AMPD2 regulates GTP synthesis and is mutated in a potentially treatable neurodegenerative brainstem disorder.

Purine biosynthesis and metabolism, conserved in all living organisms, is essential for cellular energy homeostasis and nucleic acid synthesis. The de novo synthesis of purine precursors is under tight negative feedback regulation mediated by adenosine and guanine nucleotides. We describe a distinct early-onset neurodegenerative condition resulting from mutations in the adenosine monophosphate deaminase 2 gene (AMPD2). Patients have characteristic brain imaging features of pontocerebellar hypoplasia (PCH) due to loss of brainstem and cerebellar parenchyma. We found that AMPD2 plays an evolutionary conserved role in the maintenance of cellular guanine nucleotide pools by regulating the feedback inhibition of adenosine derivatives on de novo purine synthesis. AMPD2 deficiency results in defective GTP-dependent initiation of protein translation, which can be rescued by administration of purine precursors. These data suggest AMPD2-related PCH as a potentially treatable early-onset neurodegenerative disease.

A reverse genetics and genomics approach to gene paralog function and disease: Myokymia and the juxtaparanode.

The leucine-rich glioma-inactivated (LGI) family consists of four highly conserved paralogous genes, LGI1-4, that are highly expressed in mammalian central and/or peripheral nervous systems. LGI1 antibodies are detected in subjects with autoimmune limbic encephalitis and peripheral nerve hyperexcitability syndromes (PNHSs) such as Isaacs and Morvan syndromes. Pathogenic variations of LGI1 and LGI4 are associated with neurological disorders as disease traits including familial temporal lobe epilepsy and neurogenic arthrogryposis multiplex congenita 1 with myelin defects, respectively. No human disease has been reported associated with either LGI2 or LGI3. We implemented exome sequencing and family-based genomics to identify individuals with deleterious variants in LGI3 and utilized GeneMatcher to connect practitioners and researchers worldwide to investigate the clinical and electrophysiological phenotype in affected subjects. We also generated Lgi3-null mice and performed peripheral nerve dissection and immunohistochemistry to examine the juxtaparanode LGI3 microarchitecture. As a result, we identified 16 individuals from eight unrelated families with loss-of-function (LoF) bi-allelic variants in LGI3. Deep phenotypic characterization showed LGI3 LoF causes a potentially clinically recognizable PNHS trait characterized by global developmental delay, intellectual disability, distal deformities with diminished reflexes, visible facial myokymia, and distinctive electromyographic features suggestive of motor nerve instability. Lgi3-null mice showed reduced and mis-localized Kv1 channel complexes in myelinated peripheral axons. Our data demonstrate bi-allelic LoF variants in LGI3 cause a clinically distinguishable disease trait of PNHS, most likely caused by disturbed Kv1 channel distribution in the absence of LGI3.

Conditional recurrent neural networks for broad applications in nonlinear optics.

We present a novel implementation of conditional long short-term memory recurrent neural networks that successfully predict the spectral evolution of a pulse in nonlinear periodically-poled waveguides. The developed networks offer large flexibility by allowing the propagation of optical pulses with ranges of energies and temporal widths in waveguides with different poling periods. The results show very high agreement with the traditional numerical models. Moreover, we are able to use a single network to calculate both the real and imaginary parts of the pulse complex envelope, allowing for successfully retrieving the pulse temporal and spectral evolution using the same network.

Health and wellbeing of staff working at higher education institutions globally during the post-COVID-19 pandemic period: evidence from a cross-sectional study.

BACKGROUND: The ongoing global crisis of Higher Education (HE) institutions during the post-COVID-19 pandemic period has increased the likelihood of enduring psychological stressors for staff. This study aimed to identify factors associated with job insecurity, burnout, psychological distress and coping amongst staff working at HE institutions globally. METHODS: An anonymous cross-sectional study was conducted in 2023 with staff at HE institutions across 16 countries. Job insecurity was measured using the Job Insecurity Scale (JIS), burnout using the Perceived Burnout measure question, psychological distress using the Kessler Psychological Distress Scale (K10), and coping using the Brief Resilient Coping Scale. Multivariable logistic regression with a stepwise variable selection method was used to identify associations. RESULTS: A total of 2,353 staff participated; the mean age (± SD) was 43(± 10) years and 61% were females. Most staff (85%) did not feel job insecurity, one-third (29%) perceived burnout in their jobs, more than two-thirds (73%) experienced moderate to very high levels of psychological distress, and more than half (58%) exhibited medium to high resilient coping. Perceived job insecurity was associated with staff working part-time [Adjusted Odds Ratio 1.53 (95% Confidence Intervals 1.15-2.02)], having an academic appointment [2.45 (1.78-3.27)], having multiple co-morbidities [1.86 (1.41-2.48)], perceived burnout [1.99 (1.54-2.56)] and moderate to very high level of psychological distress [1.68 (1.18-2.39)]. Perceived burnout was associated with being female [1.35 (1.12-1.63)], having multiple co-morbidities [1.53 (1.20-1.97)], perceived job insecurity [1.99 (1.55-2.57)], and moderate to very high levels of psychological distress [3.23 (2.42-4.30)]. Staff with multiple co-morbidities [1.46 (1.11-1.92)], mental health issues [2.73 (1.79-4.15)], perceived job insecurity [1.61 (1.13-2.30)], and perceived burnout [3.22 (2.41-4.31)] were associated with moderate to very high levels of psychological distress. Staff who perceived their mental health as good to excellent [3.36 (2.69-4.19)] were more likely to have medium to high resilient coping. CONCLUSIONS: Factors identified in this study should be considered in reviewing and updating current support strategies for staff at HE institutions across all countries to reduce stress and burnout and improve wellbeing.

Piper sarmentosum Roxb. Inhibits Angiotensin-Converting Enzyme Activity in Phorbol 12-Myristate-13-Acetate-Induced Endothelial Cells.

Angiotensin-converting enzyme (ACE) plays a crucial role in the pathogenesis of hypertension. Piper sarmentosum Roxb., an herb known for its antihypertensive effect, lacks a comprehensive understanding of the mechanism underlying its antihypertensive action. This study aimed to elucidate the antihypertensive mechanism of aqueous extract of P. sarmentosum leaves (AEPS) via its modulation of the ACE pathway in phorbol 12-myristate-13-acetate (PMA)-induced human umbilical vein endothelial cells (HUVECs). HUVECs were divided into five groups: control, treatment with 200 µg/mL AEPS, induction 200 nM PMA, concomitant treatment with 200 nM PMA and 200 µg/mL AEPS, and treatment with 200 nM PMA and 0.06 µM captopril. Subsequently, ACE mRNA expression, protein level and activity, angiotensin II (Ang II) levels, and angiotensin II type 1 receptor (AT1R) and angiotensin II type 2 receptor (AT2R) mRNA expression in HUVECs were determined. AEPS successfully inhibited ACE mRNA expression, protein and activity, and angiotensin II levels in PMA-induced HUVECs. Additionally, AT1R expression was downregulated, whereas AT2R expression was upregulated. In conclusion, AEPS reduces the levels of ACE mRNA, protein and activity, Ang II, and AT1R expression in PMA-induced HUVECs. Thus, AEPS has the potential to be developed as an ACE inhibitor in the future.

A founder DBR1 variant causes a lethal form of congenital ichthyosis.

DBR1 encodes the only known human lariat debranching enzyme and its deficiency has been found to cause an autosomal recessive inborn error of immunity characterized by pediatric brainstem viral-induced encephalitis (MIM 619441). We describe a distinct allelic disorder caused by a founder recessive DBR1 variant in four families (DBR1(NM_016216.4):c.200A > G (p.Tyr67Cys)). Consistent features include prematurity, severe intrauterine growth deficiency, congenital ichthyosis-like presentation (collodion membrane, severe skin peeling and xerosis), and death before the first year of life. Patient-derived fibroblasts displayed the characteristic accumulation of intron lariats in their RNA as revealed by targeted and untargeted analysis, in addition to a marked reduction of DBR1 on immunoblot analysis. We propose a novel DBR1-related developmental disorder that is distinct from DBR1-related encephalitis susceptibility and highlight the apparent lack of correlation with the degree of DBR1 deficiency.

Using the LeiCNS-PK3.0 Physiologically-Based Pharmacokinetic Model to Predict Brain Extracellular Fluid Pharmacokinetics in Mice.

INTRODUCTION: The unbound brain extracelullar fluid (brainECF) to plasma steady state partition coefficient, Kp,uu,BBB, values provide steady-state information on the extent of blood-brain barrier (BBB) transport equilibration, but not on pharmacokinetic (PK) profiles seen by the brain targets. Mouse models are frequently used to study brain PK, but this information cannot directly be used to inform on human brain PK, given the different CNS physiology of mouse and human. Physiologically based PK (PBPK) models are useful to translate PK information across species. AIM: Use the LeiCNS-PK3.0 PBPK model, to predict brain extracellular fluid PK in mice. METHODS: Information on mouse brain physiology was collected from literature. All available connected data on unbound plasma, brainECF PK of 10 drugs (cyclophosphamide, quinidine, erlotonib, phenobarbital, colchicine, ribociclib, topotecan, cefradroxil, prexasertib, and methotrexate) from different mouse strains were used. Dosing regimen dependent plasma PK was modelled, and Kpuu,BBB values were estimated, and provided as input into the LeiCNS-PK3.0 model to result in prediction of PK profiles in brainECF. RESULTS: Overall, the model gave an adequate prediction of the brainECF PK profile for 7 out of the 10 drugs. For 7 drugs, the predicted versus observed brainECF data was within two-fold error limit and the other 2 drugs were within five-fold error limit. CONCLUSION: The current version of the mouse LeiCNS-PK3.0 model seems to reasonably predict available information on brainECF from healthy mice for most drugs. This brings the translation between mouse and human brain PK one step further.

Factors associated with delayed reporting for surgical care among patients with surgical acute abdomen attended at Muhimbili National Hospital: Tanzania.

BACKGROUND: Surgical acute abdomen is a sudden onset of severe abdominal symptoms (pain, vomiting, constipation etc.) indicative of a possible life-threatening intra-abdominal pathology, with most cases requiring immediate surgical intervention. Most studies from developing countries have focused on complications related to delayed diagnosis of specific abdominal problems like intestinal obstruction or acute appendicitis and only a few studies have assessed factors related to the delay in patients with acute abdomen. This study focused on the time from the onset of a surgical acute abdomen to presentation to determine factors that led to delayed reporting among these patients at the Muhimbili National Hospital (MNH) and aimed to close the knowledge gap on the incidence, presentation, etiology, and death rates for acute abdomen in Tanzania. METHODS: We conducted a descriptive cross-sectional study at MNH, Tanzania. Patients with a clinical diagnosis of the surgical acute abdomen were consecutively enrolled in the study over a period of 6 months and data on the onset of symptoms, time of presentation to the hospital, and events during the illness were collected. RESULTS: Age was significantly associated with delayed hospital presentation, with older groups presenting later than younger ones. Informal education and being uneducated were factors contributing to delayed presentation, while educated groups presented early, albeit the difference was statistically insignificant (p = 0.121). Patients working in the government sector had the lowest percentage of delayed presentation compared to those in the private sector and self-employed individuals, however, the difference was statistically insignificant. Family and cohabiting individuals showed late presentation (p = 0.03). Deficiencies in health care staff on duty, unfamiliarity with the medical facilities, and low experience in dealing with emergency cases were associated with the factors for delayed surgical care among patients. Delays in the presentation to the hospital increased mortality and morbidity, especially among patients who needed emergency surgical care. CONCLUSION: Delayed reporting for surgical care among patients with surgical acute abdomen in underdeveloped countries like Tanzania is often not due to a single reason. The causes are distributed across several levels including the patient's age and family, deficiency in medical staff on duty and lack of experience in dealing with emergency cases, educational level, working sectors, socioeconomic and sociocultural status of the country.

Characterizing morphologic subtypes of high-grade serous ovarian cancer by CT: a retrospective cohort study.

OBJECTIVE: A novel classification system of high-grade serous ovarian carcinoma based on gross morphology observed at pre-treatment laparoscopy was recently defined. The purpose of this study was to identify radiographic features unique to each morphologic subtype. METHODS: This retrospective study included 109 patients with high-grade serous ovarian cancer who underwent pre-operative computed tomography (CT) scanning and laparoscopic assessment of disease burden between 1 April 2013 and 5 August 2015. Gross morphologic subtype had been previously assigned by laparoscopy. Two radiologists independently reviewed CT images for each patient, categorized disease at eight anatomic sites, and assessed for radiographic characteristics of interest: large infiltrative plaques, mass-like metastases, enhancing peritoneal lining, architectural distortion, fat stranding, calcifications, and lymph node involvement. Demographic and clinical information was summarized with descriptive statistics and compared using Student's t-tests, χ² tests, or Fisher exact tests as appropriate; kappa statistics were used to assess inter-reader agreement. RESULTS: Certain radiographic features were found to be associated with gross morphologic subtype. Large infiltrative plaques were more common in type 1 disease (88.7% (47/53) vs 71.4% (25/35), p=0.04), while mass-like metastases were more often present in type 2 disease (48.6% (17/35) vs 22.6% (12/53), p=0.01). Additionally, radiographic presence of disease at the falciform ligament was more common in type 1 morphology (33.9% (19/56) vs 13.2% (5/38), p=0.02). CONCLUSION: Morphologic subtypes of high-grade serous ovarian cancer were associated with specific CT findings, including the presence of large infiltrative plaques, mass-like metastases, and falciform ligament involvement.

A Feasibility Study on Deep Learning Reconstruction to Improve Image Quality With PROPELLER Acquisition in the Setting of T2-Weighted Gynecologic Pelvic Magnetic Resonance Imaging.

OBJECTIVES: Evaluate deep learning (DL) to improve the image quality of the PROPELLER (Periodically Rotated Overlapping Parallel Lines with Enhanced Reconstruction technique) for 3 T magnetic resonance imaging of the female pelvis. METHODS: Three radiologists prospectively and independently compared non-DL and DL PROPELLER sequences from 20 patients with a history of gynecologic malignancy. Sequences with different noise reduction factors (DL 25%, DL 50%, and DL 75%) were blindly reviewed and scored based on artifacts, noise, relative sharpness, and overall image quality. The generalized estimating equation method was used to assess the effect of methods on the Likert scales. Quantitatively, the contrast-to-noise ratio and signal-to-noise ratio (SNR) of the iliac muscle were calculated, and pairwise comparisons were performed based on a linear mixed model. P values were adjusted using the Dunnett method. Interobserver agreement was assessed using the κ statistic. P value was considered statistically significant at less than 0.05. RESULTS: Qualitatively, DL 50 and DL 75 were ranked as the best sequences in 86% of cases. Images generated by the DL method were significantly better than non-DL images ( P < 0.0001). Iliacus muscle SNR on DL 50 and DL 75 was significantly better than non-DL images ( P < 0.0001). There was no difference in contrast-to-noise ratio between the DL and non-DL techniques in the iliac muscle. There was a high percent agreement (97.1%) in terms of DL sequences' superior image quality (97.1%) and sharpness (100%) relative to non-DL images. CONCLUSION: The utilization of DL reconstruction improves the image quality of PROPELLER sequences with improved SNR quantitatively.

Erectile function after different techniques of bulbar urethroplasty: does urethral transection make a difference?

PURPOSE: We aimed to compare the impact of urethral transection after different techniques of bulbar urethroplasty on erectile function outcome. MATERIALS AND METHODS: We retrospectively reviewed the records for 245 patients who underwent different urethroplasty techniques for bulbar urethral stricture between February 2013 and January 2021. The comparison between the transecting and non-transecting cohorts included patients' demographics, clinicopathological features of the urethral stricture, post-urethroplasty erectile function, and success of urethroplasty. Outcomes were erectile function status verified by IIEF5-15 score at preoperative, three months, and 12 months post-surgery. We defined Post-urethroplasty ED as a decrease of 5 points or more. RESULTS: The urethroplasty success rate of the entire cohort was 86.9% after a mean follow-up of 45.59 ± 21 months. Out of 245 patients, 18 (7.3%) experienced 90-day complications. Transecting bulbar urethroplasty techniques were performed in 74 patients (30.2%), while non-transecting techniques were performed in 171 patients (69.8%). there were no differences between the cohorts regarding urethroplasty success (87.8% Vs. 86.5%, Mantel-Cox test p = 0.93) or postoperative complications (8.1% Vs. 7%, p = 0.73). Transient ED was evident in the transecting cohort as reported in 8.1% compared to 2.9% for the non-transecting (p = 0.07).Still, but de novo permanent ED was comparable (4.1% Vs. 2.9%, p = 0.65), for transecting and non-transecting, respectively. CONCLUSIONS: Unfortunately, some patients who undergo transecting techniques of bulbar urethroplasty experience transient erectile dysfunction that can improve within the first post- urethroplasty year; however, de novo permanent erectile dysfunction is uncommon after different techniques of bulbar urethroplasty and is not predisposed by urethral transection.

Ectoparasites of dogs (Canis familiaris) from northeastern Nigeria: an epidemiological study.

Ectoparasites of dogs represent an important group of parasites. They often suck blood, cause pruritis, and could serve as vectors of many pathogens of veterinary and public health importance. In northeastern Nigeria, there is a lack of data regarding ectoparasites of dogs. Therefore, this study was undertaken to explore the external parasites of dogs and the associated epidemiological risk factors. A total of 1041 dogs (mean age = 8.5 ± 2.1 months) from residential house visit (54.9%) and those attending veterinary clinic (45.1%) were sampled in northeastern Nigeria. Multivariate logistic regression analysis assessed epidemiological risk factors associated with canine ectoparasitic infections. Of the 1041 dogs screened, 92.5% (963/1047) harbored one or more ectoparasites. Rhipicephalus sanguineus (52.4%), Linognathus setosus (7.8%), Ctenocephalides canis (2.3%), and Otodectes cynotis canis (1.4%) were the significantly encountered tick, lice, fleas, and mite species, respectively. Being female dog (OR = 1.8; p = 0.01), cross (OR = 2.2; p = 0.029), and exotic breeds (OR = 2.4; p = 0.02), < 7 months (OR = 3.1; p = 0.04) and 7-12 months (OR = 2.1; p = 0.01) aged dogs as well as rainy season (OR = 1.9; p = 0.02) were strong predictors for tick infestation. Similarly, cross (OR = 7.2; p = 0.001) and local breeds (OR = 2.8; p = 0.0001), dogs aged > 12 months (OR = 2.5; p = 0.03), and dogs used for hunting (OR = 3.2; p = 0.01) and as security guards (OR = 3.8; p = 0.01) were strongly associated with lice infestation. Results from this study revealed a high prevalence of external parasites parasitizing majority of the sampled dogs. Some of these parasites may serve as vectors of zoonotic pathogens posing public health risks.

First Report of Colletotrichum gloeosporioides and Colletotrichum siamense, Causing Anthracnose Disease on coffee trees, in Saudi Arabia.

Coffee (Coffea arabica L.) is a promising agricultural commodity in many countries including Saudi Arabia, but crop production is often constrained by diseases. In December 2021, coffee trees had symptoms of anthracnose disease (CAD) were observed in Jazan Province, Saudi Arabia (17°19'00.8"N 43°11'26.8"E), and the incidence was 55%. Affected trees showed dieback and leaves necrosis. On green and ripening berries, slightly sunken and dark brown lesions were occurred; the berries finally become mummified (Fig. S1). For pathogen isolation, symptomatic tissues (4×4mm) of 30 diseased branches and berries samples were surface-sterilized in 1% sodium hypochlorite for 2 min, followed by 70% ethanol for 20 s, rinsed in sterile distilled water and placed on potato dextrose agar (PDA). Cultures were incubated at 26℃ for 8 days in the dark. Eighteen isolates were recovered, and 2 representative single spore isolates (KSU-CgM17, KSU-CsM42) were used for further study. PDA culture of KSU-CgM17 had aerial white mycelium at first and later became gray to grayish black; light salmon to orange conidial masses were observed on the mycelium plate surface as the cultures aged (Fig. S2). Colony produced by KSU-CsM42 was off-white to gray with cottony mycelia and grayish-white on the undersides of the culture after 10 days at 28° (Fig. S2). Conidial shape of these two isolates were both aseptate, cylindrical to nearly straight, hyaline, rounded at both ends. Conidia (n = 50) measurements were 16 to 18.0 µm long × 4.8 to 6.4 µm wide for KSU-CgM17 and 12.6 to 17.5 µm long × 3.2 to 4.5 µm wide for KSU-CsM42. The microscopic and culture features fitted those for Colletotrichum gloeosporioides species complex (Weir et al. 2012). To further identify these isolates, four genomic DNA loci including the partial ITS rDNA region, and CAL, TUB2, and GAPDH genes were amplified and sequenced (Hu et al., 2015). All sequences were deposited into GenBank under accession numbers: OQ791412 & OQ791413 (ITS), OQ786847 & OQ786851 (CAL), OQ786849 & OQ786850 (TUB2), and OQ786848 & OQ786852 (GAPDH) for KSU-CgM17and KSU-CsM42, respectively (Tables S1& S2). A BLAST search of GenBank showed that these pathogens were identified as C. gloeosporioides (KSU-CgM17) and C. siamense (KSU-CsM42). The pathogenicity was tested on detached coffee leaves or green and red berries (Coa et al., 2019). For inoculation, healthy leaves and berries were wounded with a sterilized needle, placed inside petri dishes containing moist filter paper, and then inoculated with a 10-µl droplet of conidial suspension (106 spores/ ml). Sterile distilled water was used as a negative control. Six replicates were tested per isolate and the experiment was repeated once. The inoculated materials were incubated at 25°C and 100% relative humidity for 8 days. Necrotic lesions developed on 100% of the inoculated coffee materials 6 days later, whereas the negative controls were asymptomatic (Fig. S2). Koch's postulates were fulfilled when typical colonies of these species were successfully re-isolated from the from symptomatic tissues. These pathogens were reported previously to affect coffee in Vietnam (Nguyen et al., 2010), China (Cao et al., 2019), and Puerto Rico (Serrato-Diaz et al., 2020). To our knowledge, this is the first record of C. gloeosporioides and C. siamense causing CAD in Saudi Arabia. Further studies on the epidemiology of CAD on arabica coffee plantations as well as effective strategies for managing this disease are needed.

Identification and distribution of the "Candidatus Liberibacter asiaticus"-Asian citrus psyllid pathosystem in Saudi Arabia.

Citrus greening disease was first reported in Saudi Arabia during the 1970's when characteristic foliar and fruit symptoms were observed in commercial citrus groves, however, "Candidatus Liberibacter asiaticus" (CLas) was not detected in symptomatic trees until 1981-1984 when CLas-like cells were observed by transmission electron microscopy in leaves collected from symptomatic citrus groves in southwestern Saudi Arabia. Despite the anticipated establishment of the CLas-Asian citrus psyllid (ACP) (Diaphorina citri Kuwayama) pathosystem, CLas presence has not been verified in suspect trees nor have ACP infestations been documented. Given the recent expansion of citrus production in Saudi Arabia, a systematic country-wide survey was carried out to determine the potential CLas distribution in the thirteen citrus-growing regions of the country. Citrus trees were surveyed for presence of CLas-psyllid vector(s) and characteristic disease symptoms in commercial and urban citrus trees. Adult psyllids collected from infested citrus trees were identified as ACP based on morphological characteristics. Real-time, quantitative PCR amplification (qPCR) of the CLas ß-subunit of the ribonucleotide reductase (RNR) gene from citrus leaf and fruit samples and/or ACP adults, revealed trees were positive for CLas detection in ten of the 13 survey regions, however, CLas was undetectable in ACP adults. Phylogenetic and SNPs analyses of a PCR-amplified, cloned fragment of the CLas 16S rRNA gene (~1.1 kbp) indicated Saudi Arabian isolates were most closely related to Florida, USA isolates. Analysis of climate variables indicated that the distribution of the ACP-CLas pathosystem observed in Saudi Arabia was consistent with published predictions of terrains most likely to support establishment.

A Real Time Method for Distinguishing COVID-19 Utilizing 2D-CNN and Transfer Learning.

Rapid identification of COVID-19 can assist in making decisions for effective treatment and epidemic prevention. The PCR-based test is expert-dependent, is time-consuming, and has limited sensitivity. By inspecting Chest R-ray (CXR) images, COVID-19, pneumonia, and other lung infections can be detected in real time. The current, state-of-the-art literature suggests that deep learning (DL) is highly advantageous in automatic disease classification utilizing the CXR images. The goal of this study is to develop models by employing DL models for identifying COVID-19 and other lung disorders more efficiently. For this study, a dataset of 18,564 CXR images with seven disease categories was created from multiple publicly available sources. Four DL architectures including the proposed CNN model and pretrained VGG-16, VGG-19, and Inception-v3 models were applied to identify healthy and six lung diseases (fibrosis, lung opacity, viral pneumonia, bacterial pneumonia, COVID-19, and tuberculosis). Accuracy, precision, recall, f1 score, area under the curve (AUC), and testing time were used to evaluate the performance of these four models. The results demonstrated that the proposed CNN model outperformed all other DL models employed for a seven-class classification with an accuracy of 93.15% and average values for precision, recall, f1-score, and AUC of 0.9343, 0.9443, 0.9386, and 0.9939. The CNN model equally performed well when other multiclass classifications including normal and COVID-19 as the common classes were considered, yielding accuracy values of 98%, 97.49%, 97.81%, 96%, and 96.75% for two, three, four, five, and six classes, respectively. The proposed model can also identify COVID-19 with shorter training and testing times compared to other transfer learning models.

Parallel CNN-ELM: A multiclass classification of chest X-ray images to identify seventeen lung diseases including COVID-19.

Numerous epidemic lung diseases such as COVID-19, tuberculosis (TB), and pneumonia have spread over the world, killing millions of people. Medical specialists have experienced challenges in correctly identifying these diseases due to their subtle differences in Chest X-ray images (CXR). To assist the medical experts, this study proposed a computer-aided lung illness identification method based on the CXR images. For the first time, 17 different forms of lung disorders were considered and the study was divided into six trials with each containing two, two, three, four, fourteen, and seventeen different forms of lung disorders. The proposed framework combined robust feature extraction capabilities of a lightweight parallel convolutional neural network (CNN) with the classification abilities of the extreme learning machine algorithm named CNN-ELM. An optimistic accuracy of 90.92% and an area under the curve (AUC) of 96.93% was achieved when 17 classes were classified side by side. It also accurately identified COVID-19 and TB with 99.37% and 99.98% accuracy, respectively, in 0.996 microseconds for a single image. Additionally, the current results also demonstrated that the framework could outperform the existing state-of-the-art (SOTA) models. On top of that, a secondary conclusion drawn from this study was that the prospective framework retained its effectiveness over a range of real-world environments, including balanced-unbalanced or large-small datasets, large multiclass or simple binary class, and high- or low-resolution images. A prototype Android App was also developed to establish the potential of the framework in real-life implementation.

Reduced-Dose Deep Learning Reconstruction for Abdominal CT of Liver Metastases.

Background Assessment of liver lesions is constrained as CT radiation doses are lowered; evidence suggests deep learning reconstructions mitigate such effects. Purpose To evaluate liver metastases and image quality between reduced-dose deep learning image reconstruction (DLIR) and standard-dose filtered back projection (FBP) contrast-enhanced abdominal CT. Materials and Methods In this prospective Health Insurance Portability and Accountability Act-compliant study (September 2019 through April 2021), participants with biopsy-proven colorectal cancer and liver metastases at baseline CT underwent standard-dose and reduced-dose portal venous abdominal CT in the same breath hold. Three radiologists detected and characterized lesions at standard-dose FBP and reduced-dose DLIR, reported confidence, and scored image quality. Contrast-to-noise ratios for liver metastases were recorded. Summary statistics were reported, and a generalized linear mixed model was used. Results Fifty-one participants (mean age ± standard deviation, 57 years ± 13; 31 men) were evaluated. The mean volume CT dose index was 65.1% lower with reduced-dose CT (12.2 mGy) than with standard-dose CT (34.9 mGy). A total of 161 lesions (127 metastases, 34 benign lesions) with a mean size of 0.7 cm ± 0.3 were identified. Subjective image quality of reduced-dose DLIR was superior to that of standard-dose FBP (P < .001). The mean contrast-to-noise ratio for liver metastases of reduced-dose DLIR (3.9 ± 1.7) was higher than that of standard-dose FBP (3.5 ± 1.4) (P < .001). Differences in detection were identified only for lesions 0.5 cm or smaller: 63 of 65 lesions detected with standard-dose FBP (96.9%; 95% CI: 89.3, 99.6) and 47 lesions with reduced-dose DLIR (72.3%; 95% CI: 59.8, 82.7). Lesion accuracy with standard-dose FBP and reduced-dose DLIR was 80.1% (95% CI: 73.1, 86.0; 129 of 161 lesions) and 67.1% (95% CI: 59.3, 74.3; 108 of 161 lesions), respectively (P = .01). Lower lesion confidence was reported with a reduced dose (P < .001). Conclusion Deep learning image reconstruction (DLIR) improved CT image quality at 65% radiation dose reduction while preserving detection of liver lesions larger than 0.5 cm. Reduced-dose DLIR demonstrated overall inferior characterization of liver lesions and reader confidence. Clinical trial registration no. NCT03151564 © RSNA, 2022 Online supplemental material is available for this article.

The Extension of the LeiCNS-PK3.0 Model in Combination with the "Handshake" Approach to Understand Brain Tumor Pathophysiology.

Micrometastatic brain tumor cells, which cause recurrence of malignant brain tumors, are often protected by the intact blood-brain barrier (BBB). Therefore, it is essential to deliver effective drugs across not only the disrupted blood-tumor barrier (BTB) but also the intact BBB to effectively treat malignant brain tumors. Our aim is to predict pharmacokinetic (PK) profiles in brain tumor regions with the disrupted BTB and the intact BBB to support the successful drug development for malignant brain tumors. LeiCNS-PK3.0, a comprehensive central nervous system (CNS) physiologically based pharmacokinetic (PBPK) model, was extended to incorporate brain tumor compartments. Most pathophysiological parameters of brain tumors were obtained from literature and two missing parameters of the BTB, paracellular pore size and expression level of active transporters, were estimated by fitting existing data, like a "handshake". Simultaneous predictions were made for PK profiles in extracellular fluids (ECF) of brain tumors and normal-appearing brain and validated on existing data for six small molecule anticancer drugs. The LeiCNS-tumor model predicted ECF PK profiles in brain tumor as well as normal-appearing brain in rat brain tumor models and high-grade glioma patients within twofold error for most data points, in combination with estimated paracellular pore size of the BTB and active efflux clearance at the BTB. Our model demonstrated a potential to predict PK profiles of small molecule drugs in brain tumors, for which quantitative information on pathophysiological alterations is available, and contribute to the efficient and successful drug development for malignant brain tumors.

Drug Distribution in Brain and Cerebrospinal Fluids in Relation to IC50 Values in Aging and Alzheimer's Disease, Using the Physiologically Based LeiCNS-PK3.0 Model.

BACKGROUND: Very little knowledge exists on the impact of Alzheimer's disease on the CNS target site pharmacokinetics (PK). AIM: To predict the CNS PK of cognitively healthy young and elderly and of Alzheimer's patients using the physiologically based LeiCNS-PK3.0 model. METHODS: LeiCNS-PK3.0 was used to predict the PK profiles in brain extracellular (brainECF) and intracellular (brainICF) fluids and cerebrospinal fluid of the subarachnoid space (CSFSAS) of donepezil, galantamine, memantine, rivastigmine, and semagacestat in young, elderly, and Alzheimer's patients. The physiological parameters of LeiCNS-PK3.0 were adapted for aging and Alzheimer's based on an extensive literature search. The CNS PK profiles at plateau for clinical dose regimens were related to in vitro IC50 values of acetylcholinesterase, butyrylcholinesterase, N-methyl-D-aspartate, or gamma-secretase. RESULTS: The PK profiles of all drugs differed between the CNS compartments regarding plateau levels and fluctuation. BrainECF, brainICF and CSFSAS PK profile relationships were different between the drugs. Aging and Alzheimer's had little to no impact on CNS PK. Rivastigmine acetylcholinesterase IC50 values were not reached. Semagacestat brain PK plateau levels were below the IC50 of gamma-secretase for half of the interdose interval, unlike CSFSAS PK profiles that were consistently above IC50. CONCLUSION: This study provides insights into the relations between CNS compartments PK profiles, including target sites. CSFSAS PK appears to be an unreliable predictor of brain PK. Also, despite extensive changes in blood-brain barrier and brain properties in Alzheimer's, this study shows that the impact of aging and Alzheimer's pathology on CNS distribution of the five drugs is insignificant.

Identification and molecular characterization of cotton leaf curl Gezira betasatellite and two distinct begomoviruses infecting papaya trees in the Kingdom of Saudi Arabia.

Begomovirus is the largest genus in the family Geminiviridae and constitutes more than 445 virus species. Begomoviruses are characterized by single-stranded circular genomes with monopartite or bipartite components and transmitted by whitefly (Bemisia tabaci). Begomoviruses cause severe diseases in many economically important crops throughout the world. Typical symptoms of a begomovirus infection including severe leaf curling, vein thickening, vein darkening and reduced leaf size were observed in papaya plants in the Dammam district of the Eastern Province of Saudi Arabia during the growing season in 2022. A total of 10 samples were collected, and total genomic DNA was isolated from naturally infected papaya tree samples and subjected to PCR amplification using universal diagnostic primers for begomoviruses and associated satellites. Three PCR-amplified genomic components of begomoviruses and betasatellite namely P61Begomo (645 bp), P62Begomo (341 bp) and P62Beta (563 bp) were sent for Sanger DNA sequencing to Macrogen Inc. These partial viral genome sequences were submitted to Genbank database and accession numbers ON206051, ON206052 and ON206050 were assigned to P61Begomo, P62Begomo and P62Beta respectively. Phylogenetic analysis and pairwise nucleotide sequence identity studies identified P61Begomo was identified as Tomato yellow leaf curl virus, P62Begomo as DNA A component of a bipartite begomovirus Watermelon chlorotic stunt virus and P62Beta as begomovirus associated betasatellite; Cotton leaf curl Gezira betasatellite. To the best of our knowledge, this is the first report of a begomovirus complex infecting papaya (Carica papaya) in the Kingdom of Saudi Arabia.