Late Disease Research Articles

Generation of two induced pluripotent stem cell lines (HIMRi006-A and HIMRi007-A) from Pompe patients with infantile and late disease onset

Here we present the generation of HIMRi006-A and HIMRi007-A Pompe disease (PD) patient derived human induced pluripotent stem cell (hiPSC) lines. HIMRi006-A represents an infantile onset disease (IOPD) phenotype caused by a homozygous c.307 T > G mutation in the GAA gene. HIMRi007-A is characterized by heterozygous mutations c.–32–13 T > G/c.1716C > G and is associated with an adult onset of disease symptoms (LOPD). Both lines are generated via lentiviral expression of OCT4, SOX2, KLF4, and c-MYC. The lines display a typical embryonic stem cell morphology, express pluripotency markers, retain a normal karyotype (46, XX/XY) and have the differentiation capacity in all three germ layers. Altogether, both lines provide a resource tool to the community for future in depth molecular studies of PD pathomechanism.

Longitudinal soluble marker profiles reveal strong association between cytokine storms resulting from macrophage activation and disease severity in COVID-19 disease

SARS-CoV2 infection results in a range of disease severities, but the underlying differential pathogenesis is still not completely understood. At presentation it remains difficult to estimate and predict severity, in particular, identify individuals at greatest risk of progression towards the most severe disease-states. Here we used advanced models with circulating serum analytes as variables in combination with daily assessment of disease severity using the SCODA-score, not only at single time points but also during the course of disease, to correlate analyte levels and disease severity. We identified a remarkably strong pro-inflammatory cytokine/chemokine profile with high levels for sCD163, CCL20, HGF, CHintinase3like1 and Pentraxin3 in serum which correlated with COVID-19 disease severity and overall outcome. Although precise analyte levels differed, resulting biomarker profiles were highly similar at early and late disease stages, and even during convalescence similar biomarkers were elevated and further included CXCL3, CXCL6 and Osteopontin. Taken together, strong pro-inflammatory marker profiles were identified in patients with COVID-19 disease which correlated with overall outcome and disease severity.

MSR35 Item Performance and Structural Validity of the Quick Motor Function Test Among Late Onset Pompe Disease Patients

MSR35 Item Performance and Structural Validity of the Quick Motor Function Test Among Late Onset Pompe Disease Patients

A real-world longitudinal assessment of the treatment-related symptoms and associated burden among patients receiving chemotherapy.

e23158 Background: For patients (pts) with cancer, treatment with cytotoxic chemotherapy is associated with a variety of treatment-related symptoms including nausea, vomiting, diarrhea and constipation. Often the ability to manage these symptoms when they occur is the difference between completion of chemotherapy and early discontinuation. The first weeks of treatment are critical for understanding the pts’ acute experience with chemotherapy. The objective of this study is to longitudinally evaluate treatment-related symptoms and associated treatment burden among chemotherapy pts through a real-world electronic remote symptom monitoring system. Methods: Pts treated with chemotherapy in U.S. academic cancer centers were enrolled in Carevive’s Patient Reported Outcomes Mobile Platform (Carevive PROmpt®) between September 2020 and Dec 2023, with 3 month median follow-up. A total of 476 pts were enrolled, across early (81%) and late (19%) stage disease. Weekly PRO-CTCAE-derived surveys assessed severity, frequency, and interference for 16 symptoms often associated with cancer treatment: anxiety, constipation, cough, decreased appetite, diarrhea, fatigue, general pain, insomnia, mouth/throat sores, muscle pain, nausea, numbness and tingling, rash, sadness, shortness of breath, and vomiting. The GP5 assessed weekly overall bother with the side effects of treatment. Questionnaires were administered weekly starting at treatment initiation. Results: The mean age of chemotherapy pts was 67.3 (SD = 13.2) years, with 75% female, and 20% African American. At treatment initiation, 302 pts reported symptoms by PRO-CTCAE, and 100 completed the GP5. At week 1, constipation, general pain (GP), nausea, numbness/tingling (N/T), and shortness of breath were experienced by 20-25% of pts. Over the first 4 weeks of treatment, pts reported an increase in constipation, decreased appetite, diarrhea, and nausea at week 2, with a return to week 1 frequency over the remaining weeks. Diarrhea, however, remained elevated. While week 1 capture rates were lower, patterns for treatment bother were similar. At week 1, 34% of pts reported being bothered at least “Somewhat” by the side effects of treatment. This increased to 48% at week 2, but returned to near the week 1 frequency over the remaining weeks. Conclusions: For remote-monitored pts in this real-world data set treated with chemotherapy both alone and in combination, the most frequent symptoms at the start of treatment were nausea, GP, and N/T. The frequency of pts with GP and N/T did not change over the course of treatment suggesting their possible presence prior to the observed regimen. Increases in chemotherapy-related symptoms show the importance of ongoing assessment over the first 4 weeks of treatment, ideally with feedback to treating physicians and concomitant symptom management to optimize successful chemotherapy completion.

Hodgkin’s lymphoma, lymphocyte-depleted, reticular: An NCDB analysis of demographic and socioeconomic factors of diagnosed patients.

e19033 Background: Lymphocyte-depleted Hodgkin's lymphoma (LDHL) is an aggressive, rare form of Hodgkin’s lymphoma (HL). The LDHL reticular subtype (LDHL-R) is characterized by a scant invasion of lymphocytes without an increase in collagen fibers by fibroblasts. Patient demographics and clinical features of LDHL-R are poorly understood, causing it to frequently be misdiagnosed as other variants of HL. At diagnosis, patients have often already progressed to late disease staging. The demographic and socioeconomic factors of patients diagnosed with LDHL-R within the National Cancer Database (NCDB) were analyzed to better understand its epidemiology. Methods: A retrospective cohort analysis was performed using data from the 2004-2020 NCDB of the 51 cases of LDHL-R (ICD-O-3 9655). Demographic and socioeconomic factors such as age, sex, race, Hispanic status, treatment facility type, Charles-Deyo score, and 90-day mortality were examined using descriptive statistics. Diagnostic trends were quantified through regression analysis. Results: A total of 51 patients were diagnosed with Hodgkin lymphoma, lymphocyte depletion, reticular subtype within the NCDB. The most common primary site of diagnosis was within lymph nodes of multiple regions (41%). The majority of patients were males (65%), White (72%), and non-Hispanic (74%). Patients tended to have residence in metropolitan counties with populations greater than 1 million (71%) and were enrolled in academic/research programs (36%). Most of the patients were privately insured (41%) followed by those insured by Medicare (29%). A higher percentage of patients were in the top quartile of income earners (31%) than those in the second, third, or fourth quartiles. The incidence rate of diagnosis remained constant from 2004 to 2020 (R² = 0.02). The mean age of diagnosis was 51 years (SD=21, Range=14–90). Using the AJCC System, patients tended to be classified as Stage IV (41%) at diagnosis and had a Charlson-Deyo comorbidity score of 0 (71%). Primary treatment methods involved chemotherapy (84%) and radiation therapy (20%). Surgical intervention was given to 14 patients, and post-surgery survival rates were 93% after 90 days. Conclusions: To the best of our knowledge, this is the first NCDB analysis of the demographic factors of patients diagnosed with LDHL-R. Consistent with previous studies about the aggressiveness of this subtype of Hodgkin’s Lymphoma, most patients received a Stage IV diagnosis. Understanding LDHL-R’s epidemiology could result in significantly earlier diagnoses and improved prognosis. Patients tended to be male, White, and non-Hispanic with a residence in metropolitan counties. To improve understanding of the impact of demographic and socioeconomic factors of the diagnosis, treatment, and survival of patients with LDHL-R, more research is recommended.

Long-term survival comparison of adjuvant FLOT versus XELOX chemotherapy for locally advanced gastric cancer in a large real-world cohort.

4080 Background: Recent Attraction-5 study has shown that logically advanced gastric cancer (LAGC) patients can't benefit from postoperative immunochemotherapy. The preferred adjuvant regimen for LAGC remains two-drug based chemotherapy as XELOX protocol, though three-drug based adjuvant FLOT regimen has not been well studied yet. This studyaimsto explore 10-year survival advantages of adjuvant FLOT versus XELOX regimen for LAGC. Methods: We retrospectively collected and analyzed data from 248 LAGC patients mainly composed of pathological T (pT) 3-4 stage, who received at least 4 cycles of FLOT or XELOX adjuvant chemotherapy at Lanzhou University Second Hospital from 2013 to 2018. To eliminate interference of confounding factors, we conducted a propensity score matching (PSM). The median follow-up time for all patients was 90.90 months. Results: After PSM, the median overall survival (OS) was 44.80 months in FLOT group and 34.87 months in XELOX group, with 5-year OS rate of 41.4% versus 25.3% and 10-year OS rate of 31.9% versus 11.8%. Subgroup analysis showed that patients with ECOG performance status 0 or pT3-4 stage attained significant survival benefits from adjuvant FLOT regimen. Grade 3-4 treatment-related adverse events occurred in 57.9% patients of FLOT group and 33.6% patients of XELOX group, while most of them were manageable. Conclusions: This study demonstrates that adjuvant FLOT regimen exhibits significantly long-term survival advantages for LAGC patients with good performance status and late disease stage compared with XELOX regimen, facilitating adjuvant FLOT regimen as a prospectively alternative option for LAGC.

Indolent nonprogressive multifocal choroidal lymphoid lesions with late development of systemic lymphoma

Purpose: To report a case of indolent nonprogressive multifocal choroidal lymphoid lesions with late development of pulmonary low-grade B-cell lymphoma after lymphoid lesion regression. Methods: Case report. Results: A 79-year-old male was followed with ocular and systemic surveillance over a sixteen-year period for unilateral nonprogressive choroidal lesions presumed to be a benign lymphocytic disease of the choroid. Workups for systemic lymphoma and birdshot chorioretinopathy were negative. After sixteen years of observation, the choroidal lesions had largely regressed. Recent diagnosis of atrial fibrillation led to an incidental discovery of a right lower lobe lung lesion measuring 4.5 cm. Computerized tomography-guided biopsy showed low-grade B-cell lymphoma. There was no additional systemic disease detected. The patient underwent right lower lobectomy revealing extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue. Conclusion: Patients with indolent nonprogressive multifocal choroidal lymphoid lesions should be monitored regularly for late systemic disease, which although rare, can develop even after years of follow-up.

P.064 A case of late onset Pompe Disease presenting in 6th decade

Background: Late onset Pompe disease (LOPD), rare autosomal recessive lysosomal storage disease, resulting from mutation in alpha glucosidase enzyme (GAA) can present even in 6th decade of life. Slowly progressive, subtle, limb girdle pattern of weakness (LGPW), with auxiliary features such as ptosis, enlarged tongue, axial rigidity, facial diplegia, variable degree of respiratory weakness is not uncommon. Hypertrophic and electrical cardiac abnormalities are well described in LOPD. Methods: We present a case of 67-year-old male presenting with proximal weakness, subtle ptosis, bilateral quadriceps and shoulder girdle atrophy, and left toe numbness. PMHx: CABG, NSTEMI. Statin use. FMHx: noncontributory. Results: EMG: L5 radiculopathy, with unexpected myopathic units in hip/pelvic/ shoulder girdle muscles with active denervation and muscle irritability. CK, CRP, SPEP, ANA, LFTs, HMG-CoA reductase: normal. GAA enzymatic activity=0.96µmol/L/hr (low), genetics: pathogenic variants in GAA gene: c.-32-13T>G and c.1194+3G>C. ECHO: severe diastolic dysfunction, restrictive left ventricular filling. PFTs: normal. Diagnosed with LOPD, started on therapy. Conclusions: LOPD remains a differential for LGPW especially in older patient population with history of cardiopulmonary features. Age-appropriate conconminant pathologies may confound the diagnostic process.Symptoms may preceed diagnosis for years.GAA enzymatic activity followed by genetic testing remains readily available and can confirm diagnosis, preventing delay of approved therapy.

Proteomic dissection of vanishing white matter pathogenesis

Vanishing white matter (VWM) is a leukodystrophy caused by biallelic pathogenic variants in eukaryotic translation initiation factor 2B. To date, it remains unclear which factors contribute to VWM pathogenesis. Here, we investigated the basis of VWM pathogenesis using the 2b5ho mouse model. We first mapped the temporal proteome in the cerebellum, corpus callosum, cortex, and brainstem of 2b5ho and wild-type (WT) mice. Protein changes observed in 2b5ho mice were then cross-referenced with published proteomic datasets from VWM patient brain tissue to define alterations relevant to the human disease. By comparing 2b5ho mice with their region- and age-matched WT counterparts, we showed that the proteome in the cerebellum and cortex of 2b5ho mice was already dysregulated prior to pathology development, whereas proteome changes in the corpus callosum only occurred after pathology onset. Remarkably, protein changes in the brainstem were transient, indicating that a compensatory mechanism might occur in this region. Importantly, 2b5ho mouse brain proteome changes reflect features well-known in VWM. Comparison of the 2b5ho mouse and VWM patient brain proteomes revealed shared changes. These could represent changes that contribute to the disease or even drive its progression in patients. Taken together, we show that the 2b5ho mouse brain proteome is affected in a region- and time-dependent manner. We found that the 2b5ho mouse model partly replicates the human disease at the protein level, providing a resource to study aspects of VWM pathogenesis by highlighting alterations from early to late disease stages, and those that possibly drive disease progression.

#1731 Clinico-epidemiological characteristics of early versus late onset cytomegalovirus disease among renal transplant recipients: two decade experience

Abstract Background and Aims The epidemiology of the Cytomegalo virus (CMV) disease among renal transplant recipients has changed with the advent of effective antiviral prophylaxis usually occurs in the later part of the post transplant period. To study the difference between CMV infections occurring in early versus late post renal transplant period with respect to nature of immunosuppressive medications (induction agents, maintenance agents and heightening of immunosuppression), type of CMV infection and occurrence of biopsy proven rejection post CMV infection. Method A single centre retrospective observational study was conducted among renal transplant recipients who underwent kidney transplant between 1st January, 2002 and 31st December, 2021. CMV disease was classified as early or late depending on detection before or after 90 days post transplant. The differences in clinical presentation between early and late onset CMV disease, use of immunosuppression, and the impact on graft outcomes were studied. Results Total number of recipients with CMV disease was 156 (7.2%) out of total 2164 renal transplant recipients. Twenty-five (16%) patients had early CMV while one hundred and thirty one (84%) had late CMV. The two groups did not differ with respect to induction or use of maintenance immunosuppressive agents. Proportion of CMV syndrome was more among early CMV group (56.0% vs 26.7%, p = 0.01) while tissue invasive disease was more frequent among late CMV group (44.0% vs. 73.3%, p = 0.01). Diarrhoea was more frequent in late (63.4%) versus early CMV (36%) (p = 0.01). Graft loss occurred in 4.0% of early and 25.2% of late CMV cases (p = 0.03). However, both groups did not differ with respect to occurrence of biopsy proven rejection post infection. Conclusion Early CMV presents more frequently as CMV syndrome while late CMV usually manifests as tissue invasive disease. Graft loss is more common in patients with late onset disease.

#3008 Very low protein diet with ketoanalogues supplementation could start haemodialysis with AVF without additional CVCs insertion

Abstract Background and Aims Nutritional interventions and a low-protein diet (LPD) are a critical point in the management of chronic kidney disease (CKD). Several protein-restricted dietary regimens have been proposed in patients with end stage kidney disease: a typical LPD provides around 0.6–0.7 g·kg meanwhile a very low-protein diet (VLPD) provides around 0.3–0.4 g·kg and it is basically a vegetarian diet which has to be supplemented with essential amino acids (EAA) to satisfy the body nitrogen need and with nitrogen-free ketoanalogues (KA) to recirculate the endogenous urea, whose serum levels are elevated in patients with CKD. KA and EAA reduce the rate of progression of chronic kidney disease and improve the inflammatory state; they reduce the absorption of phosphates and can maintain a good state of nutrition even if associated with diets with very low protein content. On the contrary, an excessively restrictive and inadequate diet in terms of EAA or calorie intake induces a negative nitrogen balance, therefore cachexia. The recommended vascular access to start dialysis treatment is represented by the arteriovenous fistula (AVF). An early referral to the vascular surgeon for vascular access creation is pivotal for deciding on a patient-specific strategy for planning access. Guidelines advise referral at least 3–6 months before the expected start of HD, because time is needed for AVF maturation and possible repeat interventions when it is impaired. An early referral results in more autologous AVFs, which have a better long-term patency, whereas late referral, results in a greater risk of AVF non-maturation and failure and therefore the need for additional central venous catheters (CVCs) to initiate dialysis. Recent studies have shown that pre-dialysis patients who undergo a VLDP + KA require less emergency dialysis access and have better elasticity of the arterial wall, better maturation rates and duration of the AVF and sometimes a reduction in the uremic toxins responsible of endothelial dysfunction. The aim of the study was to evaluate if patients could start haemodialysis with fistula cannulation, without central venous catheter insertion. Method 10 patients, late referral end stage renal disease were enrolled in a prospective, single arm study starting very low protein diet supplemented with ketoanalogues after arteriovenous fistula creation; they were followed with periodically assessment of renal function, uremic toxin, and acid-base balance until they need to start haemodialysis. It was evaluated AVF maturation and needs to additional CVC insertion. Results Patients (3 females, 7 males) mean age was 71.2 years; before AVF creation, baseline mean value was: sCr: 6.46 mg/dl, sUrea: 150 mg/dl, phosphorus: 4.45 mg/dl, bicarbonates: 19.8 mmol/l, eGFR: 8,37 ml/min. After 3 months of VLPD supplemented with KA, eGFR and sCr was stable to 8.25 ml/min and 6.69 respectively, sUrea and phosphorus reduced to 115 mg/dl and 3.8 mg/dl, and bicarbonate increased to 22.4 mmol/l. All 10 patients achieved AVF maturation within 3 months, no one needed CVC insertion. Conclusion In this small group we see how late referral ESRD patients, undergone AVF surgery, after 3 months of VLPD supplemented with KA, had stability of renal function, with reduction of urea and phosphorus, improvement of acid-base balance and achievement of AVF maturation, without needing of CVC insertion. For these reasons VLPD + KA could be useful in delaying haemodialysis start in late referral ESRD patients who have created AVF, without emergency placement of a central venous catheter.

#1854 Prevalence of Fabry disease in chronic hemodialysis patients: a multicenter screening approach

Abstract Background and Aims Fabry disease (FD), an X-linked lysosomal storage disorder caused by alpha-galactosidase A (α-Gal A) deficiency, leads to significant morbidity and early mortality due to progressive organ failure. Given the availability of enzyme replacement therapy, early identification of FD is crucial for improving patient outcomes. Method A multicenter screening was conducted among chronic hemodialysis patients across six centers. We utilized a two-tiered diagnostic approach. Initially, α-Gal A activity was measured from dried blood spots on filter paper. Subsequently, those with reduced enzyme levels underwent GLA gene mutation analysis. Results Out of 428 patients, 255 (102 females and 153 males) were selected for testing, leading to the analysis of 239 patients. In the male cohort, the average α-Gal A activity was 21.84 ± 11.9 µmol/L/h, with 34 males below the cut-off value (<15.3 µmol/L/h) but with normal lyso-Gb3 levels and no mutations. Among females, α-Gal A levels were typically within the normal range. Notably, one female was found to have a heterozygous variant of uncertain significance in the GLA gene [p.(Asp313Tyr)] in exon 6, with normal α-Gal A and lyso-Gb3 levels. Screening of other family members was not possible, as they resided abroad although we recommended it. Conclusion Screening for AFD in high-risk groups, such as hemodialysis patients, is challenging yet essential. Implementing α-Gal A measurement as a standard procedure for newly registered hemodialysis patients could prospectively identify potential Fabry carriers, offering more excellent utility than our cross-sectional study. While identifying index patients at a late disease stage may not benefit the patients themselves, it is crucial for early detection of family members, potentially altering their disease course. This proactive approach, supported by national and international guidelines, could significantly impact the management and outcomes of AFD.

Increased usage of doxycycline for young children with Lyme disease

BackgroundThe 2018 Infectious Disease Committee of the American Academy of Pediatrics stated that up to 3 weeks or less of doxycycline is safe in children of all ages. Our goal was to examine trends in doxycycline treatment for children with Lyme disease.MethodsWe assembled a prospective cohort of children aged 1 to 21 years with Lyme disease who presented to one of eight participating Pedi Lyme Net centers between 2015 and 2023. We defined a Lyme disease case with an erythema migrans (EM) lesion or positive two-tier Lyme disease serology categorized by stage: early-localized (single EM lesion), early-disseminated (multiple EM lesions, cranial neuropathy, meningitis, and carditis), and late (arthritis). We compared doxycycline treatment by age and disease stage and used logistic regression to examine treatment trends.ResultsOf the 1,154 children with Lyme disease, 94 (8.1%) had early-localized, 449 (38.9%) had early-disseminated, and 611 (53.0%) had late disease. Doxycycline treatment was more common for older children (83.3% ≥ 8 years vs. 47.1% < 8 years; p < 0.001) and with early-disseminated disease (77.2% early-disseminated vs. 52.1% early-localized or 62.1% late; p < 0.001). For children under 8 years, doxycycline use increased over the study period (6.9% 2015 to 67.9% 2023; odds ratio by year, 1.45; 95% confidence interval, 1.34–1.58).ConclusionYoung children with Lyme disease are frequently treated with doxycycline. Prospective studies are needed to confirm the safety and efficacy of doxycycline in children younger than 8 years, especially for those receiving courses longer than 3 weeks.

Long-term clinical observation of patients with heterozygous KIF1A variants.

KIF1A-related disorders (KRDs) encompass recessive and dominant variants with wide clinical variability. Recent genetic investigations have expanded the clinical phenotypes of heterozygous KIF1A variants. However, there have been a few long-term observational studies of patients with heterozygous KIF1A variants. A retrospective chart review of consecutive patients diagnosed with spastic paraplegia at Miyagi Children's Hospital from 2016 to 2020 identified six patients with heterozygous KIF1A variants. To understand the long-term changes in clinical symptoms, we examined these patients in terms of their characteristics, clinical symptoms, results of electrophysiological and neuroimaging studies, and genetic testing. The median follow-up period was 30 years (4-44 years). This long-term observational study showed that early developmental delay and equinus gait, or unsteady gait, are the first signs of disease onset, appearing with the commencement of independent walking. In addition, later age-related progression was observed in spastic paraplegia, and the appearance of axonal neuropathy and reduced visual acuity were characteristic features of the late disease phenotype. Brain imaging showed age-related progression of cerebellar atrophy and the appearance of hyperintensity of optic radiation on T2WI and FLAIR imaging. Long-term follow-up revealed a pattern of steady progression and a variety of clinical symptoms, including spastic paraplegia, peripheral neuropathy, reduced visual acuity, and some degree of cerebellar ataxia. Clinical variability between patients was observed to some extent, and therefore, further studies are required to determine the phenotype-genotype correlation.

Winter Durum Wheat Disease Severity Detection with Field Spectroscopy in Phenotyping Experiment at Leaf and Canopy Level

Accurate disease severity assessment is critical for plant breeders, as it directly impacts crop yield. While hyperspectral remote sensing has shown promise for disease severity assessment in breeding experiments, most studies have focused on either leaf or canopy levels, neglecting the valuable insights gained from a combined approach. Moreover, many studies have centered on experiments involving a single disease and a few genotypes. However, this approach needs to accurately represent the challenges encountered in field conditions, where multiple diseases could occur simultaneously. To address these gaps, our current study analyses a combination of diseases, yellow rust, brown rust, and yellow leaf spots, collectively evaluated as the percentage of the diseased leaf area relative to the total leaf area (DA) at both leaf and canopy levels, using hyperspectral data from an ASD field spectrometer. We quantitatively estimate overall disease severity across fifty-two winter durum wheat genotypes categorized into early (medium milk) and late (late milk) groups based on the phenophase. Chlorophyll content (CC) within each group is studied concerning infection response, and a correlation analysis is conducted for each group with nine vegetation indices (VI) known for their sensitivity to rust and leaf spot infection in wheat. Subsequent parametric (linear and polynomial) and nonparametric (partial least squares and kernel ridge) regression analyses were performed using all available spectral bands. We found a significant reduction in Leaf CC (>30%) in the late group and Canopy CC (<10%) for both groups. YROI and LRDSI_1 are the VIs that exhibited notable and strong negative correlations with Leaf CC in the late group, with a Pearson coefficient of −0.73 and −0.72, respectively. Interestingly, spectral signatures between the early and late disease groups at both leaf and canopy levels exhibit opposite trends. The regression analysis showed we could retrieve leaf CC only for the late group, with R2 of 0.63 and 0.42 for the cross-validation and test datasets, respectively. Canopy CC retrieval required separate models for each group: the late group achieved R2 of 0.61 and 0.37 (cross-validation and test), while the early group achieved R2 of 0.48 and 0.50. Similar trends were observed for canopy DA, with separate models for early and late groups achieving comparable R2 values of 0.53 and 0.51 (cross-validation) and 0.35 and 0.36 (test), respectively. All of our models had medium accuracy and tended to overfit. In this study, we analyzed the spectral response mechanism associated with durum wheat diseases, offering a novel crop disease severity assessment approach. Additionally, our findings serve as a foundation for detecting resistant wheat varieties, which is the most economical and environmentally friendly management strategy for wheat leaf diseases on a large scale in the future.

Genome-wide identification analysis in wild-type Solanum pinnatisectum reveals some genes defending against Phytophthora infestans.

Solanum pinnatisectum exhibits strong resistance to late blight caused by Phytophthora infestans but only an incomplete genome assembly based on short Illumina reads has been published. In this study, we generated the first chromosome-level draft genome for the wild-type potato species S. pinnatisectum in China using Oxford Nanopore technology sequencing and Hi-C technology. The high-quality assembled genome size is 664Mb with a scaffold N50 value of 49.17 Mb, of which 65.87% was occupied by repetitive sequences, and predominant long terminal repeats (42.51% of the entire genome). The genome of S. pinnatisectum was predicted to contain 34,245 genes, of which 99.34% were functionally annotated. Moreover, 303 NBS-coding disease resistance (R) genes were predicted in the S. pinnatisectum genome to investigate the potential mechanisms of resistance to late blight disease. The high-quality chromosome-level reference genome of S. pinnatisectum is expected to provide potential valuable resources for intensively and effectively investigating molecular breeding and genetic research in the future.

Seeing beyond the symptoms: biomarkers and brain regions linked to cognitive decline in Alzheimer's disease.

Early Alzheimer's disease (AD) diagnosis remains challenging, necessitating specific biomarkers for timely detection. This study aimed to identify such biomarkers and explore their associations with cognitive decline. A cohort of 1759 individuals across cognitive aging stages, including healthy controls (HC), mild cognitive impairment (MCI), and AD, was examined. Utilizing nine biomarkers from structural MRI (sMRI), diffusion tensor imaging (DTI), and positron emission tomography (PET), predictions were made for Mini-Mental State Examination (MMSE), Clinical Dementia Rating Scale Sum of Boxes (CDRSB), and Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS). Biomarkers included four sMRI (e.g., average thickness [ATH]), four DTI (e.g., mean diffusivity [MD]), and one PET Amyloid-β (Aβ) measure. Ensemble regression tree (ERT) technique with bagging and random forest approaches were applied in four groups (HC/MCI, HC/AD, MCI/AD, and HC/MCI/AD). Aβ emerged as a robust predictor of cognitive scores, particularly in late-stage AD. Volumetric measures, notably ATH, consistently correlated with cognitive scores across early and late disease stages. Additionally, ADAS demonstrated links to various neuroimaging biomarkers in all subject groups, highlighting its efficacy in monitoring brain changes throughout disease progression. ERT identified key brain regions associated with cognitive scores, such as the right transverse temporal region for Aβ, left and right entorhinal cortex, left inferior temporal gyrus, and left middle temporal gyrus for ATH, and the left uncinate fasciculus for MD. This study underscores the importance of an interdisciplinary approach in understanding AD mechanisms, offering potential contributions to early biomarker development.

Machine Learning-Based Identification of Mating Type and Metalaxyl Response in Phytophthora infestans Using SSR Markers.

Phytophthora infestans is the causal agent of late blight in potato. The occurrence of P. infestans with both A1 and A2 mating types in the field may result in sexual reproduction and the generation of recombinant strains. Such strains with new combinations of traits can be highly aggressive, resistant to fungicides, and can make the disease difficult to control in the field. Metalaxyl-resistant isolates are now more prevalent in potato fields. Understanding the genetic structure and rapid identification of mating types and metalaxyl response of P. infestans in the field is a prerequisite for effective late blight disease monitoring and management. Molecular and phenotypic assays involving molecular and phenotypic markers such as mating types and metalaxyl response are typically conducted separately in the studies of the genotypic and phenotypic diversity of P. infestans. As a result, there is a pressing need to reduce the experimental workload and more efficiently assess the aggressiveness of different strains. We think that employing genetic markers to not only estimate genotypic diversity but also to identify the mating type and fungicide response using machine learning techniques can guide and speed up the decision-making process in late blight disease management, especially when the mating type and metalaxyl resistance data are not available. This technique can also be applied to determine these phenotypic traits for dead isolates. In this study, over 600 P. infestans isolates from different populations-Estonia, Pskov region, and Poland-were classified for mating types and metalaxyl response using machine learning techniques based on simple sequence repeat (SSR) markers. For both traits, random forest and the support vector machine demonstrated good accuracy of over 70%, compared to the decision tree and artificial neural network models whose accuracy was lower. There were also associations (p < 0.05) between the traits and some of the alleles detected, but machine learning prediction techniques based on multilocus SSR genotypes offered better prediction accuracy.

USING A MULTI-OMICS LANDSCAPE OF THE MATERNAL-FETAL INTERFACE TO MODEL THE LONGITUDINAL PATHOGENESIS OF EARLY-ONSET PRE-ECLAMPSIA

Objective: Pre-eclampsia (PE) is a syndrome that affects multiple organ systems and is the most severe hypertensive disorder in pregnancy. It frequently leads to preterm delivery, maternal and fetal morbidity and mortality and life-long complications. We currently lack efficient screening tools and early therapies to address PE. Design and method: To identify candidate biomarkers and operative pathways in early onset PE (eoPE, severe PE with onset before week 34), we performed spatio-temporal multi-omics profiling of human eoPE placentae and healthy controls, and validated targets in early gestation in a longitudinal clinical cohort. We used a single-nuclei RNA-sequencing combined with spatial proteo- and transcriptomics and mechanistic in vitro signalling analyses to bridge the gap from late pregnancy disease to early pregnancy pathomechanisms. Results: We discovered a key disruption in villous trophoblast differentiation, which is driven by the increase of transcriptional coactivator p300, that ultimately ends with a senescence-associated secretory phenotype (SASP) of trophoblasts in eoPE. We found a significant increase in the senescence markers in preeclamptic maternal serum in early gestation and late gestation, before the development of clinical symptoms, indicating that the placental syndrome drives systemic maternal syndrome, even before clinical manifestation of eoPE. Conclusions: Our work describes a new disease progression model, starting with dysregulated transition in villous trophoblast differentiation. Our study identifies potential pathophysiology-relevant biomarkers for the early diagnosis of the disease as well as possible targets for interventions, which would be crucial steps toward protecting the mother and child from gestational mortality and morbidity and an increased risk of cardiovascular disease later in life.

Respiration and Cough in Pompe Disease: Results from a neuromechanical computational model of the respiratory control system

Late Onset Pompe Disease (LOPD) is an incurable, rare progressive genetic disease. It is characterized by glycogen build-up, due to mutations in the gene encoding the lysosomal enzyme acid alpha glucosidase, throughout muscle and neural regions. This accumulation is associated with cell death and muscle fiber swelling, eventually leading to respiratory insuffciency and airway clearance (i.e. cough) deficiency. Impairments in effective airway clearance result from the inability to clear normal pulmonary volume. Emerging evidence indicates significant respiratory neuron dysfunction, altering pulmonary function in humans and animal models. It has been suggested that respiratory and airway clearance insuffciency observed in LOPD may be attributed to medullary motoneurons potentially associated with the respiratory and cough pattern generators (Fuller et al., 2013; DeRuisseau et al., 2009). However, the precise neural mechanisms that suppress breathing and cough are not fully understood. One possible target for LOPD respiratory insuffciencies may be reduced medullary inspiratory neuron activity within this network, which could result in decreased phrenic motoneuron output. Using a stochastic neural network simulator that consisted of discrete “integrate and fire” populations, we simulated a systematic decrease in three medullary inspiratory neuron populations: inspiratory driver (I-Driver), inspiratory decrementing (I-Dec), or inspiratory augmenting (I-Aug) neurons. We simulated breathing and three cough trials. By targeting these populations, we expected global decreased neural bursts, suppressed inspiratory motor drive, and/or suppressed expiratory motoneuron output. Simulations indicated that when the I-Dec motoneuron population decreased by 25%, it resulted in apnea and abolished cough. Reducing the I-Aug motoneuron population by 20% resulted in longer inspiratory phase durations (TI) and a decreased respiratory rate. During cough, there was a decrease in the duration and amplitudes of the expiratory motoneuronal activity associated with decreased cough receptor and pulmonary stretch receptor afferent feedback. When the I-Driver motoneuron population was reduced by 25%, TI decreased and I amplitude increased during respiration. During cough, lumbar and phrenic motoneuron discharge duration and amplitude decreased. These results are consistent with previously reported in vivo data. Overall, our simulation data support the plausibility of glycogen storage dysfunction impairing medullary neuronal and premotoneuronal excitability within the inspiratory network. Our results also suggest that some neurons may be more sensitive to glycogen storage than others within the brainstem inspiratory network. Supported by NHLBI L30HL165496, NIH T32 HL 134621 and 3OT2OD023854. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.