P > 0.05) in CL size, P4 level, pregnancy rate and embryo/fetal losses across the treatment groups at different observation periods. There was a high (P < 0.05) incidence of early embryonic mortality in aged, multiparous, low BCS and low milk-producing buffaloes treated without GnRH. The data suggest that GnRH 200 μg at day 20 of AI improves embryo survival and pregnancy maintenance in crossbred buffaloes.

A novel variation of gamt in cerebral creatine deficiency syndrome, first complete homozygous deletion of GAMT

Cerebral Creatine Deficiency Syndromes (CCDS) are congenital metabolic disorders in the creatine metabolism pathway. In this study, we evaluated the clinical, phenotypic, radiological and genetic features of patients with CCDS. We tried to identify early diagnosis clues in patients. Especially, we reviewed the causes of delay in patients with late diagnosis. In line with these findings, the diagnosis is confirmed by enzyme tests and next generation sequencing based whole genome sequencing. In this study, 6 patients whose diagnosis was genetically confirmed were presented (5 GAMT mutations (someone is complete homozygous deletion in GAMT gene), 1 SLC6A8 mutation). 5 of these patients were from the same family, and 4 patients were patients with a late diagnosis. Two of the 4 patients who were diagnosed late were moderate and two had severe phenotype. The neurological findings consisted of patients with different clinical findings such as speech disorder, cognitive retardation, autism and epilepsy. Patients received appropriate treatment for the type of cerebral creatine deficiency. While response to treatment was good in early diagnosed cases, a partial clinical improvement was detected in cases diagnosed late. The patient, who was started treatment before neurological symptoms appeared, was neurodevelopmentally normal. It was observed that there was a strong relationship between age at diagnosis and phenotype and prognosis. We compared the clinical findings, phenotype and genotype characteristics of patients with CCDS. We reviewed the causes of delay in patients with late diagnosis. Thus, we wanted to raise awareness about early diagnosis and treatment of CCDS, one of the rare metabolic diseases.

Machine learning framework for Diabetes Retinopathy detection using hybrid logistic regression

Diabetes Retinopathy(DR) occurs due to an injury to the retina, ultimately steering towards sightlessness. DR does not provide any early clues or signs and unnoticeably associates a new blood vessel towards the back portion of the eye, resulting in clots of blood in the eye, bleeding of eyes and distorted vision. The conventional methods are failed to produce the maximum classification accuracy. Therefore, this article is focused on implementation of hybrid logistic regression (HLR)-based machine learning model for classification of DR.Initially, histogram equalization is used to enhance the region of DR image. Then, segmentation of microaneurysmsis performed by using image morphological operations. Further, features extracted using gray level co-occurrence matrix (GLCM), which shows the internal relationship of DR disease. Then, selection of features is carried out using the Gaussian Mixture Model (GMM). Finally, HLR model is applied to perform the multi class classification operation. Simulation results shows that the proposed method resulted in superior performance as compared to state of art approaches

Emergence of Early Clue to Neurodegenerative Diseases Induced in Immature Mice by Combined Exposure to Polypropylene Microplastics and Dehp and the Underlying Molecular Mechanism

Emergence of Early Clue to Neurodegenerative Diseases Induced in Immature Mice by Combined Exposure to Polypropylene Microplastics and Dehp and the Underlying Molecular Mechanism

Profile of precipitating factors and its implication in 160 Indian patients with Moyamoya angiopathy

Moyamoya angiopathy (MMA) has been known to manifest with myriad of neurological manifestations, often in association with various precipitating factors. This is the first study to systematically analyze the precipitating triggers to neurological symptoms done on the largest cohort of MMA in India. A single-centered, cross-sectional observational study, recruiting 160 patients with consecutive angiographically proven MMA over a period of 5years (2016-2021), was undertaken to evaluate the profile of immediate precipitating factors in temporal association to the neurological symptoms, along with their clinical and radiological characteristics. SPSS 25 was used for statistical analysis. Among the 160 patients (Adult-85, children-75), precipitating factors were seen in 41.3%, significantly higher in children (52%) than adults (31.8%) (p value: 0.011). The commonest triggers included fever (18.8%), emotional stress (8.1%), heavy exercise and diarrhea (6.3% each). Cold bath triggered MMA symptoms in 1.3%. Fever (p value: 0.008) and persistent crying (p value: 0.010) triggered neurological symptoms more commonly in children than in adults. Amongst MMA patients with precipitating factors, the commonest MMA presentation included cerebral infarction type (37.9%) and TIA (31.8%). The majority of precipitating factors thatpreceded an ischemic event were BP-lowing ones (54.7%). Neurological symptoms of MMA are commonly associated with several precipitating factors, including the lesser known triggers like cold bath. The frequency and profile precipitating factors varies with the age of presentation and type of MMA. It can serve as an early clue to the diagnosis of MMA and its careful avoidance can be largely beneficial in limiting the distressing transient neurological symptoms.