Inhibition of SARS-CoV-2 growth in the lungs of mice by a peptide-conjugated morpholino oligomer targeting viral RNA.

Further development of direct-acting antiviral agents against human SARS-CoV-2 infections remains a public health priority. Here, we report that an antisense peptide-conjugated morpholino oligomer (PPMO) named 5'END-2, targeting a highly conserved sequence in the 5' UTR of SARS-CoV-2 genomic RNA, potently suppressed SARS-CoV-2 growth in vitro and in vivo. In HeLa-ACE 2 cells, 5'END-2 produced IC50 values of between 40 nM and 1.15 µM in challenges using six genetically disparate strains of SARS-CoV-2, including JN.1. In vivo, using K18-hACE2 mice and the WA-1/2020 virus isolate, two doses of 5'END-2 at 10 mg/kg, administered intranasally on the day before and the day after infection, produced approximately 1.4 log10 virus titer reduction in lung tissue at 3 days post-infection. Under a similar dosing schedule, intratracheal administration of 1.0-2.0 mg/kg 5'END-2 produced over 3.5 log10 virus growth suppression in mouse lungs. Electrophoretic mobility shift assays characterized specific binding of 5'END-2 to its complementary target RNA. Furthermore, using reporter constructs containing SARS-CoV-2 5' UTR leader sequence, in an in-cell system, we observed that 5'END-2 could interfere with translation in a sequence-specific manner. The results demonstrate that direct pulmonary delivery of 5'END-2 PPMO is a promising antiviral strategy against SARS-CoV-2 infections and warrants further development.

Fluorescent Ionic Liquid Aggregates: A Self-Assembled Approach for Pesticide Detection and Catalysis.

The unregulated use of pesticides, industrial discharge of heavy metals, waste, and agricultural runoff may contaminate surface water and groundwater, consequently threatening ecosystems and human health. Thus, the sensitive detection and degradation of pesticides are essential for safety. In this context, herein, we have developed benzimidazolium-based fluorescent surfactant assemblies TA-1/SDS and TA-2/SDBS, which exhibit aggregation-induced emission enhancement in an aqueous medium. The aggregates (TA-1/SDS and TA-2/SDBS) displayed a turn-on emission response upon interaction with carbendazim and azamethiphos with limits of detection 7.5 and 7.8 nM, respectively. The FE-SEM and AFM studies revealed that TA-1/SDS and TA-2/SDBS undergo self-assembly with the addition of AZA and CBZ, resulting in the formation of dendritic structures. In addition to the quantification of AZA and CBZ, TA-1/SDS and TA-2/SDBS have also been evaluated to degrade both pesticides and validated using 31P NMR spectroscopy and LC-MS spectrometry.

Seizures and Epilepsy in Association With Neurocysticercosis: A Nosologic Proposal.

Neurocysticercosis is one of the main risk factors of seizures and epilepsy in many regions of the world, which are Taenia solium-endemic but resource-constrained to control the parasite. The nosology of seizures and the classification of epilepsy in the context of neurocysticercosis are somewhat uncertain. Many seizures associated with the infection are customarily referred to as "acute symptomatic seizures." The term, however, seems unsuitable. Neither is the condition acute nor does it allow the avoidance of long-term antiseizure medications, as is the case with acute symptomatic seizures, for instance, associated with traumatic brain injury. We propose that seizures be classified according to the evolutionary stage of parenchymal cysticercosis in addition to the conventional classification of seizures and epilepsy and identification of the epileptogenic zone. An often-ignored aspect is the identification of comorbidities, many of which are specific to neurocysticercosis.

TopoTxR: A topology-guided deep convolutional network for breast parenchyma learning on DCE-MRIs.

Characterization of breast parenchyma in dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is a challenging task owing to the complexity of underlying tissue structures. Existing quantitative approaches, like radiomics and deep learning models, lack explicit quantification of intricate and subtle parenchymal structures, including fibroglandular tissue. To address this, we propose a novel topological approach that explicitly extracts multi-scale topological structures to better approximate breast parenchymal structures, and then incorporates these structures into a deep-learning-based prediction model via an attention mechanism. Our topology-informed deep learning model, TopoTxR, leverages topology to provide enhanced insights into tissues critical for disease pathophysiology and treatment response. We empirically validate TopoTxR using the VICTRE phantom breast dataset, showing that the topological structures extracted by our model effectively approximate the breast parenchymal structures. We further demonstrate TopoTxR's efficacy in predicting response to neoadjuvant chemotherapy. Our qualitative and quantitative analyses suggest differential topological behavior of breast tissue in treatment-naïve imaging, in patients who respond favorably to therapy as achieving pathological complete response (pCR) versus those who do not. In a comparative analysis with several baselines on the publicly available I-SPY 1 dataset (N = 161, including 47 patients with pCR and 114 without) and the Rutgers proprietary dataset (N = 120, with 69 patients achieving pCR and 51 not), TopoTxR demonstrates a notable improvement, achieving a 2.6% increase in accuracy and a 4.6% enhancement in AUC compared to the state-of-the-art method.

-New frontiers in domain-inspired radiomics and radiogenomics: increasing role of molecular diagnostics in CNS tumor classification and grading following WHO CNS-5 updates.

Gliomas and Glioblastomas represent a significant portion of central nervous system (CNS) tumors associated with high mortality rates and variable prognosis. In 2021, the World Health Organization (WHO) updated its Glioma classification criteria, most notably incorporating molecular markers including CDKN2A/B homozygous deletion, TERT promoter mutation, EGFR amplification, + 7/-10 chromosome copy number changes, and others into the grading and classification of adult and pediatric Gliomas. The inclusion of these markers and the corresponding introduction of new Glioma subtypes has allowed for more specific tailoring of clinical interventions and has inspired a new wave of Radiogenomic studies seeking to leverage medical imaging information to explore the diagnostic and prognostic implications of these new biomarkers. Radiomics, deep learning, and combined approaches have enabled the development of powerful computational tools for MRI analysis correlating imaging characteristics with various molecular biomarkers integrated into the updated WHO CNS-5 guidelines. Recent studies have leveraged these methods to accurately classify Gliomas in accordance with these updated molecular-based criteria based solely on non-invasive MRI, demonstrating the great promise of Radiogenomic tools. In this review, we explore the relative benefits and drawbacks of these computational frameworks and highlight the technical and clinical innovations presented by recent studies in the landscape of fast evolving molecular-based Glioma subtyping. Furthermore, the potential benefits and challenges of incorporating these tools into routine radiological workflows, aiming to enhance patient care and optimize clinical outcomes in the evolving field of CNS tumor management, have been highlighted.

H5N1 clade 2.3.4.4b dynamics in experimentally infected calves and cows.

In March 2024, highly pathogenic avian influenza virus (HPAIV) clade 2.3.4.4b H5N1 infections in dairy cows were first reported from Texas, USA1. Rapid dissemination to more than 190 farms in 13 states followed2. Here, we provide results of two independent clade 2.3.4.4b experimental infection studies evaluating (i) oronasal susceptibility and transmission in calves to a US H5N1 bovine isolate genotype B3.13 (H5N1 B3.13) and (ii) susceptibility of lactating cows following direct mammary gland inoculation of either H5N1 B3.13 or a current EU H5N1 wild bird isolate genotype euDG (H5N1 euDG). Inoculation of the calves resulted in moderate nasal replication and shedding with no severe clinical signs or transmission to sentinel calves. In dairy cows, infection resulted in no nasal shedding, but severe acute mammary gland infection with necrotizing mastitis and high fever was observed for both H5N1 isolates. Milk production was rapidly and drastically reduced and the physical condition of the cows was severely compromised. Virus titers in milk rapidly peaked at 108 TCID50/mL, but systemic infection did not ensue. Notably, adaptive mutation PB2 E627K emerged after intramammary replication of H5N1 euDG. Our data suggest that in addition to H5N1 B3.13, other HPAIV H5N1 strains have the potential to replicate in the udder of cows and that milk and milking procedures, rather than respiratory spread, are likely the primary routes of H5N1 transmission between cattle.

Probable chlorthalidone-induced hypokalemic rhabdomyolysis.

OBJECTIVE: A case of hypokalemic rhabdomyolysis related to chlorthalidone use is reported SUMMARY: A 52-year-old male was admitted to the hospital for acute onset generalized weakness and was found to have severe hypokalemia and rhabdomyolysis. The patient had been on chlorthalidone therapy with a dose increase from 25mg daily to 50mg daily two months prior to admission. Extensive workup ruled out neurologic, rheumatologic and endocrinologic causes of hypokalemia. In the absence of other causes, it was determined that the patient was experiencing a severe presentation of chlorthalidone-induced hypokalemia resulting in rhabdomyolysis. The patient's rhabdomyolysis and weakness improved with aggressive potassium correction, and potassium wasting eventually resolved with discontinuation of chlorthalidone. CONCLUSION: Although mild hypokalemia is a known side effect of thiazide and thiazide-like diuretics, health care providers should be aware of the possibility of severe manifestations of this adverse reaction, even at relatively small dose increases.

Epilepsy Among School-Children in a Rural District in Northwest India: Prevalence Estimates Using Three Different Approaches.

OBJECTIVES: To estimate and compare the prevalence of epilepsy during childhood using several approaches and also to determine whether school-based screening campaigns can capture epilepsy cases efficiently. METHODS: Epilepsy prevalence determined from cases captured through the Rashtriya Bal Swasthya Karyakram (RBSK), a nationwide school-health screening framework, were compared with estimates derived from school- and community-based surveys in one Indian district. Level-1 screen comprised perusal of child health registers maintained by the RBSK teams over one year to estimate the documented number of children with epilepsy; Level-2 screen comprised a questionnaire-based school survey among 10,000 school children; and Level-3 screen-a door-to-door community-based survey among 10,000 children in the district. RESULTS: Prevalence estimates of childhood epilepsy varied significantly across screening methods. The child health register identified lower crude and age-adjusted prevalences of 40 (95% CI, 24 to 55) and 36 (95% CI, 20 to 51)/1,00,000 vis-à-vis both the school survey [crude and age-adjusted prevalences of 354 (95% CI, 221 to 487) and 340 (95% CI, 181 to 517) per 100,000] and the community survey [crude and age-adjusted prevalences of 759 (95% CI, 591 to 927) and 746 (95% CI, 579 to 914) per 100,000]. The community survey identified 15 children with epilepsy (20%) who had dropped out of school. Also, it recaptured a small number of children previously identified by the school or child health register surveys. CONCLUSIONS: The present findings underscore the need to scale up the capacity of public programs to screen epilepsy among school children and underline the high frequency of school dropouts among children with epilepsy in resource-limited settings.

Thematic analysis of patient perspectives in a randomized controlled trial for a remote perioperative telemonitoring program.

BACKGROUND: Remote patient telemonitoring programs offer the potential to enhance access and communication with medical providers. This study assessed the patient-reported experience during perioperative telemonitoring for gastrointestinal (GI) oncologic surgery. METHODS: Between October 2021 and July 2023, patients with GI cancer were enrolled in the remote telemonitoring trial and randomized into the intervention or enhanced usual care arm. Although the enhanced usual care arm adhered to standard protocols for problem reporting, the intervention arm received active nursing support for monitoring data deviations from predetermined thresholds. The program culminated in a 15-minute exit interview comprised 9 total questions to gather insights into the patient experiences with device usage, symptom reporting, and communication with the healthcare team. Thematic analysis was conducted on all responses to present a patient-centric summary. RESULTS: Of the 114 patients completing the study, 100 patients (88%) participated in the exit interview. Most enrolled patients (n = 68) were diagnosed as having colorectal cancer. The intervention arm reported greater ease and accessibility in electronic data reporting and communication with healthcare team compared to the enhanced usual care arm (94% vs 69%). Qualitative analysis identified 3 themes used to describe the program: "instilling an affirmative and proactive mindset toward recovery," "receiving timely attention from healthcare team," and "benefits of device usage and electronic health surveys." The subthemes highlighted an appreciative and empowering mindset among most patients. CONCLUSION: Most enrolled patients expressed satisfaction with the program to facilitate their postoperative recovery. These positive testimonials present a promising outlook for future implementation from the patient perspective.

Safety of pressurized intraperitoneal aerosolized chemotherapy in biliary cancer patients with peritoneal metastases.

Biliary tract cancers are a rare diagnosis with a rising incidence. Up to 20% of patients have peritoneal metastases, resulting in symptoms of ascites, abdominal pain and potential bowel obstruction. A standard of care systemic treatment comprises gemcitabine, cisplatin and durvalumab (gem/cis/durva). However, the clinical benefit among patients with peritoneal metastases remains unknown. Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) delivers chemotherapy directly to the peritoneal space, which could potentially improve efficacy with minimal systemic toxicity. We describe the design of a Phase I study investigating PIPAC with nab-paclitaxel plus systemic gem/cis/durva among biliary tract cancer patients with peritoneal metastases who have not received prior systemic treatment. The primary end point is safety of PIPAC with nab-paclitaxel in combination with systemic gem/cis/durva.Clinical Trial Registration: NCT05285358 (ClinicalTrials.gov).

[Box: see text].

Adolescent Substance Use Disorder in Primary Care: Challenges in Treatment Referral Beyond Access Availability.

OBJECTIVE: Fatal overdoses are the third leading cause of death in the pediatric population. Substance use disorders (SUD) screening is not routinely done in primary care practices. Early screening and intervention for adolescent SUD could mitigate future harm. METHODS: We conducted a 3-month pilot adapting universal screening using the CRAFFT tool in patients aged 12 to 17 presenting to an urban and a rural primary care practice during well-child and acute/sick-child visits. We collaborated with our pediatric addiction service to ensure access availability for further assessment and treatment for all positively screened patients; this was broadly communicated to primary care providers. RESULTS: There was a higher CRAFFT completion rate in the urban site (90%, vs 52.6% in our rural site). The majority of CRAFFT questionnaires were completed during acute/sick-child visits in both study sites. Moreover, we found a higher positive screen rate in our rural practice (14.6%, vs 2.4% in our urban practice). Only 27% of positively screened patients had substance use addressed by their providers. No pediatric addiction referrals were made. CONCLUSIONS: Findings suggest provider-level barriers exist despite having adequate specialty referral sources and institutional encouragement. Future work is needed to explore these barriers.

Liver Resection for Gastroenteropancreatic Neuroendocrine Tumors with Extrahepatic Disease.

Background: Although survival outcomes for neuroendocrine liver metastases (NETLM) are improved with liver-direct therapies (LDT), including hepatic debulking and nonsurgical trans-arterial embolization, the benefit is less established in the setting of concurrent extrahepatic disease (EHD). We performed a population-based study to characterize the rates of LDT being performed for NETLM with EHD patients and whether LDT is associated with survival outcomes. Methods: Patients with NETLM and EHD were identified using the California Cancer Registry database merged with data from the California Office of Statewide Health Planning and Development between 2000 and 2012. Demographics, clinical characteristics, and survival outcomes were analyzed for these patients with and without LDT. Results: 327 NETLM patients with EHD were identified. EHD sites included lung, peritoneum, bone, and brain. A total of 71 (22%) of these patients underwent LDT. Compared to NETLM with EHD patients who did not undergo LDT, patients who received LDT had longer median overall survival (27 vs. 16 months, p = 0.006). Within the LDT group, 23 patients underwent liver resection. Liver resection was associated with longer median overall survival compared to nonsurgical LDT (138 vs. 13 months, p < 0.001). Conclusions: LDT candidacy should be determined for patients on a case-by-case basis, but the presence of EHD should not preclude LDT with appropriate patient selection.

Portable UV-C Device to Treat High Flow of Infectious Aerosols Generated during Clinical Respiratory Care.

Respiratory interventions including noninvasive ventilation, continuous positive airway pressure and high-flow nasal oxygen generated infectious aerosols may increase risk of airborne disease (SARS-CoV-2, influenza virus) transmission to healthcare workers. We developed/tested a prototype portable UV-C254 device to sterilize high flows of viral-contaminated air from a simulated patient source at airflow rates of up to 100 l/m. Our device consisted of a central quartz tube surrounded 6 high-output UV-C254 lamps, within a larger cylinder allowing recirculation past the UV-C254 lamps a second time before exiting the device. Testing was with nebulized A/PR/8/34 (H1N1) influenza virus. RNA extraction and qRT-PCR showed virus transited through the prototype. Turning on varying numbers of lamps controlled the dose of UVC. Viability experiments at low, medium and high (100 l/min) flows of contaminated gas were conducted with 6, 4, 2 and 1 lamp activated (single-pass and recirculation were tested). Our data show 5-log reduction in particle forming units from a single lamp (single- pass and recirculated conditions) at high and low flows. UVC dose at 100 l/m was calculated at 11.6 mJ/cm2 single pass and 104 mJ/cm2 recirculated. The protype device shows high efficacy in killing nebulized influenza virus in a high flow of contaminated air.

Outcome of H5N1 clade 2.3.4.4b virus infection in calves and lactating cows.

In March 2024, highly pathogenic avian influenza virus (HPAIV) clade 2.3.4.4b H5N1 infections in dairy cows were first reported from Texas, USA. Rapid dissemination to more than 190 farms in 13 states followed. Here, we provide results of two independent clade 2.3.4.4b experimental infection studies evaluating (i) oronasal susceptibility and transmission in calves to a US H5N1 bovine isolate genotype B3.13 (H5N1 B3.13) and (ii) susceptibility of lactating cows following direct mammary gland inoculation of either H5N1 B3.13 or a current EU H5N1 wild bird isolate genotype euDG (H5N1 euDG). Inoculation of the calves resulted in moderate nasal replication and shedding with no severe clinical signs or transmission to sentinel calves. In dairy cows, infection resulted in no nasal shedding, but severe acute mammary gland infection with necrotizing mastitis and high fever was observed for both H5N1 genotypes/strains. Milk production was rapidly and drastically reduced and the physical condition of the cows was severely compromised. Virus titers in milk rapidly peaked at 108 TCID50/mL, but systemic infection did not ensue. Notably, adaptive mutation PB2 E627K emerged after intramammary replication of H5N1 euDG. Our data suggest that in addition to H5N1 B3.13, other HPAIV H5N1 strains have the potential to replicate in the udder of cows and that milk and milking procedures, rather than respiratory spread, are likely the primary routes of H5N1 transmission between cattle.

Dissipation behaviour and dietary risk evaluation of pesticides on cucumber.

Cucumber (Cucumis sativus L.) is the world's most widely consumed salad vegetable, and it is frequently treated with pesticides to prevent pest and disease outbreaks. Pesticide residues in food commodities impede trade and pose a major health risk. Prior to residue estimation, the QuEChERS approach was validated utilising criteria such as limit of detection, limit of quantitation, linearity, accuracy, and precision. The residues of carbendazim, cypermethrin, ethion, profenofos, quinalphos, and triazophos were examined using a Gas Chromatograph equipped with an Electron Capture Detector or a Flame Photometric Detector and a high-performance liquid chromatography coupled to a photo diode array. The initial deposits of carbendazim, cypermethrin, ethion, profenofos, quinalphos, and triazophos at the prescribed dose were 1.235, 0.407, 0.817, 0.960, 0.628, and 0.985 mg/kg, respectively, with a pre-harvest interval of 5.58-11.30 days. According to the consumer risk evaluation data, the Hazard Quotient is less than one, and the Theoretical Maximum Dietary Intake is less than the Maximum Permissible Intake and Maximum Residue Limit, both of which are considered safe for human consumption at the authorised dose.

Invasive aspergillosis due to cryptic Aspergillus species: A prospective study from a single centre in India.

BACKGROUND: & objective: The existence of visually identical cryptic Aspergillus species that can be distinguished only by molecular techniques is becoming more widely acknowledged. For the majority of antifungal drugs, these are known to exhibit a greater minimal inhibitory concentration in vitro. For the purpose of receiving the proper care, it is crucial to identify these species at right time. Our aim in this work is to identify and describe the Aspergillus species that are cryptic from all of the clinical samples. METHODS: Routine samples from inpatients and outpatients received in department of Microbiology, All India Institute of Medical Sciences, New Delhi, showing growth of Aspergillus species were included in this study. Phenotypic and Matrix Assisted Laser Desorption Ionisation - Time of Flight identified isolates were analysed for cryptic species, by PCR and ITS/ß - tubulin sequencing. In accordance with CLSI recommendations, antifungal susceptibility testing was conducted using micro broth dilution. RESULTS: Of the 94 isolates, 54 A. fumigatus, 34 A. flavus, 3 A. nidulans, 2 A. terreus, and 1 A. niger were morphologically identified. MALDI-TOF misidentified 2 A. nidulans isolates and 1 A, stellatus isolate. The ß - tubulin sequence analysis revealed that 2 isolates (2.08 %) were cryptic, one was A. stellatus and another one was A. tubingensis.