Disease Onset Time Research Articles

Construction of a digital twin of chronic graft vs. host disease patients with standard of care

There is an unmet medical need for new clinical trials to evaluate novel therapies in chronic graft-versus-host disease (cGvHD). Disease rarity, ethical issues regarding placebo arms, time, and cost impede clinical trial conduct. Digital twin (DT) technology enables virtual clinical trial arm construction using historical data, circumventing these obstacles. We evaluated the feasibility of constructing a DT trial arm using a large database of real-world clinical trial data and performed an efficacy assessment of a standard-of-care (SOC) drug to examine agreement with literature data. We constructed a flGvHD DT cohort (cGvHD patients at first-line treatment) (2042 patients; 32 cohorts) using the Trial Accelerator™ Digital Twin platform and derived an SOC arm from this cohort (flGvHD DT SOC cohort) (438 patients; eight cohorts); we analyzed the efficacy of SOC (prednisone) (overall response rate (ORR)) at six months. Our analysis results are in agreement with literature: flGvHD DT: disease onset time: 7.58 months post-allogeneic hematopoietic cell transplantation; most used graft source: peripheral blood stem cells; flGvHD DT SOC: ORR at six months for prednisone: 52.7%. It is feasible to construct a DT cohort using existing clinical trial data; a DT SOC arm can potentially replace a control arm in clinical trials.

Impact of age at diagnosis on long-term prognosis in patients with intestinal Behçet's disease.

Although age at disease onset is considered to be a significant factor in the prognosis of Crohn's disease, little is known about its influence on the long-term prognosis of those with intestinal Behçet's disease (BD). This study aimed to evaluate the long-term clinical outcomes of patients with intestinal BD according to age of disease onset. Patients diagnosed with intestinal BD at <18, 18-60, and >60years of age were classified into early-onset, adult-onset, and late-onset groups, respectively. The influence of disease onset time on clinical prognosis, including specific medical requirements, BD-related intestinal surgery, hospitalization, and emergency room visits, was compared using the log-rank test in a large cohort of patients with intestinal BD. Among 780 patients, 21 (2.7%), 672 (86.2%), and 87 (11.1%) comprised the early-onset, adult-onset, and late-onset groups, respectively. Patients in the early-onset group were more likely to require immunosuppressants than those in the adult-onset group (P=0.048). Nine (42.9%), 158 (23.5%), and 18 (20.7%) patients in the early-onset, adult-onset, and late-onset groups, respectively, underwent intestinal resection. The early-onset group exhibited a higher risk for intestinal resection than the late-onset (P=0.043) and adult-onset (P=0.030) groups. The late-onset group exhibited a higher risk for BD-related hospitalization than the adult-onset group (P=0.023). Age at diagnosis affected the clinical course of intestinal BD, including intestinal surgery, hospitalization, and specific medical requirements. Different treatment strategies should be established according to age at diagnosis.

Neurological injury in primary Sjogren's syndrome.

Forty-eight patients with primary Sjogren's syndrome, attending outpatient clinics at Damascus Hospital between January 2020 and January 2022 in this cross-sectional study at the outpatient clinics, were interviewed and examined, and the necessary laboratory and radiological examinations were demanded. Information was collected on disease duration, onset time, and patterns of neurological symptoms. Forty-eight patients, including 42 females, aged 56.1±10.3 years were enroled.Central nervous system involvement was found in 34 patients. 85% of patients had generalized nerve manifestations, while local nerve manifestations were found in 77,5% of patients. The common neurological manifestation was headaches, then cognitive disorders, and the most common pattern of headache was migraine. Beck Depression Index showed a significant increase in the apathy evaluation scale.The study of cognitive changes showed a significant increase in the Mini-Mental State Examination (MMSE) index.Carotid Doppler showed the presence of injury in 42.4% of patients. The magnetic resonance imaging showed positive findings in 21 patients and positive evoked potentials in 52% of patients. Studies showing the prevalence of Sjogren's neurological injury patterns are insufficient, but this was changed when the criteria for diagnosing Sjogren's syndrome was modified, and the definition of neurological traits in the context of the syndrome was expanded.The presence of a high rate of headaches, cognitive changes, and fatigue confirms that generalized nervous system injuries are more common than local injuries. Migraine was the most common pattern of headache found in patients with the syndrome compared with other patterns such as tension headaches and headaches due to medications, especially analgesics.This was associated with the presence of anti-SSA antibodies and Raynaud's phenomenon, which suggest that the headache mechanism may be due to vascular endothelial dysfunction or an immune-mediated inflammation injury of the neurovascular system.The changes that appeared on the MRI images suggested premotor cortex involvement rather than mesolimbic cortical impairment, and its presence was also associated with SSA antibody positivity, and it is caused by inflammation. Primary Sjogren's syndrome should be considered as having any unspecified or specific neurological disorder.

Vibrio splendidus Fur regulates virulence gene expression, swarming motility, and biofilm formation, affecting its pathogenicity in Apostichopus japonicus.

Vibrio splendidus is an opportunistic pathogen that causes skin ulcer syndrome and results in huge losses to the Apostichopus japonicus breeding industry. Ferric uptake regulator (Fur) is a global transcription factor that affects varieties of virulence-related functions in pathogenic bacteria. However, the role of the V. splendidus fur (Vsfur) gene in the pathogenesis of V. splendidus remains unclear. Hence, we constructed a Vsfur knock-down mutant of the V. splendidus strain (MTVs) to investigate the role of the gene in the effect of biofilm, swarming motility, and virulence on A. japonicus. The result showed that the growth curves of the wild-type V. splendidus strain (WTVs) and MTVs were almost consistent. Compared with WTVs, the significant increases in the transcription of the virulence-related gene Vshppd mRNA were 3.54- and 7.33-fold in MTVs at the OD600 of 1.0 and 1.5, respectively. Similarly, compared with WTVs, the significant increases in the transcription of Vsm mRNA were 2.10- and 15.92-fold in MTVs at the OD600 of 1.0 and 1.5, respectively. On the contrary, the mRNA level of the flagellum assembly gene Vsflic was downregulated 0.56-fold in MTVs at the OD600 of 1.0 compared with the WTVs. MTVs caused delayed disease onset time and reduced A. japonicus mortality. The median lethal doses of WTVs and MTVs were 9.116 × 106 and 1.658 × 1011 CFU·ml-1, respectively. Compared with WTVs, the colonization abilities of MTVs to the muscle, intestine, tentacle, and coelomic fluid of A. japonicus were significantly reduced. Correspondingly, the swarming motility and biofilm formation in normal and iron-replete conditions were remarkably decreased compared with those of WTVs. Overall, these results demonstrate that Vsfur contributes to the pathogenesis of V. splendidus by regulating virulence-related gene expression and affecting its swarming and biofilm formation abilities.

Predicting Alzheimer’s disease progression in healthy and MCI subjects using multi‐modal deep learning approach

AbstractBackgroundAlzheimer’s disease (AD) is a complex disorder influenced by many factors, but it is unclear how each factor contributes to disease progression. An in‐depth examination of these factors may yield an accurate estimate of time‐to‐conversion to AD for patients at various disease stages. Recent advances in deep learning have enabled researchers to predict patient’s disease onset time by exploring the influencing factors in AD progression.MethodWe used 543 subjects with 63 features from 3 data modalities from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. The following modalities were used: 1) MRI, 2) genetic and 3) DTC (Demographic, cognitive Tests and Cerebrospinal fluid). The 21 most important features were automatically selected for the three modalities.We used a Deep Learning‐based survival analysis model that extends the classic Cox regression model to predict the subjects' disease onset time. Here we re‐define the non‐AD‐progression as “survivor”, and AD‐progression as “non‐survivor”. The subjects were divided into two groups: progressive subjects (non‐survivor), who were either healthy or diagnosed with Mild Cognitive Impairment (MCI) at initial clinical visit and later developed AD, and non‐progressive subjects ("survivor”), who were either healthy or MCI at initial visit but did not develop AD later. We used 10 random sub‐samples, selecting 80% of the subjects for training and 20% for testing each time; 20% of training data was used for internal validation.ResultFigure 1 shows the estimated survival rates over 10 years. Both groups had a high survival chance at the start. The progressive group’s survival chance dropped much faster and fell below 20% by the end of the period. The non‐progressive group’s survival chance remained around 50%.Feature importance analysis is displayed in Figure 2. Eight of the top ten most important features are from the cognitive tests, demonstrating their importance in survival analysis. Amygdala and Hippocampus regions, as well as age, are also notable features.ConclusionOur study demonstrated that using powerful predictive models on multi‐modal data can improve prediction of time‐to‐conversion. This not only leads to a better understanding of AD, but also provides essential tools for practitioners who wish to follow their patients' disease progression.

Early electroacupuncture intervention delays progression of disease in mice with amyotrophic lateral sclerosis by down-regulating TLR4/NF-κB signaling

To observe the effect of early electroacupuncture (EA) intervention on Toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) signaling pathway in mice with amyotrophic lateral sclerosis (ALS), so as to explore its mechanisms underlying alleviation of ALS. Fifty-four ALS (ALS-SOD1G93A) mice with SOD1G93A gene mutation identified by PCR were randomly divided into model group, 60 day(d) EA group and 90 d EA group(n=18 mice in each group), and other 18 ALS-SOD1G93A negative mice were used as the control group. At the age of 60 and 90 days, mice of the two EA groups received EA (2 Hz, 1 mA) stimulation of bilateral "Jiaji" (EX-B2) of L1-L2 and L5-L6 for 20 min, twice a week for 4 weeks,respectively. When being 60 days old, the mice in the model and control groups were subjected to the same binding as that in the two EA groups but without EA intervention. The tail suspension test was used to judge the onset time of disease and the survival period, and rotary rod fatigue test was used to evaluate the hind limb motor function. Nissl staining method was used to observe the content of Nissl bodies in the anterior horn of the lumbar spinal cord. Immunohistochemical staining was used to observe the expression of ionized calcium binding adaptor molecule-1 (Iba-1) in the anterior horn of the lumbar spinal cord, and Western blot was used to detect the relative expression of TLR4, NF-κB and tumor necrosis factor-α (TNF-α) in the lumbar spinal cord. The disease onset time apparently delayed in the 60 d EA group than in the model group (P<0.01). The survival time was apparently shorter in the model group than in the control group (P<0.01), and obviously prolonged in the 60 d EA and 90 d EA groups than in the model group (P<0.01). The rotatory rod time was obviously shorter in the model group than in the control group (P<0.05), and apparently longer in the 60 d EA group than in the model group and 90 d EA group (P<0.05). Compared with the control group, the model group had a decrease in the number of Nissl bodies in the anterior horn of the lumbar spinal cord (P<0.01), and an increase in the expression levels of Iba-1, TLR4, NF-κB and TNF-α in the lumbar spinal cord (P<0.01). In contrast to the model group, both 60 d EA and 90 d EA groups had an apparent increase in the number of Nissl bodies and a marked decrease in the expression levels of Iba-1, TLR4, NF-κB and TNF-α in the lumbar spinal cord (P<0.05, P<0.01). The therapeutic effects of 60 d EA group were evidently superior to those of 90 d EA group in delaying the onset time of disease, prolonging the survival time and rotatory rod time, increasing the number of Nissl bodies, and in down-regulating the expression of Iba-1, TLR4, NF-κB and TNF-α (P<0.05, P<0.01). The early intervention of EX-B2 EA is more effective in delaying the progression of ALS than post-onset intervention in ALS-SOD1G93A mice, which may be related to its functions in inhibiting the excessive activation of microglia, and down-regulating TLR4/NF-κB signaling.

Unexpected thermodynamic signature for the interaction of hydroxymethylated DNA with MeCP2

Hydroxymethylated cytosine (5hmC) is a stable DNA epigenetic mark recognized by methyl-CpG binding protein 2 (MeCP2), which acts as a transcriptional regulator and a global chromatin-remodeling element. Because 5hmC triggers a gene regulation response markedly different from that produced by methylated cytosine (5mC), both modifications must affect DNA structure and/or DNA interaction with MeCP2 differently. MeCP2 is a six-domain intrinsically disordered protein (IDP) with two domains responsible for dsDNA binding: methyl-CpG binding domain (MBD) and intervening domain (ID). Here we report the detailed thermodynamic characterization of the interaction of hmCpG-DNA with MeCP2. We find that hmCpG-DNA interacts with MeCP2 in a distinctly different mode with a particular thermodynamic signature, compared to methylated or unmethylated DNA. In addition, we find evidence for Rett syndrome-associated mutations altering the interaction of MeCP2 with dsDNA in a cytosine modification-specific manner which may correlate with disease onset time and clinical severity score.

Overweight and Obesity as Risk Factors for Recurrent Herpetic Stromal Keratitis during Long-Term Antiviral Prophylaxis.

Although past research has shown an association between obesity and herpes simplex virus infection, the relationship between body mass index (BMI) and herpetic stromal keratitis (HSK) recurrence has never been investigated. In this study, we included HSK patients who received oral valacyclovir as prophylactic treatment between January 2016 and January 2021. Recurrence, possible risk factors, and the time to recurrence were recorded during follow-ups. Among the 56 patients included in this study, recurrence was reported in 21 (37.5%) patients. The age at disease onset and mean follow-up time were not significantly different in the recurrence and non-recurrence groups. However, in the Cox regression analysis, BMI ≥ 24 kg/m2 was noted as the variable having significant correlation with recurrence (p = 0.01 in univariate analysis and p = 0.001 in multivariate analysis). In conclusion, overweight and obesity were revealed as risk factors for HSK recurrence in patients receiving long-term antiviral prophylaxis. Further studies are needed to determine the appropriate acyclovir concentrations in the blood or aqueous humour in order to achieve desirable prophylactic effects, especially in the overweight and obese patients.

Predicting Alzheimer's disease progression in healthy and MCI subjects using multi-modal deep learning approach.

Alzheimer's disease (AD) is a complex disorder influenced by many factors, but it is unclear how each factor contributes to disease progression. An in-depth examination of these factors may yield an accurate estimate of time-to-conversion to AD for patients at various disease stages. Recent advances in deep learning have enabled researchers to predict patient's disease onset time by exploring the influencing factors in AD progression. We used 543 subjects with 63 features from 3 data modalities from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. The following modalities were used: 1) MRI, 2) genetic and 3) DTC (Demographic, cognitive Tests and Cerebrospinal fluid). The 21 most important features were automatically selected for the three modalities. We used a Deep Learning-based survival analysis model that extends the classic Cox regression model to predict the subjects' disease onset time. Here we re-define the non-AD-progression as "survivor", and AD-progression as "non-survivor". The subjects were divided into two groups: progressive subjects (non-survivor), who were either healthy or diagnosed with Mild Cognitive Impairment (MCI) at initial clinical visit and later developed AD, and non-progressive subjects ("survivor"), who were either healthy or MCI at initial visit but did not develop AD later. We used 10 random sub-samples, selecting 80% of the subjects for training and 20% for testing each time; 20% of training data was used for internal validation. Figure 1 shows the estimated survival rates over 10 years. Both groups had a high survival chance at the start. The progressive group's survival chance dropped much faster and fell below 20% by the end of the period. The non-progressive group's survival chance remained around 50%. Feature importance analysis is displayed in Figure 2. Eight of the top ten most important features are from the cognitive tests, demonstrating their importance in survival analysis. Amygdala and Hippocampus regions, as well as age, are also notable features. Our study demonstrated that using powerful predictive models on multi-modal data can improve prediction of time-to-conversion. This not only leads to a better understanding of AD, but also provides essential tools for practitioners who wish to follow their patients' disease progression.

Population genomics of Group B Streptococcus reveals the genetics of neonatal disease onset and meningeal invasion

Group B Streptococcus (GBS), or Streptococcus agalactiae, is a pathogen that causes preterm births, stillbirths, and acute invasive neonatal disease burden and mortality. Here, we investigate bacterial genetic signatures associated with disease onset time and meningeal tissue infection in acute invasive neonatal GBS disease. We carry out a genome-wide association study (GWAS) of 1,338 GBS isolates from newborns with acute invasive disease; the isolates had been collected annually, for 30 years, through a national bacterial surveillance program in the Netherlands. After controlling for the population structure, we identify genetic variation within noncoding and coding regions, particularly the capsule biosynthesis locus, statistically associated with neonatal GBS disease onset time and meningeal invasion. Our findings highlight the impact of integrating microbial population genomics and clinical pathogen surveillance, and demonstrate the effect of GBS genetics on disease pathogenesis in neonates and infants.

Semisupervised Calibration of Risk with Noisy Event Times (SCORNET) using electronic health record data.

Leveraging large-scale electronic health record (EHR) data to estimate survival curves for clinical events can enable more powerful risk estimation and comparative effectiveness research. However, use of EHR data is hindered by a lack of direct event time observations. Occurrence times of relevant diagnostic codes or target disease mentions in clinical notes are at best a good approximation of the true disease onset time. On the other hand, extracting precise information on the exact event time requires laborious manual chart review and is sometimes altogether infeasible due to a lack of detailed documentation. Current status labels-binary indicators of phenotype status during follow-up-are significantly more efficient and feasible to compile, enabling more precise survival curve estimation given limited resources. Existing survival analysis methods using current status labels focus almost entirely on supervised estimation, and naive incorporation of unlabeled data into these methods may lead to biased estimates. In this article, we propose Semisupervised Calibration of Risk with Noisy Event Times (SCORNET), which yields a consistent and efficient survival function estimator by leveraging a small set of current status labels and a large set of informative features. In addition to providing theoretical justification of SCORNET, we demonstrate in both simulation and real-world EHR settings that SCORNET achieves efficiency akin to the parametric Weibull regression model, while also exhibiting semi-nonparametric flexibility and relatively low empirical bias in a variety of generative settings.

Progression of powdery mildew in susceptible‐resistant wheat (Triticum aestivum) cultivars sown at different dates

AbstractA better understanding of non‐climatic predictors of temporal dynamics of wheat powdery mildew is needed to improve accuracy of disease measurement for breeding and control programmes. The present study examined fourteen types of standard curves to model powdery mildew progress data collected from 282 plots of commercial wheat cultivars sown at different dates over four growing seasons (2013–2017). An exponential model was fitted to disease progress data, and then, relationships between commonly used disease descriptors and exponential parameters were examined. From exponential function, parameters b and r defined disease increase factor and rate of disease increase, respectively. This model described a slow increase of wheat powdery mildew at first, followed by a more rapid increase lacking bound. According to Kruskal–Wallis one‐way ANOVA results, wheat resistance and sowing date were significantly effective on area under disease progress curve (AUDPC), maximum disease severity and exponential parameter b. Greatest mean values for AUDPC, maximum severity and exponential parameter b were detected in later sowings of susceptible cultivars. There were significant correlations between powdery mildew curve elements. Based on principal component analysis, AUDPC, disease onset time, maximum severity and exponential parameters b and r accounted for 77% of total data variance. This information on specific predictors of wheat powdery mildew progress may improve accuracy of future disease estimates in breeding and control programmes.

Effect of electroacupuncture on expression of heat shock protein 70 in mice with amyotrophic lateral sclerosis

To observe the effects of electroacupuncture (EA) on the body weight, disease progression and the expression of heat shock protein 70 (HSP70) in lumbar spinal cord of amyotrophic lateral sclerosis (ALS) mice, so as to explore the mechanism of EA on treating ALS. Eighteen ALS transgenic SOD1G93A mice were randomly divided into model, EA and medication groups, with 6 mice in each group, and six C57BL/6J mice were used as the normal group. Mice in the EA group received EA at "Quchi"(LI11)-"Hegu"(LI4), "Zusanli"(ST36)- "Sanyinjiao"(SP6), 30 min/time, 5 times/week, for 8 weeks.Mice in the medication group were given riluzole solution (7.6 mg·kg-1·d-1) by gavage for 8 weeks. The body weight of the mice was recorded and the motor function of the hind limbs was evaluated by the neurological function scoring stan-dard of the ALS Therapeutic Development Institute. The expression of HSP70 in lumbar spinal cord was detected by Western blot and immunohistochemistry, respectively. Compared with the normal group, the body weight and the expression of HSP70 in the model group decreased significantly (P<0.05), while no significant difference in the body weight was found among other groups(P>0.05). After intervention and in comparison with the model group, the disease onset time and paralysis time of the EA group and the medication group were significantly delayed (P<0.05, P<0.01), the expression of HSP70 in the EA group and the medicine group was significantly increased (P<0.05, P<0.01).But there was no significant difference in the survival time among all groups(P＞0.05). The disease onset time of the EA group was shorter than that in the medication group (P<0.05). EA can increase the expression of HSP70 in lumbar spinal cord, thereby delaying the progression of ALS.

Ultrasound patterns of localized cutaneous leishmaniasis and clinical correlations.

A single-center retrospective study reviewed the following sonographic features of 18 confirmed cases of localized cutaneous leishmaniasis to identify shared presentation patterns: echotexture, lesion borders, hypodermal involvement, soft-tissue changes, and vascular pattern. A second objective was to correlate these patterns with clinical characteristics, including sex, age, anatomical location, nodule vs. plaque presentation, raised borders, granulation tissue, swelling, hyperkeratotic crusting, disease onset, and healing time. Two main patterns were identified with high-frequency ultrasonography. The first pattern was characterized by a high level of inflammation and deep hypodermal involvement, while the second variant showed involvement limited to the dermis, with minimal inflammation. The "inflammatory pattern" showed ill-defined borders, mixed echotexture, prominent vascularity with central distribution, and was correlated with clinical signs of ulceration, granulation tissue, raised borders, and longer healing time (p < 0.05). The "pauci-inflammatory pattern" presented a well-defined structure with decreased echogenicity, reduced or absent vascularity with minimal soft-tissue changes, and was associated with a shorter healing time (p < 0.05).

Factors affecting the length of hospital stay after laparoscopic appendectomy: A single center study.

AimThis study aimed to explore factors may affect the length of hospital stay after laparoscopic appendectomy.MethodsThe data of 636 patients undergoing laparoscopic appendectomy between July 2016 and July 2019 in Beijing Tsinghua Changgung Hospital were retrospectively analyzed. The patients were divided into group A (hospital stay ≤3 days, 348 patients) and group B (hospital stay >3 days, 288 patients) according to their hospital stay.Sex, age, disease onset time(time from onset to admission), nausea, vomiting, diarrhea, peritonitis, comorbidities, and history of appendicitis; preoperative body temperature (T), white blood cell (WBC) count, percentage of neutrophilic granulocytes, and preoperative C-reactive protein (CRP) level; time from diagnosis to surgery. appendix diameter, appendicolith, and ascites in ultrasound or CT; surgical time(the surgery start time was the time of skin incision, and the end time was the time the anesthesia intubation was removed), intraoperative blood loss (the volume of blood infiltrating into a gauze was calculated by weighing the gauze infiltrated with water and calculating the volume of water), intraoperative adhesions or effusions, and stump closure methods, convert to open appendectomy, appendix pathology(perforated or gangrenous appendicitis were defined as complicated appendicitis and simple or suppurative appendicitis were defined as uncomplicated appendicitis) and antibiotic treatment schemes were analyzed.ResultsSignificant differences were detected between group A and group B in age (37.10 ± 13.52y vs 42.94 ± 15.57y, P<0.01), disease onset time (21.36 ± 16.56 h vs 32.52 ± 27.99 h, P <0.01), time from diagnosis to surgery (8.63 ± 7.29 h vs 10.70 ± 8.47 h, P<0.01); surgical time(64.09 ± 17.24 min vs 86.19 ± 39.96 min, P < 0.01); peritonitis(52.9% vs 74%, P < 0.01), comorbidities (12.4% vs 20.5%, P < 0.01), appendicolith (27.6% vs 41.7%, P < 0.01), ascites before the surgery(13.8% vs 22.9%, P < 0.01), intraoperative adhesions or effusions(56% vs 80.2%, P < 0.01); preoperative temperature (37.11 ± 0.64°C vs 37.54 ± 0.90°C, P < 0.01); preoperative WBC count (13.06 ± 3.39 × 109/L vs 14.21 ± 4.54 × 109/L, P = 0.04);preoperative CRP level(18.99 ± 31.72 mg/L vs 32.46 ± 46.68 mg/L, P < 0.01); appendix diameter(10.22 ± 2.59 mm vs 11.26 ± 3.23 mm, P < 0.01); intraoperative blood loss (9.36 ± 7.29 mL vs 13.74 ± 13.49 mL, P < 0.01); using Hem-o-lok for stump closure(30.7% vs 38.5%, P = 0.04); complicated appendicitis (9.5% vs 45.8%, P < 0.01); and using ertapenem for antibiotic treatment after the surgery(4.3% vs 21.5%, P < 0.01). Multivariate analysis demonstrated that age (OR = 1.021; 95%CI = 1.007–1.036), peritonitis (OR = 1.603; 95% CI = 1.062–2.419), preoperative WBC count (OR = 1.084; 95% CI = 1.025–1.046), preoperative CRP level (OR = 1.010; 95% CI = 1.005–1.015), time from diagnosis to surgery (OR = 1.043; 95% CI = 1.015–1.072), appendicolith (OR = 1.852; 95% CI = 1.222–2.807), complicated appendicitis (OR = 3.536; 95% CI = 2.132–5.863), surgical time (OR = 1.025; 95% CI = 1.016–1.034), use of Hem-o-lok for stump closure (OR = 1.894; 95% CI = 1.257–2.852), and use of ertapenem for antibiotic treatment (OR = 3.076; 95% CI = 1.483–6.378) were the risk factors for a prolonged hospital stay.ConclusionsThe patient with appendicitis was older and had peritonitis, higher preoperative WBC count or CRP level, longer time from diagnosis to surgery, appendicolith, and complicated appendicitis, predicting a prolonged hospital stay. Shorter surgical time and the use of silk ligation for stump closure and cephalosporins + metronidazole for antibiotic treatment might be better choices to obtain a shorter hospital stay.

Structural characterization of stripe rust progress in wheat crops sown at different planting dates

An advanced insight into characterizing stripe rust progress curves is required to improve accuracy and efficiency of future research for disease measurement and estimation purposes. The rate of stripe rust increase in wheat crops is highly variable, resulting in variations and uncertainties in evaluating disease progress over time. This variability was described by fitting standard curves to disease severity data collected over a four-season experiment to identify effective disease curve elements in Iranian wheat cultivars planted at different dates. Gaussian curves appeared to be the best fitted models for all four growing seasons. Three Gaussian parameters in combination with the area under the disease progress curve (AUDPC), disease onset time, maximum disease incidence and severity were then considered to describe the rate of disease increase. Based on H-tests of Kruskal-Wallis one-way analysis of variance, cultivar and planting date significantly affected AUDPC, maximum disease incidence and severity. There were significant correlations between continuous disease descriptors. Then, significant associations were determined between AUDPC, disease onset time, Gaussian parameters, maximum disease incidence and severity according to factor analysis. With these novel findings, we should be aware of descriptive value of wheat-stripe-rust progress variables. Such information will assist with stripe rust measurements for wheat breeding programs, yield loss estimation, development of disease control strategy, and epidemiological studies.

P0052EMERGING CONCEPTS IN KIDNEY ATTR AMYLOIDOSIS: CHRONIC ADMINISTRATION OF TAFAMIDIS

Abstract Background and Aims Transthyretin (TTR) amyloidosis is a disease characterized by destabilization of the native TTR tetramer. It can be caused by aging or due to pathogenic mutations, and its diagnosis is often missed. Hereditary transthyretin amyloidosis (ATTRv), due to Val50Met mutation, is frequently linked with polyneuropathy but it can cause nephropathy too, causing wide range levels of albuminuria and renal dysfunction. Tafamidis, a TTR tetramer stabilizer, has been associated with significant decrease of albuminuria in ATTRv. However, TTR nephropathy is not an approved indication for its use. Plus, the renal effects of chronic oral administration of this TTR stabilizer are yet to be understood. This study evaluated longitudinal changes of eGFR-EPI within 72 months of therapy with tafamidis and identified factors associated with these changes. Method A retrospective cohort, single centre study was conducted. We have followed consecutive ATTRv Val50Met patients on tafamidis therapy from July 2012 to March 2019. Men and women aged 18-85 years were eligible if they had neuropathy stage I, were anti-amyloid treatment-naïve patients that accomplished at least 60 months of tafamidis therapy and had eGFR over 45 ml/min/1.73m2 with any grade of albuminuria. Exclusion criteria were: pregnancy, malignancies, diabetes and concurrent etiologies for nephropathy. Statistical analyses included Mann-Whitney test and linear mixed models to analyze the longitudinal changes in eGFR of the two groups of patients (albumunuric/ non-albuminuric at baseline), by controlling for variables that could be associated with eGFR EPI Cystatin C course. Results From 366 patients, biopsy-proven ATTR amyloidosis, treated with tafamidis, 122 patients met our criteria (56 males, 66 females) and had a median age of 36 (IQR: 32-46) years old. Twenty-eight had pathological urinary albumin-to-creatinine ratio (ACR), defined by ACR &amp;gt;30 mg/dL, and ACR &amp;gt;300 mg/dL was only found in females. In univariate analysis no significant differences were found between median eGFR decline in albuminuric versus non-albuminuric patients (p=0.330). At all time points, mean eGFR levels were significantly lower in baseline albuminuric patients. According to our estimation, eGFR at baseline was 11.2 mL/min/1.73 m2 lower in baseline albuminuric patients, adjusted for age at the disease onset and time between symptom onset and tafamidis initiation. Baseline albuminuria status (p=0,005), age at the disease onset (p&amp;lt;0,001) and time between initiation of symptoms and initiation of tafamidis (p=0,016) were the only independent factors associated with longitudinal changes of eGFR (higher age at the disease onset and higher time between symptom onset and tafamidis initiation were associated with lower levels of eGFR). Figure 1 shows the predicted eGFR EPI trajectories over time for baseline albuminuric/ non-albuminuric subjects. Conclusion This study represents a real-life experience of oral chronic administration of tafamidis and its effects on ATTR nephropathy, concerning albuminuria reduction and renal function decline. Our analysis had shown similar decline rates in eGFR, irrespectively the degree of albuminuria at baseline, differently from what would be expected, since higher grades of albuminuria are related with more rapidly kidney function deterioration. Besides its capacity of stabilizing TTR tetramers, tafamidis could have an enhancing role in the podocyte regeneration process through potential cofactors for amyloid fibrils toxic effect, that could be present in the glomerular basement membrane and mesangium. This nephroprotector effect should be considered when a switch of therapy is demanded by the neuropathy status and a second line treatment is considered. Presence of renal disease may be an indication for tafamidis maintenance and combined therapy.

Phenotypic Characterization of Very Early-Onset Inflammatory Bowel Disease with Interleukin-10 Signaling Deficiency: Based on a Large Cohort Study.

Interleukin-10 (IL10)/interleukin-10 receptor (IL10R) deficiency is a rare disease with life-threatening infantile-onset colitis. We sought to accurately phenotype this disorder based on a large cohort of patients with a proven defect of IL10 signaling and to clarify the effects of allogeneic hematopoietic stem cell transplantation (HSCT). We analyzed the phenotypes of our 61 patients and reviewed 78 other previously reported cases with identified mutations in the genes encoding IL10 or IL10R. We also compared the clinical features of patients with interleukin-10 receptor B (IL10RB), interleukin-10 receptor A (IL10RA), and IL10 mutations. The therapeutic effects of allogeneic HSCT were evaluated. We found that the disease onset time was extremely early: 70.3% within 30 days postnatal and 94.9% within the first 6 months of life. In addition, 94.2% of patients typically presented with perianal lesions. Oral ulcers and skin rash were common extra-intestinal manifestations (33.8% and 51.8%, respectively). There was no statistically significant difference in disease onset time, perianal lesion involvement, or mortality rate among patients with IL10RB, IL10RA, or IL10 deficiency. However, the surgery rate was higher in patients with IL10RB mutations than in those with IL10 or IL10RA mutations (P < 0.05). Compared with those with IL10RA deficiency, a higher percentage (32%, 9 of 28) of patients with IL10RB mutations developed B-cell lymphoma (P < 0.01). Compared with other regions, a higher percentage (98.7%) of IL10RA mutations was detected among patients in East Asia countries (P < 0.01), with hot-spot mutation sites of c.C301T and c.G537A. Allogeneic HSCT is efficacious but has a high mortality rate (17.5%, 7 of 40). Our study expands the current knowledge on the genotype-correlated phenotypes with a defect of IL10 signaling. B-cell lymphoma was more frequent than would be expected in patients with IL10RB mutations. There may be a unique genetic architecture among Eastern Asia compared with other populations. Although allogeneic HSCT represents a causal therapeutic approach for IL10-and IL10R-deficient patients, a word of caution is warranted.

Disease outbreak accompanies the dispersive structure of shrimp gut bacterial community with a simple core microbiota

Increasing evidence has emerged supporting a tight link between gut bacterial community and shrimp health. However, the knowledge about the variation of gut bacterial community, especially with different disease onset time, remains elusive. Here, healthy and diseased shrimps were collected at 3 disease-outbreak times (day 70, 80 and 85) to investigate the variation of gut bacterial community and its underlying ecological process with 16S rRNA gene amplicon sequencing. The gut bacterial community of diseased shrimp was distinct from the healthy one and temporally less stable, characterized by decreased alpha-diversity and dispersive structure. And its dominant ecological process experienced a transition with disease onset time, although deterministic process mainly governed the healthy gut bacterial assembly. In addition, the core microbiota of healthy shrimp gut harbored more diverse bacterial taxa with more cooperative interactions, while the diseased core microbiota showed opposite pattern with significantly higher abundance of opportunistic pathogens as well. These findings indicate that shrimp heath is highly relevant to the homeostasis of its gut bacterial community. Preservation and restoration of the bacterial community equilibrium could represent an effective strategy for shrimp disease prevention.

Association of Regulatory T-Cell Expansion With Progression of Amyotrophic Lateral Sclerosis

Neuroinflammation appears to be a key modulator of disease progression in amyotrophic lateral sclerosis (ALS) and thereby a promising therapeutic target. The CD4+Foxp3+ regulatory T-cells (Tregs) infiltrating into the central nervous system suppress neuroinflammation and promote the activation of neuroprotective microglia in mouse models of ALS. To our knowledge, the therapeutic association of host Treg expansion with ALS progression has not been studied in vivo. To assess the role of Tregs in regulating the pathophysiology of ALS in humans and the therapeutic outcome of increasing Treg activity in a mouse model of the disease. This prospective multicenter human and animal study was performed in hospitals, outpatient clinics, and research institutes. Clinical and function assessment, as well as immunological studies, were undertaken in 33 patients with sporadic ALS, and results were compared with 38 healthy control participants who were consecutively recruited from the multidisciplinary ALS clinic at Westmead Hospital between February 1, 2013, and December 31, 2014. All data analysis on patients with ALS was undertaken between January 2015 and December 2016. Subsequently, we implemented a novel approach to amplify the endogenous Treg population using peripheral injections of interleukin 2/interleukin 2 monoclonal antibody complexes (IL-2c) in transgenic mice that expressed mutant superoxide dismutase 1 (SOD1), a gene associated with motor neuron degeneration. In patients with ALS, Treg levels were determined and then correlated with disease progression. Circulating T-cell populations, motor neuron size, glial cell activation, and T-cell and microglial gene expression in spinal cords were determined in SOD1G93A mice, as well as the association of Treg amplification with disease onset and survival time in mice. The cohort of patients with ALS included 24 male patients and 9 female patients (mean [SD] age at assessment, 58.9 [10.9] years). There was an inverse correlation between total Treg levels (including the effector CD45RO+ subset) and rate of disease progression (R = -0.40, P = .002). Expansion of the effector Treg population in the SOD1G93A mice was associated with a significant slowing of disease progression, which was accompanied by an increase in survival time (IL-2c-treated mice: mean [SD], 160.6 [10.8] days; control mice: mean [SD], 144.9 [10.6] days; P = .003). Importantly, Treg expansion was associated with preserved motor neuron soma size and marked suppression of astrocytic and microglial immunoreactivity in the spinal cords of SOD1G93A mice, as well as elevated neurotrophic factor gene expression in spinal cord and peripheral nerves. These findings establish a neuroprotective effect of Tregs, possibly mediated by suppression of toxic neuroinflammation in the central nervous system. Strategies aimed at enhancing the Treg population and neuroprotective activity from the periphery may prove therapeutically useful for patients with ALS.